БОЛЕЗНЬ ФАБРИ

Болезнь Фабри (БФ) представляет собой прогрессирующее наследственное, сцепленное с Х-хромосомой нарушение метаболизма гликосфинголипидов, обусловленное снижением или полным отсутствием активности лизосомальной α-галактозидазы А. БФ встречается у представителей всех без исключения этнических групп, но опубликованные данные о встречаемости БФ – 1 на 100000 могут тыть, вероятно, ниже истинной распространённости данного заболевания. При классическом варианте болезни у гемизиготных мужчин с отсутствием остаточной активности α-галактозидазы А могут иметься все характерные симптомы – неврологические (боль), кожные (ангиокератома), почечные (протеинурия, почечная недостаточность), сердечно-сосудистые (кардиомиопатия, аритмия), а также кохлеовестибулярные и цереброваскулярные (транзиторные ишемические атаки, инсульты), тогда как у гетерозиготных женщин симптомы обыкновенно варьируют от очень мягких до тяжелых. Считается, что недостаточность активности лизосомальной α-галактозидазы А приводит к прогрессивному накоплению в лизосомах глоботриозилцерамида, что и запускает каскад клеточных процессов. Обнаружение значимой недостаточности α-галактозидазы является определяющим при постановке диагноза у гемизиготных мужчин. Иногда ферментный анализ помогает в обнаружении гетерозигот, однако нередко не позволяет сделать окончательный вывод из-за случайной инактивации Х- хромосомы, в связи с чем проведение молекулярных исследований (генотипирование) у женщин является обязательным. У пациентов детского возраста необходимо исключение других возможных причин болевого синдрома, таких как ревматоидный артрит и невралгические боли. У взрослых в ряде случаев требуется проведение дифференциальной диагностики с рассеянным склерозом. Пренатальная диагностика, осуществляемая путём установления активности ферментов или исследования ДНК в ворсинах хориона или культивированных амниотических клетках, по этическим причинам проводится только у плодов мужского пола. Возможна также преимплантационная диагностика. Однако существование атипичных вариантов и широкая доступность специфической терапии существенно затрудняют генетическое консультирование. Не так давно был предложен специфический метод лечения – заместительная энзимная терапия, заключающаяся в использовании рекомбинантной человеческой α-галактозидазы А, но анализ её отдалённых результатов пока не завершен. Традиционное лечение включает использование анальгетиков для облегчения болевого синдрома, нефропротективной (ингибиторы ангиотензин превращающего фермента и блокаторы АТ1-рецепторов) и антиаритмической терапии, а для пациентов с терминальной почечной недостаточностью – диализа и трансплантации почки. С возрастом прогрессирует повреждение жизненно важных органов и систем, с развитием, на определенном этапе, их функциональной недостаточности. Терминальная почечная недостаточность, угрожающие жизни сердечно-сосудистые или цереброваскулярные осложнения сокращают продолжительность жизни мужчин и женщин, не получающих терапию, в сравнении с общей популяцией на 20 и 10 лет соответственно. Наряду с тем, что существуют веские доказательства того, что длительная энзимная терапия может замедлять прогрессирование заболевания, необходимо подчеркнуть важность применения дополнительных методов лечения и возможности разработки пероральной терапии, что стимулирует исследования в области действующих на активные участки, шаперонов. 

Признательности. Я особенно благодарен моим пациентам и их семьям. Я благодарю своего сотрудника Dr. Karelle BENISTAN, MD. Я благодарю Genzyme Corporation и Shire HGT за их постоянную научную поддержку. Эта работа была поддержана Министерством Здоровья Франции в рамках программы «Plan National Maladies Rares».

Конфликт интересов. Доминик П. Гермэйн является консультантом Genzyme Corporation и Shire HGT. Он получил оплату выступлений, поддержку исследований и гонорар от Genzyme Corporation и Shire HGT.

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