Клинико-генетические характеристики понтоцеребеллярной гипоплазии, обусловленной мутациями в гене TSEN54 (OMIM: 277470)

Introduction. The description of the clinical and genetic characteristics of eight patients with autosomal-recessive variant pontocerebellar hypoplasia due to mutations in the TSEN54 gene.Purpose. Description of clinical and genetic characteristics of Russian patients with type 2A and type 4 of pontocerebellar hypoplasia.Materials and methods. The diagnosis of pontocerebellar hypoplasia was established on the basis of the specific features of clinical manifestations and detection of mutations in the gene TSEN54 based on the analysis of the results of exome sequencing. Results. 8 patients with pontocerebellar hypoplasia caused by mutations in the TSEN54 gene were identified. Discussion. Based on the features of clinical manifestations and severity of the disease in 5 patients diagnosed pontocerebellar hypoplasia type 2A, and in 3 patients – type 4. In patients with type 2A of pontocerebellar hypoplasia discovered mutation c. 919G>T (p.Ala307Ser)  in a homozygous state. Patients with type 4 of pontocerebellar hypoplasia this mutation is detected in the compound heterozygous state with c.670_671delAA (p.Lys224fs) and c.1264C>T (p.Gln422fs).Conclusion. The obtained results allow us to conclude that, as well as in European populations, the mutation c.919G>T (p. Ala307Ser) is a major in Russian patients with pontocerebellar hypoplasia 2A and 4 types, which account for about half of all cases of this disease group. The search for this mutation should be the first stage of molecular genetic diagnosis in patients with clinical and magnetic resonance signs of pontocerebellar hypoplasia.Введение. Представлено описание клинико-генетических характеристик 8 больных с аутосомно-рецессивным вариантом понтоцеребеллярных гипоплазий, обусловленных мутациями в гене TSEN54.Цель исследования – описание клинико-генетических характеристик российских больных с понтоцеребеллярной гипоплазией 2А и 4 типа.Материалы и методы. Диагноз понтоцеребеллярной гипоплазии устанавливался на основании особенностей клинических проявлений и обнаружения мутаций в гене ТSEN54 путем анализа результатов секвенирования экзома.Результаты. Выявлено 8 больных с понтоцеребеллярной гипоплазией, обусловленной мутациями в гене ТSEN54.Заключение. На основании особенностей клинических проявлений и тяжести течения заболевания у 5 больных диагностирована понтоцеребеллярная гипоплазия 2А типа, а у 3 больных – 4 типа. У больных с понтоцеребеллярной гипоплазией 2А типа обнаружена мутация с.919G>T (p.Ala307Ser) в гомозиготном состоянии. У больных с типом 4 эта мутация обнаружена в компаундгетерозиготном состоянии с мутациями c.670_671delAA (p.Lys224fs) и c.1264C>T (p.Gln422fs).Заключение. Полученные результаты позволяют сделать заключение, что, так же как и в европейских популяциях, мутация с.919G>T (p.Ala307Ser) является мажорной у российских больных с понтоцеребеллярной гипоплазией 2А и 4 типа, на долю которых приходится около половины всех случаев этой группы заболеваний. Поиск этой мутации должен быть первым этапом проведения молекулярно-генетической диагностики у больных с клиническими и магнитно-резонансными признаками понтоцеребеллярной гипоплазии

ETIOLOGICAL STRUCTURE OF NONGLAUCOMATOUS OPTIC NEUROPATHIES

Purpose: to study the etiological structure and incidence rate of various genesis optical neuropathies (ON) according to the own observation data. Material and methods. The study is based on the data analysis from a survey of 658 patients (982 eyes) with ON. The results of routine physical examination of all patients were analyzed to determine the genesis of ON. Results. The most common cases of ON were ischemic ON (31.2 % of all cases), as well as optic neuritis (18.3 % of cases). The anterior optic pathway tumor or infiltrative lesions were detected in 9.9 %, dysthyroid ON was found in 7.2 %. Acute and chronic ON with the optic nerve drusen accounted for 12.4 % of all cases of ON, was found in 60.5 % of all patients with the optic nerve drusen. Hereditary ON was found in 10 % of all cases of ON, toxic - in 4,3 % as a result of acute and chronic alcohol intoxication, chronic narcotic poisoning, drug poisoning. Traumatic ON was found in 6.7 % of all cases of ON. Conclusions. The causes of ON are diverse, vary from innate changes to diseases of the optic nerve as a result of serious therapeutic and neurosurgical pathology, which threaten not only the ophthalmologic, but also the life prediction. The patient thorough clinical study is required to determine the disease genesis at the time of ON symptoms identifying

Clinical and genetic characteristics of ponto-cerebellar hypoplasia caused by mutations in the TSEN54 gene (OMIM: 277470)

Introduction. The description of the clinical and genetic characteristics of eight patients with autosomal-recessive variant pontocerebellar hypoplasia due to mutations in the TSEN54 gene.Purpose. Description of clinical and genetic characteristics of Russian patients with type 2A and type 4 of pontocerebellar hypoplasia.Materials and methods. The diagnosis of pontocerebellar hypoplasia was established on the basis of the specific features of clinical manifestations and detection of mutations in the gene TSEN54 based on the analysis of the results of exome sequencing. Results. 8 patients with pontocerebellar hypoplasia caused by mutations in the TSEN54 gene were identified. Discussion. Based on the features of clinical manifestations and severity of the disease in 5 patients diagnosed pontocerebellar hypoplasia type 2A, and in 3 patients – type 4. In patients with type 2A of pontocerebellar hypoplasia discovered mutation c. 919G>T (p.Ala307Ser)  in a homozygous state. Patients with type 4 of pontocerebellar hypoplasia this mutation is detected in the compound heterozygous state with c.670_671delAA (p.Lys224fs) and c.1264C>T (p.Gln422fs).Conclusion. The obtained results allow us to conclude that, as well as in European populations, the mutation c.919G>T (p. Ala307Ser) is a major in Russian patients with pontocerebellar hypoplasia 2A and 4 types, which account for about half of all cases of this disease group. The search for this mutation should be the first stage of molecular genetic diagnosis in patients with clinical and magnetic resonance signs of pontocerebellar hypoplasia

Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder.

To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder