Ферментопатии

Ферментопати́и

(фермент[ы] (Ферменты) + греч. pathos страдание, болезнь; синоним энзимопатии)

болезни и патологические состояния, обусловленные полным отсутствием синтеза ферментов или стойкой функциональной недостаточностью ферментных систем органов и тканей.

Наследственные ферментопатии. Генетически детерминированные нарушения обмена веществ вследствие Ф. лежат в основе многих наследственных болезней (Наследственные болезни). При этом может полностью отсутствовать Ген, контролирующий синтез белковой молекулы фермента (апофермента), либо апофермент синтезируется, но активность фермента отсутствует или резко снижена. В результате генных мутаций может изменяться последовательность аминокислот в структуре активного центра фермента или в регионе связывания апофермента с коферментом (чаще всего витамином или металлом). Кроме того, могут синтезироваться нестабильные легко распадающиеся молекулы ферментов. Все эти изменения структуры белков-ферментов называют молекулярными болезнями, или молекулярной патологией. Известно более 150 наследственных Ф., для которых установлена сущность генной мутации, определены ошибки в синтезе белковой молекулы фермента, а соответствующие мутантные гены картированы на хромосомах (т.е. установлена их локализация на одной из 22 аутосом или Х-хромосоме). Примерно 75% генных мутаций, ведущих к развитию Ф., представляют собой замену оснований в молекуле ДНК, что приводит к изменению генетического кода и соответственно к замене одной аминокислоты на другую в полипептидной цепи фермента.

Выпадение каталитической функции фермента создает метаболический блок соответствующей биохимической реакции. Патологические проявления блока могут быть связаны с накоплением веществ, образующихся до блока, или с дефицитом продуктов реакции, которые обычно синтезируются в результате воздействия фермента. Существует большая группа Ф., получивших название болезней накопления (Болезни накопления), или тезаурисмозов, при которых вещества — предшественники реакции депонируются в клетках (например, гликоген при гликогенозах (Гликогенозы), гликопротеины, гликолипиды при ряде лизосомных болезней, мукополисахариды при мукополисахаридозах (Мукополисахаридозы)). Многие патологические состояния обусловлены дефицитом конечных продуктов реакции, остановленной в результате Ф., приводящих к снижению биосинтеза гормонов (врожденная дисфункция коры надпочечников (Врождённая дисфункция коры надпочечников), Гипотиреоз, Гипопаратиреоз и др.). Соединения, накапливающиеся до метаболического блока, нередко становятся токсичными в результате их прео бразования в обходных биохимических реакциях. При недостаточности фенилаланин-гидроксилазы в крови и тканях скапливается не только фенилаланин, но и продукт его переаминирования — фенилпировиноградная кислота, токсически воздействующая на мозг ребенка при фенилпировиноградной олигофрении (см. Фенилкетонурия). Ферментопатии синтеза мочевины ведут к накоплению аммиака в крови и тканях, что сопровождается токсическим поражением ц.н.с.

Ферментопатии могут быть связаны с патологическими изменениями клеточных рецепторов. Так, наследственная недостаточность мембранных рецепторов липопротеинов низкой плотности приводит к нарушению регулирования активности ферментов синтеза Холестерина и гиперхолестеринемии (см. Дислипопротеинемии). Некоторые Ф. проявляются нарушениями активного мембранного транспорта (например, транспорта аминокислот и цистина при цистинурии (Цистинурия), глюкозы при гликогеновой болезни, глюкуроновой кислоты при врожденной гипербилирубинемии).

По принципу ведущих нарушений обмена веществ наследственные Ф. разделяют на следующие типы: I. ферментопатии обмена аминокислот (Аминокислоты) (алкаптонурия, альбинизм, гипервалинемия, гистидинемия, гомоцистинурия, гиперлизинемия, лейциноз, тирозиноз, фенилкетонурия, цистатионинурия, цистиноз); II. обмена углеводов (Галактоземия, гликогенозы, Лактат-ацидоз, непереносимость фруктозы); III. обмена липвдов (Липидозы) плазматические (наследственная гиперлипидемия, гиперхолестеринемия, недостаточность лецитин-холестеринацилтрансферазы) и клеточные (ганглиозидозы, муколипидозы, сфингомиелинозы, цереброзидозы); IV обмена пуринов и пиримидинов (Подагра, синдром Леша — Найхана, оротовая ацидурия); V. биосинтеза кортикостероидов (адреногенитальный синдром, гипоальдостеронизм); VI. порфиринового (Порфирии) и билирубинового) обмена (см. Гепатозы); VII. соединительной ткани (Марфана синдром, Элерса — Данлоса синдром)', VIII. обмена металлов — Гепатоцеребральная дистрофия и болезнь Менкеса (обмен меди), Гемохроматоз (обмен железа), семейный периодический паралич (обмен калия); IX. ферментопатии эритрона — гемолитические Анемии, недостаточность глюкозо-6-фосфатдегидрогеназы и глютатионредуктазы в эритроцитах, анемия Фанкони (недостаточность супероксиддисмутазы); X. ферментопатии лимфоцитов и лейкоцитов — иммунодефицитные состояния при недостаточности аденозин-деаминазы, пурин-нуклеотид-фосфорилазы, септический гранулематоз; XI. ферментопатии транспортных систем почек (Тубулопатии) почечный канальцевый ацидоз, болезнь де Тони — Дебре — Фанкони, фосфат-диабет (см. Рахитоподобные болезни), XII. ферментопатии желудочно-кишечного тракта — Мальабсорбции синдром при недостаточности дисахаридаз, патология кишечного транспорта глюкозы и галактозы, врожденная хлоридная диарея.

По клиническим проявлениям наследственные Ф. могут быть подразделены на нейромышечные (миопатии), эндокринные, печеночные, ферментопатии обмена соединительной ткани, кишечные, эритроцитарные и лейкоцитарные, Ф. репарации ДНК (синдромы с высоким риском злокачественных заболеваний), лизосомные ферментопатии.

Распознавание Ф. по клиническим признакам весьма затруднительно, один и тот же симптомокомплекс может быть вызван различными Ф. (например, гемолитическая анемия, молочнокислый Ацидоз, гипогликемия, Олигофрения, рахитоподобные болезни). С другой стороны, дефициты в системе одного фермента могут вести к различным клиническим проявлениям. Так, дефицит фосфофруктокиназы является причиной одного из типов гликогеновой болезни, но также и липоматоза. Существуют наследственные болезни, связанные с дефектами многих ферментов (муколипидоз II, так называемая I-клеточная болезнь — I-cell disease). Несмотря на значительное многообразие клин. проявлений наследственных Ф., можно выделить такие общие признаки, которые позволяют предполагать наличие метаболической болезни у ребенка для целенаправленного биохимического обследования. К таким признакам относятся: задержка умственного развития, атетозы и атаксия, судорожный синдром, повторные коматозные состояния и синдром Рейе, рецидивы кетоацидоза, специфический запах мочи или тела (потных ног, кошачьей мочи, мышиный запах, запах солода или кленового сиропа), миопатии, аномалии скелета, необъяснимые лейко- и тромбоцитопении, иммунодефицит, изменения волос и кожи, катаракта, увеличение размеров печени и селезенки, синдром мальабсорбции, необъяснимые случаи смерти сибсов.

Многие Ф. проявляются уже в периоде новорожденности, но нередко трактуются врачами как последствия пре- и постнатальной гипоксии, внутричерепной родовой травмы (см. Родовая травма (Родовая травма новорождённых) новорожденных), фетального респираторного дистресса. Отличительной особенностью наследственных Ф. у новорожденных служит наличие бессимптомного периода (2—3 сут. после рождения). Состояние ухудшается внезапно с проявлениями энцефалопатии (нейродистресс-синдрома). Различные аномалии обмена, обусловленные многими Ф., редко имеют специфические черты, но по клиническим проявлениям могут быть объединены в энцефалопатии токсического и гипоэнергетического типов.

Энцефалопатии токсического типа (табл. 1) связаны с накоплением токсических продуктов до ферментативного блока в метаболической цепи. Ими могут быть органические кислоты (кетокислоты с разветвленной углеродной цепью, метилмалоновая, пропионовая, изовалериановая кислоты), аммиак, галактозо-1-фосфат и галактитол и др. Общие проявления патологии: отказ от груди, рвота, летаргия и кома, судороги, остановка дыхания и печеночная недостаточность, гипертония и клонус мышц, дегидратация, ацидоз, кетоз, гипераммониемия.

