LAMA2-associated muscular dystrophy is a rare genetic disorder caused by pathogenic or likely pathogenic variants in the LAMA2 gene. The aim of this study is to characterize the spectrum of pathogenic/likely pathogenic variants in the LAMA2 gene among Russian patients, identify frequent pathogenic variants specific to this population, and estimate the prevalence of this disorder in Russia. Data were collected and analyzed from patients with confirmed diagnoses of LAMA2-associated muscular dystrophy using various molecular genetic methods in research centers from 2008 to 2024. Data were obtained from 90 unrelated patients with LAMA2-associated muscular dystrophy, out of which 83 presented with the more severe form, MDC1A1, while seven had milder form of LAMA2-associated muscular dystrophy. The most common pathogenic variants identified were nonsense mutations (40% of cases), followed by frameshift variants (29.3%), splicing variants (21.4%), gross deletions (5.3%), and missense variants (4%). It is worth noting that missense variants were found exclusively in patients with the milder form of LAMA2-associated muscular dystrophy. The most prevalent identified pathogenic variant was c.7536del (15%), characteristic of Slavic populations with an established founder effect. Additionally, a common pathogenic variant, c.8245-2A>G, was found predominantly in Kazan Tatars. The estimated prevalence of LAMA2-associated muscular dystrophy in Russia is approximately 1 in 117,700.

Background. Hereditary motor and sensory neuropathies (HMSN) are a genetically diverse group of disorders of the peripheral nerves characterized by gradual development of weakness, muscular hypo-/atrophy, sensory disturbances in distal areas of the extremities. Currently among the recessive forms, the most prevalent HMSN is associated with the ganglioside-induced differentiation associated-protein 1 (GDAP1) gene (GDAP1-HMSN).The objective is to present an observation of a family case of HMSN type IVA with unusual genealogy.Materials and methods. Clinical, electrophysiological, and genetic characteristics of a Russian family with GDAP1-HMSN were examined.Results. We describe a family with autosomal recessive HMSN and unusual genealogy due to homozygous and compound heterozygous mutations of GDAP1.Conclusion. The particularity of the described family case is the unusual genealogy with the patients in two non-consecutive generations. This type of inheritance is caused by presence of mutations in compound heterozygous state in the proband's grandson which was confirmed by genetic analysis. The presented case demonstrates the importance and necessity of full analysis of the GDAP1 gene or identification of 2 mutations in trans-position in the proband and subsequent assessment of possible risks for future generations. Multiple stroke-like episodes in the 2 affected members of the family are described that have not been previously reported for GDAP1-HMSN. Stroke has been presented in HMSN associated with mitofusin-2 gene which also as GDAP1, affects mitochondrial function in the neurons.

Описан семейный случай редкой аутосомно-доминантной болезни Альцгеймера, связанной с геном PSEN1 (БА3, OMIM 607822) и отличающейся от частой многофакторной формы значительно более ранним началом и в части случаев наличием неврологических симптомов, особенно прогрессирующего спастического парапареза. У женщины-пробанда и сына первым признаком был парапарез, манифестировавший в 29 лет и 21 год соответственно, быстро присоединились когнитивные расстройства; прежний диагноз: наследственная спастическая параплегия с когнитивными нарушениями. При обследовании больной в 33 года (2008 г.) диагноз не установили. У сына, обследованного в 27 лет (2022 г.), полноэкзомное секвенирование выявило новую миссенс-мутацию p.Thr421Ala в гене PSEN1; при верификации по Сэнгеру мутация подтверждена у него, найдена у пробанда, находившейся в состоянии глубокой психоневрологической инвалидизации, и исключена у ее здоровой матери. Кроме различия возраста начала, болезнь у пробанда и сына протекала сходно, но в целом БА3 разнообразна, в том числе внутрисемейно, что затрудняет клиническую диагностику. Высокопроизводительное экзомное секвенирование — надежный диагностический метод БА3 и сходных болезней.

Introduction. Charcot–Marie–Tooth disease type 4D is a hereditary demyelinating neuropathy, that occurs with the high frequency in patients of Roma origin. It is characterized by early onset at the age of 2–10 years and hearing impairment, manifested by the 3rd decade of life.Aim of the study. To describe the clinical and genetic characteristics of Charcot–Marie–Tooth disease type 4D in Russian patients of Roma origin.Materials and methods. For 14 probands from unrelated families of Roma origin with a clinical diagnosis of Charcot–Marie–Tooth disease, genetic tests for the pathogenic variants c. 442CT in the NDRG1 gene and c. 3325CT in the SH3TC2 gene was carried out. For 8 patients with Charcot–Marie–Tooth disease type 4D, detailed clinical and electrophysiological examination was performed.Results. In 11 families of Roma origin, the c. 442CT pathogenic variant in the NDRG1 gene in a homozygous state was detected, which accounted for 79 % all observed Roma patients with Charcot–Marie–Tooth disease. There are 12 of the 14 tested families live in the European part of Russia, 7 of them are from nearby regions. The average age of onset was 3.3 years. The first symptom in 7 of 8 patients was gait disturbances. At the time of examination (age range 6–19 years), all patients showed marked hypotrophy and weakness of the feet, lower leg, hands muscles, feet deformities, reduction or loss of tendon reflexes.Discussion. Due to the detection of only one pathogenic variant in most Russian patients of Roma origin with Charcot–Marie–Tooth disease, the knowledge of the ethnicity of a proband with early myelinopathy can significantly simplify the confirmation of the diagnosis on the molecular level.