Neuromuscular DiseasesNeuromuscular DiseasesНервно-мышечные болезни2222-87212413-0443Publishing House ABV Press42410.17650/2222-8721-2021-11-1-25-38ORIGINAL REPORTSОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯDiversity of VCP-related phenotypes: case report and literature reviewРазнообразие фенотипов, связанных с геном VCP: клиническое наблюдение и обзор литературыhttps://orcid.org/0000-0002-8244-9367RudenskayaG. E.РуденскаяГ. Е.
Russian Federation

Galina Evgenyevna Rudenskaya

1 Moskvorech’e St., Moscow 115522

Галина Евгеньевна Руденская 

115522 Москва, ул. Москворечье, 1

rudenskaya@med-gen.ruhttps://orcid.org/0000-0003-0351-1271MironovichO. L.МироновичО. Л.
Russian Federation

1 Moskvorech’e St., Moscow 115522

115522 Москва, ул. Москворечье, 1

https://orcid.org/0000-0001-7023-7378MurtazinaA. F.МуртазинаА. Ф.
Russian Federation

1 Moskvorech’e St., Moscow 115522

115522 Москва, ул. Москворечье, 1

https://orcid.org/0000-0003-4905-1303ShchaginaO. A.ЩагинаО. А.
Russian Federation

1 Moskvorech’e St., Moscow 115522

115522 Москва, ул. Москворечье, 1

Research Centre for Medical GeneticsФГБНУ «Медико-генетический научный центр им. академика Н.П. Бочкова»1904202111125381904202119042021Copyright ©; 2021, Rudenskaya G.E., Mironovich O.L., Murtazina A.F., Shchagina O.A.Copyright ©; 2021, Руденская Г.Е., Миронович О.Л., Муртазина А.Ф., Щагина О.А.2021Rudenskaya G.E., Mironovich O.L., Murtazina A.F., Shchagina O.A.Руденская Г.Е., Миронович О.Л., Муртазина А.Ф., Щагина О.А.https://creativecommons.org/licenses/by/4.0https://nmb.abvpress.ru/jour/article/view/424

Background. Gene VCP encoding multifunctional protein valosin produces a number of rare autosomal dominant late-onset disorders with multiple symptoms (muscular dystrophy with inclusion bodies in part of cases, Paget disease of bone, frontotemporal dementia, amyotrophic lateral sclerosis and few others) in different combinations often varying in one family. Rare unusual phenotypes are difficult for recognition. Molecular methods facilitate diagnostics.Objective: to describe first Russian VCP-related familial case detected by exome sequencing and present a review on poorly known disorder.Materials and methods. In a Russian family with 4 patients in 2 generations 6 persons were examined: 2 patients, 3 clinically unaffected possible heterozygous carriers and patient’s mother with no genetic risk; medical information was received about two deceased patients. Methods: clinical and genealogical; biochemical: blood creatine kinase, alpha-glucosidase; molecular: clinical exome sequencing, Sanger familial sequencing, bioinformatical analysis.Results. In 48-year-old proband and 50-year-old brother whose former diagnosis was hereditary neuropathy proximal muscular dystrophy with onset in 43–45 years, rapid progression and moderately raised creatine kinase (341–572 U/l) was found out. Since 45 years the proband also had Paget disease. Both brothers had no evident dementia (neuropsychological examination was not performed). The younger brother since 32 years suffered typical amyotrophic lateral sclerosis, evidently combined with dementia, he died in 43 years being severely disabled; brain is not described in autopsy record. The father had rapidly progressing walking difficulties since 40 years without mental, speech or swallowing disturbances; he was never examined and died in 48 years of heart disease (?). Clinical exome sequencing in the proband detected in VCP exon 5 one of common mutations с.463С>T (p.Arg155Cys) in heterozygous state. Familial Sanger sequencing found out the mutation in him, in the brother and in clinically unaffected 36-year-old sister, 22-year-old daughter and 15-year old son, thus diagnosing preclinical stage of the disease.Conclusions. The case illustrates diversity of VCP-related disorders and necessity to take into consideration all phenotype spectrum. DNA-confirmed diagnosis permits genetic counseling.

Введение. Ген VCP, кодирующий многофункциональный белок валозин, вызывает ряд редких аутосомно-доминантных клинических форм с поздним началом и разнообразными симптомами (мышечная дистрофия, в части случаев с включениями в мышцах; костная болезнь Педжета; лобно-височная деменция; боковой амиотрофический склероз; более редкие симптомы), сочетания которых варьируют, в частности, внутрисемейно. Редкость патологии и необычное сочетание симптомов затрудняют клиническую диагностику. Молекулярно-генетические методы необходимы для установления диагноза.Цель исследования – описать первый российский семейный случай VCP-связанной патологии, диагностированный методом клинического экзомного секвенирования, представить обзор литературы о малоизвестной болезни.Материалы и методы. В русской семье с 4 больными в 2 поколениях обследованы 2 больных, 3 клинически здоровых возможных гетерозиготных носителей и мать больных, не имеющая риска носительства; получены сведения о 2 умерших больных. Методы: клинико-генеалогический; биохимические: определение креатинфосфокиназы и альфа-глюкозидазы в крови; молекулярно-генетические: клиническое экзомное секвенирование, семейная верификация по Сэнгеру, биоинформатический анализ.Результаты. У пробанда 48 лет и его брата 50 лет с прежним диагнозом наследственной нейропатии выявлена проксимальная мышечная дистрофия с началом в 43–45 лет, быстрым прогрессированием и умеренно повышенным уровнем креатинфосфокиназы (341–572 Ед/л). У пробанда с 45 лет болезнь Педжета; брат в этом плане не обследован, клинических симптомов нет. У обоих нет явной деменции (специальное обследование не проводили). Третий брат с 32 лет страдал типичным боковым амиотрофическим склерозом, очевидно, в сочетании с деменцией; умер в 43 года, головной мозг в протоколе аутопсии не описан. Отец с 40 лет с трудом ходил, с 43 лет с опорой; интеллект, речь, глотание не страдали; не обследован: умер в 48 лет (болезнь сердца?). Клиническое экзомное секвенирование у пробанда выявило в экзоне 5 гена VCP частую мутацию с.463С>T (p.Arg155Cys) в гетерозиготном состоянии. При семейном секвенировании по Сэнгеру мутация найдена у пробанда и брата, а также у здоровых сестры 36 лет, дочери 22 лет и сына 15 лет (доклиническая стадия болезни).Выводы. Наблюдение иллюстрирует многообразие VCP-связанной патологии и важность учета в клинической диагностике всего спектра фенотипов. Установленный диагноз позволяет проводить медико-генетическое консультирование в семьях.

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