Таблица 1

Наиболее частые ферментопатии, обусловливающие развитие метаболической энцефалопатии (нейродистресс-синдрома) в периоде новорожденности


| Биохимические проявления                           | Отсутствующий фермент                                  |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

Ферментопатии токсического типа (с кетозом и кетоацидозом)                                   |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

1. Органические ацидемии                      |                                                                          |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Лейциноз (болезнь с запахом мочи                | Декарбоксилаза кетокислот с разветвленной     |

| кленового сиропа)                                         | углеродной цепью                                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Метилмалоновая ацидемия                           | Метил-малонил-КоА-мутаза                               |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Пропионовая ацидемия                                 | Пропионил-КоА-карбоксилаза                            |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Изовалериановая ацидурия                           | Изовалерил-КоА-дегидрогеназа                         |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

2. Гипераммониемия                                 |                                                                          |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Цитруллинемия                                             | Синтетаза аргининянтарной кислоты                 |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Аргининянтарная ацидурия                            | Лиаза аргининянтарной кислоты                        |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Гипераргининемия                                         | Аргиназа                                                           |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Гиперлизинемия                                            | Лизин-НАД-оксидоредуктаза                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

3. Галактоземия                                         | Галактозо-1-фосфатуридил-трансфераза          |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Ферментопатии гипоэнергетического типа                                                                                |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Лактат-ацидоз                                               | Пируваткарбоксилаза, пируватдетдрогеназа,    |

|                                                                      | ферменты дыхательной цепи                            |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Недостаточность сульфитоксидазы              | Сульфитоксидаза                                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Пероксисомная патология (синдром              | Дигидрооксиацетон-фосфат-ацилтрансфераза, |

| Целльвегера, адренолейкодистрофия)          | оксидазы жирных кислот с длинной                   |

|                                                                      | углеродной цепью                                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Дефицит карнитина                                       | Ферменты транспорта карнитина, пальмитоил-  |

|                                                                      | карнитин-трансфераза                                      |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Патология дыхательной цепи                         | Ферменты митохондриальных комплексов         |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

Ферментопатии, проявляющиеся гипогликемией                                                            |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Гликогеновая болезнь, тип I                           | Глюкозо-6-фосфатаза                                       |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Гликогеновая болезнь, тип III                         | Амило-1,6-гликозидаза                                      |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Непереносимость фруктозы                          | Фруктозо-1,6-бифосфатальдолаза                     |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Галактоземия                                                | УДФ-галактозотрансфераза                               |

|-------------------------------------------------------------------------------------------------------------------------------------------------|

| Тирозинемия                                                 | Формил-ацето-ацетаза                                       |


Энцефалопатии гипоэнергетического типа обусловлены либо истощением запасов энергетических субстратов, либо невозможностью их использования организмом вследствие ферментативного блока. Это наблюдается при Ф. глюконеогенеза, гликолиза, окисления жирных кислот, недостаточности митохондриальных дегидрогеназ, когда развивается такая же клиническая симптоматики, как и при токсических энцефалопатиях (рвота, сонливость, кома), но с выраженной мышечной гипотонией, гипорефлексией, кардиомиопатией, сосудистой недостаточностью и коллапсом, внезапной смертью.

Как правило, Ф. наследуются по аутосомно-рецессивному типу (за исключением отдельных форм подагры, синдрома Леша — Найхана, гемолитичсской анемии, обусловленной дефицитом глюкозо-6-фосфатдегидрогсназы, мукополисахаридоза типа Гунтера, наследуемых в сцеплении с полом). Это не позволяет получить необходимых сведений из анализа родословных больных по двум причинам: родители и их родственники, как правило, не имеют признаков болезни; ограниченное число детей в современных семьях не позволяет выявить случаев аналогичных заболеваний у сибсов. Более надежная доклиническая диагностика осуществляется с помощью скрининг-тестов, что позволяет осуществлять меры превентивной терапии (диета, витамины) до развития тяжелых проявлений при таких заболеваниях, как фенилкетонурия, лейциноз, гистидинемия, тирозиноз, галактоземия, адреногенитальный синдром.

Разработаны методы дородовой диагностики наследственных Ф. (антенатальная диагностика), которая основана на определении активности ферментов в клетках хориона или амниотической жидкости, полученной при амниоцентезе на 16-й неделе беременности. Для диагностики используются также геноспецифические зонды (клонированные молекулы ДНК или синтезированные последовательности нуклеотидов, соответствующие структуре гена) или непрямые методы, если структура гена соответствующего фермента не установлена, — исследования полиморфизма длин рестриктов (фрагментов) ДНК, предположительно включающих этот ген, или пограничных с ним участков (фланкирующие последовательности). Прямые методы генно-инженерной диагностики уже разработаны для таких ферментопатий, как септический гранулематоз, синдром Леша — Найхана, недостаточность орнитин-транскарбамилазы, сцепленный с полом ихтиоз, семейная гиперхолестеринемия. Непрямые методы используются для диагностики фенилкетонурии, адренолейкодистрофии, адреногенитального синдрома. Методы генно-инженерной диагностики Ф. охватывают все более широкий перечень заболеваний и в ближайшем будущем займут ведущее место, хотя и не исключают необходимость исследования активности ферментов биохимическими приемами.

Ведущее значение в лечении наследственных Ф. имеет диетотерапия, в основу которой положен принцип исключения из питания предшественников токсических продуктов, образующихся в результате метаболического блока. Предложено множество продуктов лечебного питания, назначаемых сразу же после выявления Ф., включая переход на безмолочное питание. Диетотерапия позволяет сохранить нормальный фенотип, т.е. обеспечить удовлетворительное нервно-психическое и физическое развитие ребенка. При Ф. эндокринной системы удается добиться моделирования нормативного фенотипа путем назначения соответствующих гормональных препаратов. Некоторые Ф. поддаются лечению высокими дозами витаминов (пиридоксина — при синдроме Комровера — Кнаппа, при цистатионинурии, гомоцистинурии; витамина D — при фосфат-диабете, биотина — при карбоксилазной недостаточности и др.). Терапия Ф. путем введения очищенных ферментов обычно безуспешна вследствие иммунологических реакций организма на чужеродные белки, вводимые парентерально. Некоторый эффект получен от парентерального введения очищенных плацентарных ферментов (церамид-тригексозидазы при болезни Фабри, глюкоцереброзидазы при болезни Гоше) при нетяжелых формах патологии.

Альтернативой служат введение здоровых клеток, пересадка костного мозга, трансплантация органов. Применение подсадок фибробластов под кожу при мукополисахаридозе II приводило к снижению экскреции мукополисахаридов, но не влияло на клинические проявления болезни: патологический фенотип был уже сформирован. Переливания эритроцитарной массы восстанавливают активность аденозиндезаминазы при тяжелом иммунодефиците, связанном с дефицитом данного фермента. Пересадка почки при болезни Фабри обеспечивает клиническое и биохимическое улучшение. Продолжаются попытки усовершенствования методов ферментотерапии. Чтобы защитить ферменты от инактивации, предложено заключать их в липосомы и в таком виде вводить больным. Липосомы, поступающие в кровоток, захватываются печенью и селезенкой, поэтому введение ферментов в липосомах обосновано при болезнях накопления. Липосомы не проникают через гематоэнцефалический барьер, поэтому такой путь введения ферментов не эффективен при поражении мозга.

Ведутся разработки в области генной терапии Ф. Нуклеотидные последовательности, соответствующие мутантному гену фермента, вводятся с помощью вектора (ретровирус) в геном культуры клеток больного (лейкоциты, фибробласты), и после этого производится их реимплантация этому больному. Предложены, в частности, методы пересадки синтезированных аденозиндсаминазы, супероксиддисмутазы.

Приобретенные ферментопатии могут быть следствием токсического воздействия ксенобиотиков и мутагенов внешней среды, они ответственны за многообразные проявления так называемые экопатологии человека. Токсическое действие на многие ферменты оказывают тяжелые металлы (свинец, ртуть и др.), широко распространенные во внешней среде. Свинец вызывает стойкое угнетение фермента аминолевулинатдегидразы, участвующей в синтезе порфобилиногена и гемма, что проявляется развитием анемии у детей городов (источник свинца — выхлопные газы автотранспорта). Соединения ртути подавляют активность ферментов дыхания тканевого (Дыхание тканевое), связывая SH-группировки молекул. В результате интоксикации развивается токсическая энцефалопатия («странная» болезнь Минаматы). Свободные радикалы кислорода, перекиси, озон, образующиеся при фотохимическом смоге в городах, повреждают фермент аденозиндезаминазу лимфоцитов: в результате у детей формируются признаки вторичной иммунной недостаточности. Мутагенные и генотоксические факторы, в т.ч. ионизирующее излучение в окружающей среде, вызывают соматические мутации гена гипоксантин-гаунин-фосфорибозил-трансферазы. Наследственная патология данного фермента крайне редка (синдром Леша — Найхана), тогда как приобретенная встречается часто. Однако последняя проявляется не в нервно-психических расстройствах, как при синдроме Леша — Найхана, а в повышении концентрации мочевой кислоты в крови и моче, развитии иммунодефицита, а также риском злокачественных опухолевых заболеваний. Фосфорорганические пестициды (хлорофос, метафос и др.) избирательно повреждают ацетилхолинэстеразу, что может приводить к мышечной слабости, нейровегетативной дистонии. Действие полициклических углеводородов, образующихся при сгорании твердого и жидкого топлива (бензпирены, бензантрацены и др.) реализуется через систему монооксигеназ (цитохромоксидаз) и проявляется как парциальный иммунодефицит и склонность клеток к злокачественному росту.

В последние годы стали известны нормальные вариации активности ферментов, участвующих в инактивации токсических продуктов как экзогенных, так и образующихся в процессе обмена веществ. Эти вариации наследуются в соответствии с законами Менделя и определяют существование в популяции фенотипов быстрых и медленных инактиваторов. Они установлены для таких ферментов, как арилуглеводород-гидроксилаза (скорость окисления полициклических углеводородов), параоксоназа (гидролиз фосфоорганических пестицидов), семейство цитохром Р-450-оксидаз (чувствительность организма к действию многих лекарственных препаратов), N-ацетилтрансфераза (ацетилирование некоторых ксенобиотиков), трансфераза глюкуроновой кислоты (гликозилирование эндогенных и экзогенных соединений) и ряда др. Такие генетически детерминированные варианты ферментативной активности изучают экогенетика и фармакогенетика человека.

Ферментопатии могут быть обусловлены витаминной недостаточностью (Витаминная недостаточность), т.к. витамины выполняют функции кофакторов многих ферментов. При этом низкая активность ферментов определяется как дефицитом витаминов, так и нарушением их связывания апоферментом с белковой молекулой фермента. Ф., как следствие гиповитаминозов, представлены в табл. 2.

Таблица 2

Ферментопатии как следствие гиповитаминозов


| Витамин-              | Ферменты                             | Проявления дефицита                             |

| кофактор              |                                              |                                                                |

|---------------------------------------------------------------------------------------------------------------------------------------------|

| Никотинамид        | Никотиновые дегидрогеназы  | Пеллагра, аллергические желудочно-      |

|                             | (НАД- и НАДФ-                      | кишечные проявления (диарея)               |

|                             | дегидрогеназы)                     |                                                                |

|---------------------------------------------------------------------------------------------------------------------------------------------|

| Фолиевая кислота | Ферменты переноса              | Поражение кроветворной ткани (анемии, |

|                             | одноуглеродных                    | лейкопении), слизистой оболочки            |

|                             | фрагментов                          | кишечника; тератогенный эффект в        |

|                             |                                              | тканях с интенсивным синтезом ДНК      |

|---------------------------------------------------------------------------------------------------------------------------------------------|

| Биоптин                | Синтетаза                             | Неонатальный тип; поражение кожи,       |

|                             | голокарбоксилазы,                | алопеция, болезнь Лейнера, анемия,       |

|                             | нарушение связывания с       | возможна атаксия                                   |

|                             | транспортным белком           |                                                                |

|---------------------------------------------------------------------------------------------------------------------------------------------|

| Тиамин (витамин  | Дегидрогеназы кетокислот     | Бери-бери, нервно-мышечные                 |

| В1)                        | (пируватдегидрогеназа,         | нарушения, потеря массы тела,              |

|                             | транскетолаза и др.)             | ахлоргидрия, сердечная                          |

|                             |                                              | недостаточность                                     |

|---------------------------------------------------------------------------------------------------------------------------------------------|

| Рибофлавин         | Флавиновые дегидрогеназы  | Хейлит, себорейный дерматит, глоссит,  |

| (витамин В2)         | (ФАД-дегидрогеназы)            | конъюнктивит                                          |

|---------------------------------------------------------------------------------------------------------------------------------------------|

| Пиридоксин          | Трансаминазы и другие         | Задержка роста, хейлит, себорейный      |

| (витамин В6)         | пиридоксальзависимые         | дерматит, раздражительность или          |

|                             | ферменты                             | депрессия, оксалурия                             |

|---------------------------------------------------------------------------------------------------------------------------------------------|

| Цианокобаламин   | Метилмалонилмутаза,           | Гиперхромная макроцитарная анемия,    |

| (витамин В12)        | метионинсинтетаза               | ахлоргидрия, полиневриты                      |

|---------------------------------------------------------------------------------------------------------------------------------------------|

| Витамин К            | Гамма-карбоксилаза              | Геморрагический диатез у                       |

|                             | глютаминовой кислоты          | новорожденных, кровоточивость у          |

|                             |                                              | детей и взрослых                                    |


Ферментопатии у детей формируются также при белковом голодании, когда возникают глубокие нарушения анаболических процессов или всасывания белковых соединений (аминокислот) из кишечника у больных с хроническим расстройством пищеварения, инфекционной патологией желудочно-кишечного тракта. Причиной Ф. может быть дефицит биомикроэлементов. Более 180 ферментов человеческого организма представляют собой металлопротеины, т.е. имеют в составе молекулы ионы металлов. Медь входит в состав церулоплазмина (медь-оксидазы), лизилоксидазы, тирозиназы, цитохромоксидазы и др. ферментов. Цинк — важнейший элемент угольной ангидразы, лактатдегидрогеназы, щелочной фосфатазы, альдолазы, полимераз нуклеиновых кислот. Многие ферменты имеют в составе молекулы марганец, магний, молибден, кобальт, селен. Дефицит биомикроэлементов может быть обусловлен геохимическими особенностями среды обитания, но чаще связан с нарушениями всасывания или транспорта металлов. Это выявлено при таких Ф., как дефицит церулоплазмина (болезнь Менкеса), молибденового кофактора при недостаточности сульдент-оксида. Ф., в основе которых лежат белковое голодание, гиповитаминозы, дефицит биомикроэлементов, названы алиментарными, поэтому решающее значение в их лечении имеют методы диетической коррекции.

Наибольшую проблему представляют наследственные Ф., сведения о которых представлены в табл. 3.

Таблица 3

Наследственные ферментопатии


| Синдром и частота его                  | Дефектный фермент                                | Возраст к началу   | Основные                 | Лабораторная              | Лечение,              |

| встречаемости                              |                                                                 | заболевания          | клинические              | диагностика                 | прогноз,               |

|                                                      |                                                                 |                              | проявления               |                                    | профилактика       |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| 1                                                   | 2                                                              | 3                           | 4                               | 5                                 | 6                          |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Ферментопатии синтеза мочевины                                                                                                                                                                                                       |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Цитруллинемия. Встречается        | Синтетаза аргининянтарной кислоты        | Период                  | Тремор конечностей, | Выявление                  | Ограничение        |

| редко (частота не установлена)     |                                                                 | новорожденности  | рвота, судороги,        | цитруллина и аммиака | белка в диете и    |

|                                                      |                                                                 | и первые месяцы   | гиперрефлексия,       | в крови и моче.            | применение          |

|                                                      |                                                                 | жизни                    | мышечная                 | Диагноз                       | смеси                   |

|                                                      |                                                                 |                              | гипотония,                 | подтверждается          | эссенциальных     |

|                                                      |                                                                 |                              | коматозные               | определением             | аминокислот         |

|                                                      |                                                                 |                              | состояния, задержка | активности фермента  |                             |

|                                                      |                                                                 |                              | нервно-психического | в биоптате печени или |                             |

|                                                      |                                                                 |                              | развития,                  | в культуре                   |                             |

|                                                      |                                                                 |                              | остеопороз,               | фибробластов             |                             |

|                                                      |                                                                 |                              | увеличение печени.   |                                    |                             |

|                                                      |                                                                 |                              | Существуют легкие   |                                    |                             |

|                                                      |                                                                 |                              | формы                      |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Аргининянтарная ацидурия.          | Лиаза аргининянтарной кислоты               | Ранние формы —  | Ранние формы          | Выявление                  | Ограничение        |

| Частота 1: 60 000                          |                                                                 | период                  | сходны с                   | повышения уровня       | белка в диете и    |

|                                                      |                                                                 | новорожденности;  | цитруллинемией.      | аргининянтарной          | применение          |

|                                                      |                                                                 | поздние — 1—2-й  | Поздние формы:       | кислоты, аммиака в     | эссенциальных     |

|                                                      |                                                                 | годы жизни            | неврологическая       | крови и моче.              | аминокислот         |

|                                                      |                                                                 |                              | симптоматика,          | Определение               |                             |

|                                                      |                                                                 |                              | задержка                  | фермента в биоптате   |                             |

|                                                      |                                                                 |                              | умственного              | печени и эритроцитах  |                             |

|                                                      |                                                                 |                              | развития, ломкие      |                                    |                             |

|                                                      |                                                                 |                              | волосы                      |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Гипераргининемия. Встречается   | Аргиназа                                                  | Неврологические   | Фебрильные              | Повышение                  | То же                   |

| редко (частота не установлена)     |                                                                 | отклонения с         | судороги,                  | содержания аргинина  |                             |

|                                                      |                                                                 | первых дней          | гиперрефлексия,       | в крови, определение  |                             |

|                                                      |                                                                 | жизни, полная        | спастическая            | аргиназы в биоптатах  |                             |

|                                                      |                                                                 | картина — к 4—5-  | диплегия, атаксия,    | печени и эритроцитах  |                             |

|                                                      |                                                                 | му годам жизни     | гепатомегалия,          |                                    |                             |

|                                                      |                                                                 |                              | задержка                  |                                    |                             |

|                                                      |                                                                 |                              | умственного              |                                    |                             |

|                                                      |                                                                 |                              | развития                   |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Карбоксилазная                            | Биотинидаза                                            | Неонатальная и     | Ацидоз, судороги,     | Низкая активность       | Биотин                 |

| недостаточность                           |                                                                 | поздняя формы     | алопеция,                  | биотинидазы крови      |                             |

| (множественный дефект в             |                                                                 |                              | кератоконъюнктивит, |                                    |                             |

| системе карбоксилаз)                    |                                                                 |                              | периоральные           |                                    |                             |

|                                                      |                                                                 |                              | эрозии, задержка      |                                    |                             |

|                                                      |                                                                 |                              | нервно-психического |                                    |                             |

|                                                      |                                                                 |                              | развития, сыпи,         |                                    |                             |

|                                                      |                                                                 |                              | глухота, миопия,       |                                    |                             |

|                                                      |                                                                 |                              | иммунная                  |                                    |                             |

|                                                      |                                                                 |                              | недостаточность       |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

Аномалии обмена аминокислот, содержащих серу                                                                                                                                                                    |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Гомоцистинурия. Частота 1: 36     | Цистатионин-β-синтетаза                         | 1—2-й год жизни    | Ускорение роста       | Повышенная                | Цианокобаламин,  |

| 000                                               |                                                                 |                              | скелета в длину,       | экскреция                    | пиридоксин,         |

|                                                      |                                                                 |                              | остеопороз,               | гомоцистина с мочой,  | фолиевая             |

|                                                      |                                                                 |                              | кифосколиоз,            | повышение                  | кислота                |

|                                                      |                                                                 |                              | походка Чаплина,      | гомоцистина и             |                             |

|                                                      |                                                                 |                              | снижение темпов      | метионина в плазме     |                             |

|                                                      |                                                                 |                              | нервно-психического | крови, снижение          |                             |

|                                                      |                                                                 |                              | развития, эктопия     | активности фермента  |                             |

|                                                      |                                                                 |                              | хрусталика,               | в биоптате печени       |                             |

|                                                      |                                                                 |                              | судороги (у 10—15% |                                    |                             |

|                                                      |                                                                 |                              | больных),                  |                                    |                             |

|                                                      |                                                                 |                              | склонность к             |                                    |                             |

|                                                      |                                                                 |                              | тромбоэмболии         |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Цистатионинурия. Частота 1: 18    | Цистатиониназа                                       | 1—2-й год жизни    | Задержка нервно-     | Низкая активность       | Пиридоксин          |

| 000                                               |                                                                 |                              | психического            | ферментов в               | (эффективен у     |

|                                                      |                                                                 |                              | развития                   | биоптатах печени и      | части больных)     |

|                                                      |                                                                 |                              |                                  | лейкоцитах;                 |                             |

|                                                      |                                                                 |                              |                                  | цистатионин в крови и  |                            |

|                                                      |                                                                 |                              |                                  | моче                            |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

Аномалии обмена тирозина, гистидина                                                                                                                                                                                        |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Тирозиноз (тирозинемия) тип I       | Фурамил-ацетоацетаза (накопление          | Период                  | Гепаторенальный      | Определение               | Диета с низким     |

|                                                      | сукцинил-ацетоацетата, сукцинил-            | новорожденности  | синдром. Общее       | тирозина в крови и       | содержанием       |

|                                                      | ацетона)                                                   |                              | возбуждение,            | моче. Исследование    | фенилаланина и   |

|                                                      |                                                                 |                              | сомнолентность,       | активности фермента  | тирозина смеси    |

|                                                      |                                                                 |                              | кровоточивость,        | в биоптатах печени.     | аминокислот         |

|                                                      |                                                                 |                              | гипогликемия,           | Определение               |                             |

|                                                      |                                                                 |                              | желтуха, развитие     | сукцинил-ацетона в      |                             |

|                                                      |                                                                 |                              | цирроза печени,        | крови                           |                             |

|                                                      |                                                                 |                              | рахитоподобное        |                                    |                             |

|                                                      |                                                                 |                              | поражение костной    |                                    |                             |

|                                                      |                                                                 |                              | системы (синдром     |                                    |                             |

|                                                      |                                                                 |                              | Фанкони).                  |                                    |                             |

|                                                      |                                                                 |                              | Отставание в            |                                    |                             |

|                                                      |                                                                 |                              | физическом и (в        |                                    |                             |

|                                                      |                                                                 |                              | меньшей степени) в  |                                    |                             |

|                                                      |                                                                 |                              | нервно-психическом  |                                    |                             |

|                                                      |                                                                 |                              | развитии                   |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| тип II                                             | Тирозин-аминотрансфераза                     | Проявляется в       | Задержка                  | То же с определением | То же                   |

|                                                      |                                                                 | раннем возрасте    | умственного и           | активности                  |                             |

|                                                      |                                                                 |                              | физического             | соответствующих        |                             |

|                                                      |                                                                 |                              | развития,                  | ферментов                  |                             |

|                                                      |                                                                 |                              | изъязвления              |                                    |                             |

|                                                      |                                                                 |                              | роговицы, кератоз     |                                    |                             |

|                                                      |                                                                 |                              | ладоней и стоп.         |                                    |                             |

|                                                      |                                                                 |                              | Вторичная порфирия |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| тип III                                            | Оксидаза 4-гидроксинил-                          | То же                    | То же                        | То же                          | Возможен             |

|                                                      | пировиноградной кислоты                        |                              |                                  |                                    | пренатальный       |

|                                                      |                                                                 |                              |                                  |                                    | диагноз                |

|                                                      |                                                                 |                              |                                  |                                    | (определение       |

|                                                      |                                                                 |                              |                                  |                                    | сукцинил ацетона |

|                                                      |                                                                 |                              |                                  |                                    | в амниотической  |

|                                                      |                                                                 |                              |                                  |                                    | жидкости) или      |

|                                                      |                                                                 |                              |                                  |                                    | активности           |

|                                                      |                                                                 |                              |                                  |                                    | ферментов           |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Гистидинемия. Частота 1:10 000   | Гистидаза (накопление                             | 1 год — 5 лет        | Снижение                  | Определение               | Диета с                |

| — 1:45 000                                    | имидазолкарбоновых кислот)                   | (возможен             | интеллекта (у 50%     | гистидина в крови и     | ограничением       |

|                                                      |                                                                 | скрининг                | детей); иногда           | моче, активность         | гистидина             |

|                                                      |                                                                 | новорожденных)    | гидроцефалия,          | гистидазы в роговом    |                             |

|                                                      |                                                                 |                              | изменение                 | слое кожи, биоптате    |                             |

|                                                      |                                                                 |                              | мышечного тонуса.   | печени                         |                             |

|                                                      |                                                                 |                              | Клиническая             |                                    |                             |

|                                                      |                                                                 |                              | симптоматика может |                                    |                             |

|                                                      |                                                                 |                              | отсутствовать           |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

Аномалии обмена аминокислот с разветвленной углеродной цепью (лейцин, изолейцин, валин)                                                                                      |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Лейциноз (моча с запахом             | Декарбоксилаза аминокислот                   | Период                  | Рвота, летаргия,       | Повышение уровня      | Ограничение        |

| кленового сиропа). Частота           |                                                                 | новорожденности  | судороги,                  | лейцина, изолейцина,   | белка в питании.   |

| 1:120 000                                      |                                                                 |                              | неврологические       | валина, кетокислот в   | Смеси                  |

|                                                      |                                                                 |                              | симптомы,                | крови и моче               | эссенциальных     |

|                                                      |                                                                 |                              | гипорефлексия,         |                                    | аминокислот.        |

|                                                      |                                                                 |                              | нистагм, задержка    |                                    | Тиамин                 |

|                                                      |                                                                 |                              | психомоторного        |                                    |                             |

|                                                      |                                                                 |                              | развития,                  |                                    |                             |

|                                                      |                                                                 |                              | специфический         |                                    |                             |

|                                                      |                                                                 |                              | запах мочи.               |                                    |                             |

|                                                      |                                                                 |                              | Существуют легкие   |                                    |                             |

|                                                      |                                                                 |                              | формы (только          |                                    |                             |

|                                                      |                                                                 |                              | задержка нервно-      |                                    |                             |

|                                                      |                                                                 |                              | психического            |                                    |                             |

|                                                      |                                                                 |                              | развития)                  |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Изовалериановая ацидурия           | Дегидрогеназа изовалериановой              | Период                  | Рвота, ацидоз,          | Повышение уровня      | Общие принципы  |

| (синдром с запахом «потных         | кислоты                                                   | новорожденности  | судороги,                  | изовалериановой         | лечения такие      |

| ног»)                                             |                                                                 |                              | гиперрефлексия,       | кислоты (метаболит     | же, как при           |

|                                                      |                                                                 |                              | атаксия, лейкопения: | лейцина) в крови и       | лечении                |

|                                                      |                                                                 |                              | специфический         | моче                            | лейциноза            |

|                                                      |                                                                 |                              | запах, исходящий от |                                    |                             |

|                                                      |                                                                 |                              | больных; умеренное  |                                    |                             |

|                                                      |                                                                 |                              | отставание в             |                                    |                             |

|                                                      |                                                                 |                              | нервно-психическом  |                                    |                             |

|                                                      |                                                                 |                              | развитии                   |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Сфинголипидозы                                                                                                                                                                                                                                  |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Липогранулематоз Фарбера           | Недостаточность церамидазы (ацил-        | Первые месяцы     | Низкий голос,            | Пенистые лимфоциты  | Лечение,              |

|                                                      | сфингозиндеацилаза)                               | жизни                    | стридор, отечность   | и клетки в тканях,        | профилактика не  |

|                                                      |                                                                 |                              | суставов,                  | цитоплазматические    | разработаны.        |

|                                                      |                                                                 |                              | подкожные узелки,    | включения.                  | Многие больные   |

|                                                      |                                                                 |                              | задержка                  | Повышенное                | погибают в           |

|                                                      |                                                                 |                              | психомоторного        | содержание церамида | первые годы         |

|                                                      |                                                                 |                              | развития,                  | в биоптатах кожи,        | жизни                   |

|                                                      |                                                                 |                              | увеличение               | лимфатических узлов, |                             |

|                                                      |                                                                 |                              | размеров печени,      | низкая активность       |                             |

|                                                      |                                                                 |                              | лимфатических         | церамидазы                 |                             |

|                                                      |                                                                 |                              | узлов, пигментные    |                                    |                             |

|                                                      |                                                                 |                              | пятна на коже,          |                                    |                             |

|                                                      |                                                                 |                              | субфебрилитет. При  |                                    |                             |

|                                                      |                                                                 |                              | поздних формах —   |                                    |                             |

|                                                      |                                                                 |                              | подкожные                |                                    |                             |

|                                                      |                                                                 |                              | гранулемы                |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Болезнь Ниманна — Пика.            | Недостаточность сфингомиелиназы         | Первые месяцы     | Рвота, потеря массы | Пенистые клетки в       | Эффективного     |

| Частота не установлена                |                                                                 | жизни                    | тела, мышечная        | тканях (костный мозг,  | лечения нет.         |

| Острая младенческая форма        |                                                                 |                              | гипотония,                 | мононуклеары,            | Прогноз                |

| (тип А)                                          |                                                                 |                              | гипорефлексия,         | альвеолярный              | неблагоприятный, |

|                                                      |                                                                 |                              | нарушение нервно-    | эпителий).                   | дети рано             |

|                                                      |                                                                 |                              | психичекого и           | Повышенное                | погибают              |

|                                                      |                                                                 |                              | физического             | содержание                 |                             |

|                                                      |                                                                 |                              | развития, повторные | сфингомиелина в         |                             |

|                                                      |                                                                 |                              | пневмонии, гепато- и | биоптатах печени,       |                             |

|                                                      |                                                                 |                              | спленомегалия,         | костного мозга             |                             |

|                                                      |                                                                 |                              | вишнево-красные      |                                    |                             |

|                                                      |                                                                 |                              | пятна на глазном       |                                    |                             |

|                                                      |                                                                 |                              | дне                           |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Хроническая висцеральная           | То же                                                       | Нормальное           | Гепато- и                   | Пенистые клетки в       | Прогноз                |

| форма (тип В)                               |                                                                 | развитие в             | спленомегалия без    | тканях (костный мозг,  | неблагоприятный, |

|                                                      |                                                                 | первые годы          | вовлечения ц.н.с.      | мононуклеары),           | но летальный       |

|                                                      |                                                                 | жизни                    |                                  | альвеолярный              | исход наступает   |

|                                                      |                                                                 |                              |                                  | эпителий. Низкая         | в подростковом    |

|                                                      |                                                                 |                              |                                  | активность                  | возрасте              |

|                                                      |                                                                 |                              |                                  | сфингомиелиназы в     |                             |

|                                                      |                                                                 |                              |                                  | фибробластах кожи     |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Маннозидоз                                                    | α-Маннозилаза                       | Ранний возраст     | Вначале частые        | α-Маннозидаза            | Возможность        |

|                                                                        |                                               | (1—3 года)             | острые                      | лейкоцитов                  | пренатальной       |

|                                                                        |                                               |                              | респираторные          |                                    | диагностики         |

|                                                                        |                                               |                              | вирусные                  |                                    |                             |

|                                                                        |                                               |                              | заболевания. отиты:  |                                    |                             |

|                                                                        |                                               |                              | задержка развития,   |                                    |                             |

|                                                                        |                                               |                              | нарушение речи.       |                                    |                             |

|                                                                        |                                               |                              | аномалии                  |                                    |                             |

|                                                                        |                                               |                              | поведения; атаксия,  |                                    |                             |

|                                                                        |                                               |                              | глухота, грубые         |                                    |                             |

|                                                                        |                                               |                              | черты лица,               |                                    |                             |

|                                                                        |                                               |                              | дизостозы,                |                                    |                             |

|                                                                        |                                               |                              | помутнение               |                                    |                             |

|                                                                        |                                               |                              | хрусталика,               |                                    |                             |

|                                                                        |                                               |                              | роговицы, миопия,     |                                    |                             |

|                                                                        |                                               |                              | гепато- и                   |                                    |                             |

|                                                                        |                                               |                              | спленомегалия          |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

Муколипидозы                                                                                                                                                                                                                                  |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| GM-гангиозидоз                                              | Кислая β-галактозидаза          | Вскоре после         | Задержка                  | Обнаружение               | Летальный исход |

| Тип I (детский)                                                |                                               | рождения              | физического, а          | вакуолей в                   | от пневмонии в     |

|                                                                        |                                               |                              | позднее нервно-        | фибробластах,            | возрасте до 2 лет |

|                                                                        |                                               |                              | психического            | «вишневой косточки»   |                             |

|                                                                        |                                               |                              | развития, судороги,  | на сетчатке,                 |                             |

|                                                                        |                                               |                              | гепато- и                   | выделение                   |                             |

|                                                                        |                                               |                              | спленомегалия,         | олигосахаридов с        |                             |

|                                                                        |                                               |                              | мышечная                 | мочой, низкая              |                             |

|                                                                        |                                               |                              | гипотония, грубые     | активность фермента  |                             |

|                                                                        |                                               |                              | черты лица,               | в лейкоцитах               |                             |

|                                                                        |                                               |                              | макроглоссия,           |                                    |                             |

|                                                                        |                                               |                              | кифосколиоз, затем  |                                    |                             |

|                                                                        |                                               |                              | децеребрационная    |                                    |                             |

|                                                                        |                                               |                              | ригидность,               |                                    |                             |

|                                                                        |                                               |                              | вишнево-красное       |                                    |                             |

|                                                                        |                                               |                              | пятно на глазном       |                                    |                             |

|                                                                        |                                               |                              | дне                           |                                    |                             |

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| Тип II (ювенильный)                                         | То же                                     | 1 год                     | Атаксия, задержка    | То же (но «вишневая   | Прогноз                |

|                                                                        |                                               |                              | физического             | косточка» на сетчатке  | неблагоприятный. |

|                                                                        |                                               |                              | развития, потери       | отсутствует)                | но летальный       |

|                                                                        |                                               |                              | координации             |                                    | исход наступает   |

|                                                                        |                                               |                              | движения,                 |                                    | позднее                |

|                                                                        |                                               |                              | прогрессирование     |                                    |                             |

|                                                                        |                                               |                              | нервно-психических  |                                    |                             |

|                                                                        |                                               |                              | проявлений:              |                                    |                             |

|                                                                        |                                               |                              | спастическая ди- и    |                                    |                             |

|                                                                        |                                               |                              | тетраплегия,             |                                    |                             |

|                                                                        |                                               |                              | судороги, страбизм,  |                                    |                             |

|                                                                        |                                               |                              | нистагм. Слепота      |                                    |                             |

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| Тип III (взрослый)                                             | То же                                     | То же                    | Прогрессирующая     | Тоже                           | Прогноз                |

|                                                                        |                                               |                              | спастическая ди- и    |                                    | неблагоприятный  |

|                                                                        |                                               |                              | тетраплегия,             |                                    |                             |

|                                                                        |                                               |                              | атаксия, медленное  |                                    |                             |

|                                                                        |                                               |                              | прогрессирование     |                                    |-----------------------------|

|                                                                        |                                               |                              | интеллектуальных     |                                    |                             |

|                                                                        |                                               |                              | нарушений                |                                    |                             |

|                                                                        |                                               |                              |                                  |                                    |                             |

|                                                                        |                                               |                              |                                  |                                    |                             |

|                                                                        |                                               |                              |                                  |                                    |                             |

|                                                                        |                                               |                              |                                  |                                    |                             |

|                                                                        |                                               |                              |                                  |                                    |                             |

|                                                                        |                                               |                              |                                  |                                    |                             |

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| I-клеточная болезнь, болезни клеток с             | Множественная                      | С периода             | Задержка роста,       | Обнаружение клеток с | Летальный исход  |

| включениями (инклюзионно-клеточная             | недостаточность лизосомных | новорожденности  | грубые черты лица,   | вакуолями в тканях,    | от сердечно-        |

| болезнь), псевдо-Гурлер синдром, GM2-         | гидролаз                                |                              | макроглоссия,           | отсутствие изменений  | легочной              |

| ганглиозидоз                                                   |                                               |                              | кифоз, большой        | в спектре                     | недостаточности  |

|                                                                        |                                               |                              | живот, грыжи,           | мукополисахаридов     | в возрасте до 4    |

|                                                                        |                                               |                              | тугоподвижность       | мочи                            | лет                       |

|                                                                        |                                               |                              | суставов (сходство   |                                    |                             |

|                                                                        |                                               |                              | с синдромом             |                                    |                             |

|                                                                        |                                               |                              | Гурлер), глубокое      |                                    |                             |

|                                                                        |                                               |                              | отставание в             |                                    |                             |

|                                                                        |                                               |                              | нервно-психическом  |                                    |                             |

|                                                                        |                                               |                              | развитии;                  |                                    |                             |

|                                                                        |                                               |                              | систолический шум   |                                    |                             |

|                                                                        |                                               |                              | в сердце, размеры    |                                    |                             |

|                                                                        |                                               |                              | печени и селезенки   |                                    |                             |

|                                                                        |                                               |                              | не увеличены            |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Болезнь Тея — Сакса, GM2-ганглиозидоз,       | N-ацетил-гексозаминидаза А  | 3—6 мес. жизни     | Кукольное лицо,        | Определение               | Дети погибают в   |

| тип I; амавротическая идиотия                        |                                               |                              | задержка                  | активности фермента  | возрасте 2—6       |

|                                                                        |                                               |                              | физического и           | в крови                        | лет. Возможна      |

|                                                                        |                                               |                              | нервно-психического |                                    | пренатальная       |

|                                                                        |                                               |                              | развития, судороги,  |                                    | диагностика         |

|                                                                        |                                               |                              | вишнево-красные      |                                    |                             |

|                                                                        |                                               |                              | пятна на глазном       |                                    |                             |

|                                                                        |                                               |                              | дне, слепота,            |                                    |                             |

|                                                                        |                                               |                              | глухота.                    |                                    |                             |

|                                                                        |                                               |                              | Олигосахариды в      |                                    |                             |

|                                                                        |                                               |                              | моче                         |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Болезнь Сандхоффа; GM2-ганглиозидоз,        | N-ацетил-гексозаминидазы А  | Ранний возраст     | Клинически сходна с | То же                          | Прогноз такой       |

| тип II. Встречается реже, чем болезнь Тея      | и В                                         |                              | болезнью Тея —       |                                    | же, как при           |

| — Сакса                                                         |                                               |                              | Сакса                        |                                    | болезни Тея —     |

|                                                                        |                                               |                              |                                  |                                    | Сакса                   |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Болезнь Гоше (глюкоцереброзид липидоз).      | Кислая β-глюкозидаза            | 6-й месяц жизни    | Ригидность               | Пенистые клетки Гоше | Методы лечения   |

| Детская острая прогрессирующая форма       |                                               |                              | затылочных мышц,    | в лимфатических         | не разработаны.   |

| нейропатическая                                             |                                               |                              | мышечная                 | узлах, печени,             | Частичная            |

|                                                                        |                                               |                              | гипертензия,             | селезенке, других        | спленэктомия.      |

|                                                                        |                                               |                              | страбизм, стридор,   | органах; в клетках       | Летальный исход |

|                                                                        |                                               |                              | судороги, апатия,      | мочевого осадка.         | на                        |

|                                                                        |                                               |                              | гепато- и                   | Определение β-           | 1 -м году жизни    |

|                                                                        |                                               |                              | спленомегалия,         | глюкозидазы в             |                             |

|                                                                        |                                               |                              | пневмонии                | лейкоцитах.                 |                             |

|                                                                        |                                               |                              |                                  | Определение               |                             |

|                                                                        |                                               |                              |                                  | цереброзидов в           |                             |

|                                                                        |                                               |                              |                                  | фибробластах и           |                             |

|                                                                        |                                               |                              |                                  | клетках мочи               |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| То же, ювенильная подострая форма              | То же                                     | 1—2-й годы жизни  | Гепато- и                  | То же                          | Прогноз                |

|                                                                        |                                               |                              | спленомегалия,         |                                    | неблагоприятный  |

|                                                                        |                                               |                              | лихорадка,                |                                    |                             |

|                                                                        |                                               |                              | абдоминальные         |                                    |                             |

|                                                                        |                                               |                              | колики, гипертония    |                                    |                             |

|                                                                        |                                               |                              | мышц,                       |                                    |                             |

|                                                                        |                                               |                              | гиперрефлексия,       |                                    |                             |

|                                                                        |                                               |                              | хореоатетоидные      |                                    |                             |

|                                                                        |                                               |                              | движения, анемия,    |                                    |                             |

|                                                                        |                                               |                              | тромбоцитопения      |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| То же, хроническая висцеральная форма        | То же                                     | Проявляется у       | Боли в костях,          | То же                          | Прогноз                |

| взрослого типа                                                |                                               | взрослых               | деформации,            |                                    | неблагоприятный  |

|                                                                        |                                               |                              | некрозы, переломы,  |                                    |                             |

|                                                                        |                                               |                              | увеличение               |                                    |                             |

|                                                                        |                                               |                              | размеров селезенки  |                                    |                             |

|                                                                        |                                               |                              | и печени, анемия.     |                                    |                             |

|                                                                        |                                               |                              | Коричневая               |                                    |                             |

|                                                                        |                                               |                              | пигментация кожи     |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Болезнь Краббе (глобоидно-клеточная             | Галакто-цереброзид-β-            | Первые недели и   | Повышение нервно-   | Определение               | Методы лечения   |

| лейкодистрофия)                                            | галактозидаза                        | месяцы жизни,       | мышечной                 | фермента в                 | не разработаны.   |

|                                                                        |                                               | иногда в воззасте  | возбудимости,          | лейкоцитах, биоптатах | Прогноз                |

|                                                                        |                                               | 2—5 лет                | лихорадочные           | печени,                        | неблагоприятный. |

|                                                                        |                                               |                              | кризы, рвота,            | фибробластах;            | Возможна             |

|                                                                        |                                               |                              | нарушение                | глобоидные клетки в    | пренатальная       |

|                                                                        |                                               |                              | нервнопсихического  | ц.н.с. (гистиоциты с     | диагностика         |

|                                                                        |                                               |                              | развития,                  | аккумулированным      | (определение       |

|                                                                        |                                               |                              | опистотонус,             | галактозилцерамидом) | активности           |

|                                                                        |                                               |                              | судороги,                  |                                    | фермента в          |

|                                                                        |                                               |                              | гидроцефалия,          |                                    | ворсинах              |

|                                                                        |                                               |                              | атрофия зрительных |                                    | хориона)               |

|                                                                        |                                               |                              | нервов, слепота,       |                                    |                             |

|                                                                        |                                               |                              | глухота,                    |                                    |                             |

|                                                                        |                                               |                              | децеребрационная    |                                    |                             |

|                                                                        |                                               |                              | ригидность                |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Метахроматическая лейкодастрофия.             | Арилсульфатаза А                 | 9 мес. — 2 года     | Повышенная нервно- | Определение               | Методы лечения   |

| Частота 1:40 000                                             | (галактозил-3-                         |                              | мышечная                 | активности                  | и профилактики    |

|                                                                        | сульфатцерамидсульфатаза) |                              | возбудимость,          | изоферментов             | не разработаны    |

|                                                                        |                                               |                              | нарушение нервно-    | арилсульфатазы А, В, |                             |

|                                                                        |                                               |                              | психического            | С в фибробластах,      |                             |

|                                                                        |                                               |                              | развития, атаксии,    | лейкоцитах;                 |                             |

|                                                                        |                                               |                              | некоординированные | метахроматические     |                             |

|                                                                        |                                               |                              | движения,                 | включения в клетки     |                             |

|                                                                        |                                               |                              | мышечная гипотония | биоптатов, а также в    |                             |

|                                                                        |                                               |                              | или спастическая      | клетках мочевого         |                             |

|                                                                        |                                               |                              | параплегия ног.         | осадка. Накопление     |                             |

|                                                                        |                                               |                              | Серая                       | галактозил-3-               |                             |

|                                                                        |                                               |                              | депигментация          | сульфатцерамида в     |                             |

|                                                                        |                                               |                              | пятна зрительного     | тканях                         |                             |

|                                                                        |                                               |                              | нерва;                       |                                    |                             |

|                                                                        |                                               |                              | прогрессирование     |                                    |                             |

|                                                                        |                                               |                              | болезни                     |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Поздняя форма                                               | То же                                     | 5—10 лет               | Аномалии                  | То же                          | То же                   |

|                                                                        |                                               |                              | поведения,                |                                    |                             |

|                                                                        |                                               |                              | нарушение зрения,    |                                    |                             |

|                                                                        |                                               |                              | медленная                |                                    |                             |

|                                                                        |                                               |                              | регрессия нервно-     |                                    |                             |

|                                                                        |                                               |                              | психического            |                                    |                             |

|                                                                        |                                               |                              | развития,                  |                                    |                             |

|                                                                        |                                               |                              | психические              |                                    |                             |

|                                                                        |                                               |                              | отклонения, сходные |                                    |                             |

|                                                                        |                                               |                              | с шизофренией         |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Болезнь Фабри (церамид-тригексозидоз,         | Церамид-тригексозидаза        | 5—15 лет               | Поражение кожи,       | Недостаточность         | Методы лечения   |

| гликосфинголипидоз, диффузная                    |                                               |                              | темно-красные          | фермента                    | отсутствуют.        |

| ангиокератома). Частота 1: 40 000                   |                                               |                              | телеангиэктазии,       | определяется в           | Разработаны        |

|                                                                        |                                               |                              | ангиокератома, боли  | плазме крови, моче.    | методы                |

|                                                                        |                                               |                              | в конечностях,          | Выявление мутации с  | пренатальной       |

|                                                                        |                                               |                              | аневризмы,               | помощью ДНК-зонда.  | диагностики          |

|                                                                        |                                               |                              | тромбозы в сетчатке | Повышенное                |                             |

|                                                                        |                                               |                              | глаз, поражение        | содержание ди- и        |                             |

|                                                                        |                                               |                              | почек с развитием     | тригексозилцерамидов |                             |

|                                                                        |                                               |                              | хронической              | в плазме крови и моче |                             |

|                                                                        |                                               |                              | почечной                   |                                    |                             |

|                                                                        |                                               |                              | недостаточности,      |                                    |                             |

|                                                                        |                                               |                              | сердечная                 |                                    |                             |

|                                                                        |                                               |                              | недостаточность,      |                                    |                             |

|                                                                        |                                               |                              | иногда                      |                                    |                             |

|                                                                        |                                               |                              | церебральные           |                                    |                             |

|                                                                        |                                               |                              | симптомы, головные  |                                    |                             |

|                                                                        |                                               |                              | боли, судороги,         |                                    |                             |

|                                                                        |                                               |                              | гемиплегия, афазия  |                                    |                             |

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Лизосомные ферментопатии (гликопротеинозы)                                                                                                                                                                         |

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| Сиалидоз тип I                                                | Нейраминидаза                      | 8—12 лет               | Миоклонус, боли в    | Олигосахариды,          | Лечение не           |

|                                                                        |                                               |                              | конечностях,             | сиаловая кислота в      | разработано.        |

|                                                                        |                                               |                              | полиневропатия,       | моче. Определение     | Прогноз плохой    |

|                                                                        |                                               |                              | вишнево-красные      | активности                  |                             |

|                                                                        |                                               |                              | пятна на глазном       | нейраминидазы в         |                             |

|                                                                        |                                               |                              | дне                           | культуре                      |                             |

|                                                                        |                                               |                              |                                  | фибробластов             |                             |

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| Тип II                                                               | То же                                     | Новорожденные     | То же                        | То же                          | То же —               |

|                                                                        |                                               | — 4-й год жизни    |                                  |                                    | летальный исход  |

|                                                                        |                                               |                              |                                  |                                    | в возрасте 4—5    |

|                                                                        |                                               |                              |                                  |                                    | лет                       |

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| Фукозидоз тип I                                               | α-Фукозидаза печени,            | Грудной возраст    | Мышечная                | Вакуолизированные     | Возможно             |

|                                                                        | лейкоцитов плазмы                | (5—8 мес.)             | гипотония,                 | лимфоциты в крови.    | исследование       |

|                                                                        |                                               |                              | сменяющаяся           | Льюис-антиген в          | альфа-                 |

|                                                                        |                                               |                              | гипертонусом,           | эритроцитах.               | фукозидазы в       |

|                                                                        |                                               |                              | задержка развития,   | Повышение                  | клетках                |

|                                                                        |                                               |                              | переходящая в         | содержания натрия и   | амниотической     |

|                                                                        |                                               |                              | глубокое отставание  | хлора в поте.              | жидкости для       |

|                                                                        |                                               |                              | (деменция), грубые   | олигосахариды мочи    | пренатальной       |

|                                                                        |                                               |                              | черты лица, кифоз    |                                    | диагностики         |

|                                                                        |                                               |                              | (не всегда),               |                                    |                             |

|                                                                        |                                               |                              | увеличение               |                                    |                             |

|                                                                        |                                               |                              | размеров печени,      |                                    |                             |

|                                                                        |                                               |                              | селезенки, частые     |                                    |                             |

|                                                                        |                                               |                              | респираторные          |                                    |                             |

|                                                                        |                                               |                              | инфекции                  |                                    |                             |

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| Тип II                                 | То же                                                                  | Ранний возраст     | Нарушение походки,  | То же, но содержание | То же                   |

|                                          |                                                                            | (1—2 года)             | атаксия, задержка     | натрия и хлора в          |                             |

|                                          |                                                                            |                              | нервно-психического | потовой жидкости в     |                             |

|                                          |                                                                            |                              | развития, гипотония  | пределах нормы          |                             |

|                                          |                                                                            |                              | мышц или                  |                                    |                             |

|                                          |                                                                            |                              | гипертонус,               |                                    |                             |

|                                          |                                                                            |                              | телеангиэктазии на   |                                    |                             |

|                                          |                                                                            |                              | коже, увеличение      |                                    |                             |

|                                          |                                                                            |                              | печени и селезенки,  |                                    |                             |

|                                          |                                                                            |                              | кифосколиоз,            |                                    |                             |

|                                          |                                                                            |                              | повторные вирусные |                                    |                             |

|                                          |                                                                            |                              | инфекции                  |                                    |                             |

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Ферментопатия обмена соединительной ткани                                                                                                                                                                           |

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| Гиперлизинемия                                              | Лизин-кето-                            | 2-й год жизни и      | Задержка нервно-     | Определение               | Ограничение        |

|                                                                        | глютаратредуктаза                 | старше                  | психического и          | содержания лизина в   | белка (лизина) в   |

|                                                                        |                                               |                              | физического             | плазме, фермента в    | диете                   |

|                                                                        |                                               |                              | развития, костные     | биоптатах печени        |                             |

|                                                                        |                                               |                              | аномалии                  |                                    |                             |

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| Синдром Элерса — Данлоса (около 14            | Лизил-гидро-ксилаза              | Вскоре после         | Задержка                  | Определение               | Аскорбиновая       |

| подтипов). Наследование аутосомно-              |                                               | рождения              | физического и           | содержания                 | кислота (большие |

| рецессивное, аутосомно-доминантное,            |                                               |                              | нервно-психического | гидроксилизина в         | дозы)                   |

| сцепленное с полом                                        |                                               |                              | развития,                  | биоптатах кожи,           |                             |

|                                                                        |                                               |                              | чрезмерная               | активность лизил-        |                             |

|                                                                        |                                               |                              | растяжимость           | гидроксилазы в            |                             |

|                                                                        |                                               |                              | суставов, кожи,         | фибробластах             |                             |

|                                                                        |                                               |                              | грыжи, кифосколиоз, |                                    |                             |

|                                                                        |                                               |                              | плохое заживание     |                                    |                             |

|                                                                        |                                               |                              | ран, варикозные        |                                    |                             |

|                                                                        |                                               |                              | расширения вен,       |                                    |                             |

|                                                                        |                                               |                              | пролапс                    |                                    |                             |

|                                                                        |                                               |                              | митрального              |                                    |                             |

|                                                                        |                                               |                              | клапана, иногда —    |                                    |                             |

|                                                                        |                                               |                              | прогерия.                  |                                    |                             |

|                                                                        |                                               |                              | Марфаноподобный    |                                    |                             |

|                                                                        |                                               |                              | синдром                    |                                    |                             |

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Другие аномалии обмена, связанные с ферментопатиями                                                                                                                                                       |

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| Синдром Леша— Найхана (наследование        | Гипоксантин-гуанин-               | Первые месяцы     | Рвота, гипотония       | Повышение                  | Аллопуринол,       |

| рецессивное, сцепленное с полом). Описано   | фосфорибозилтрансфераза   | жизни                    | мышц, задержка        | содержания мочевой   | щелочные            |

| более 100 больных                                          |                                               |                              | психомоторного        | кислоты в крови и        | минеральные        |

|                                                                        |                                               |                              | развития. Позднее    | моче. Определение     | воды Разработан  |

|                                                                        |                                               |                              | гиперрефлексия,       | активности фермента  | метод                   |

|                                                                        |                                               |                              | гипертонус мышц,     | в эритроцитах,             | пренатальной       |

|                                                                        |                                               |                              | опистотонус,             | биоптатах печени        | диагностики.        |

|                                                                        |                                               |                              | самоповреждения,    |                                    |                             |

|                                                                        |                                               |                              | нефропатия, анемия  |                                    |                             |

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| Острая перемежающаяся порфирия.              | Синтетаза уропорфириногена | Подростковый       | Приступы болей в     | Определение амино-    | Диета,                  |

| Частота 1:50 000                                             | (порфобилиноген-деаминаза)  | возраст                 | животе, запоры,        | левулиновой кислоты   | обогащенная        |

|                                                                        |                                               |                              | задержка                  | в крови,                       | углеводами,         |

|                                                                        |                                               |                              | мочеотделения.        | порфобилиногена в      | психотропные       |

|                                                                        |                                               |                              | Судороги,                 | моче                            | препараты            |

|                                                                        |                                               |                              | психотические          |                                    |                             |

|                                                                        |                                               |                              | состояния,                |                                    |                             |

|                                                                        |                                               |                              | парестезии,               |                                    |                             |

|                                                                        |                                               |                              | артериальная            |                                    |                             |

|                                                                        |                                               |                              | гипертензия              |                                    |                             |

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| Лейкоцитарные ферментопатии                                                                                                                                                                                                            |

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| Тяжелая                 | Аденозиндезаминаза лимфоцитов                                                  | 3—6       | Задержка развития,  | Исследование общего  | Антибиотики,        |

| комбинированная    |                                                                                                       | мес.       | лимфопения,             | числа лимфоцитов, их | переливание         |

| иммунологическая  |                                                                                                       | жизни    | гнойничковые            | субпопуляций.             | крови;                  |

| недостаточность     |                                                                                                       |              | заболевания кожи,    | Определение               | разрабатывают     |

|                               |                                                                                                       |              | гнойные отиты,          | активности                  | методы генной     |

|                               |                                                                                                       |              | септический              | ферментов в               | терапии                |

|                               |                                                                                                       |              | процесс, грибковый   | эритроцитах                |                             |

|                               |                                                                                                       |              | сепсис,                     |                                    |                             |

|                               |                                                                                                       |              | рахитоподобные        |                                    |                             |

|                               |                                                                                                       |              | изменения костей      |                                    |                             |

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| То же                      | Пурин-нуклеотид-фосфорилаза лимфоцитов                                  | То же     | Синдром                   | То же                          | То же                   |

|                               |                                                                                                       |              | иммунодефицита, Т- |                                    |                             |

|                               |                                                                                                       |              | клеточная                 |                                    |                             |

|                               |                                                                                                       |              | недостаточность.      |                                    |                             |

|                               |                                                                                                       |              | Рецидивирующие      |                                    |                             |

|                               |                                                                                                       |              | микробно-                 |                                    |                             |

|                               |                                                                                                       |              | воспалительные        |                                    |                             |

|                               |                                                                                                       |              | заболевания легких,  |                                    |                             |

|                               |                                                                                                       |              | кожи, хронические    |                                    |                             |

|                               |                                                                                                       |              | вирусные инфекции  |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Хроническая           | Оксидаза НАД- и НАДФ-фагоцитов                                                | Ранний  | Рецидивирующие      | Выявление                  | Антибиотики.        |

| гранулематозная     |                                                                                                       | возраст  | гнойные процессы и  | нейтрофильного          | Прогноз                |

| болезнь. Описано   |                                                                                                       |              | образование              | лейкоцитоза.                | неблагоприятный  |

| наследование,        |                                                                                                       |              | множественных         | Исследование             |                             |

| сцепленное с          |                                                                                                       |              | гранулем в легких,    | дыхательного              |                             |

| полом. Частота не  |                                                                                                       |              | печени и др.              | «взрыва» фагоцитов,   |                             |

| установлена           |                                                                                                       |              | органах,                    | NBT-тест,                    |                             |

|                               |                                                                                                       |              | остеомиелиты,          | фагоцитарные             |                             |

|                               |                                                                                                       |              | гепато- и                   | функции                      |                             |

|                               |                                                                                                       |              | спленомегалия.         |                                    |                             |

|                               |                                                                                                       |              | Перикардиты;            |                                    |                             |

|                               |                                                                                                       |              | септический процесс |                                    |                             |

|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|

| Дефицит                 | Миелопероксидаза                                                                         | То же     | Повторные                | Определение               | Прогноз более      |

| миелопероксидазы. |                                                                                                       |              | микробно-                 | фагоцитарных             | благоприятный,    |

| Частота 1: 2000      |                                                                                                       |              | воспалительные        | функций,                     | чем при                |

|                               |                                                                                                       |              | заболевания легких,  | миелопероксидазы      | хронической         |

|                               |                                                                                                       |              | грибковые инфекции  |                                    | гранулематозной  |

|                               |                                                                                                       |              |                                  |                                    | болезни                |

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Библиогр.: Вельтищев Ю.Е. и др. Обмен веществ у детей, М., 1983; Врожденные и приобретенные энзимопатии, под ред. Т. Ташева, пер. с болг., М., 1980; Детские болезни, под ред. А.Ф. Тура и др., с. 564, М., 1985; Руководство по педиатрии, под ред. Р.Е. Бермака и В.К. Вогана, пер. с англ., т. 6, М., 1989.

Источник: Медицинская энциклопедия на Gufo.me


Значения в других словарях

  1. ФЕРМЕНТОПАТИИ — ФЕРМЕНТОПАТИИ — то же, что энзимопатии. Большой энциклопедический словарь
  2. Ферментопатии — Энзимопатии, заболевания, обусловленные врождённым дефектом обмена веществ вследствие ферментных нарушений; относятся к группе наследственных заболеваний (См. Наследственные заболевания). В основе... Большая советская энциклопедия