Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disease and is characterized by considerable clinical and genetic heterogeneity¹. We previously reported a Russian family with autosomal dominant axonal CMT and assigned the locus underlying the disease (CMT2F; OMIM 606595) to chromosome 7q11–q21 (ref. 2). Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F. Screening for mutations in HSPB1 in 301 individuals with CMT and 115 individuals with distal hereditary motor neuropathies (distal HMNs) confirmed the previously observed mutation and identified four additional missense mutations. We observed the additional HSPB1 mutations in four families with distal HMN and in one individual with CMT neuropathy. Four mutations are located in the Hsp20–α-crystallin domain, and one mutation is in the C-terminal part of the HSP27 protein. Neuronal cells transfected with mutated HSPB1 were less viable than cells expressing the wild-type protein. Cotransfection of neurofilament light chain (NEFL) and mutant HSPB1 resulted in altered neurofilament assembly in cells devoid of cytoplasmic intermediate filaments.

Under the implementation of the “Advanced neonatal screening” Federal Program and the Ministry of Healthcare of Russia Order No. 274n “On approval of the Procedure for providing medical care to patients with congenital and/or hereditary diseases” that started jointly on Jan. 01, 2023 overall Russia, the examination of all newborns for the 29 nosologies of exchange disorders by tandem mass spectrometry as well as spinal muscular atrophy and primary immunodeficiencies by polymerase chain reaction had begun. Circa 1 million and 230 thousand newborns were examined in 85 Russia regions during 2023 with the level of births coverage exceeding 98%. As a result, a risk group that amounted to 1.86% of all examined was formed with confirming diagnostics performed for 8712 neonatal patients at risk, of which 676 have had their deceases confirmed including 379 hereditary metabolic diseases, 117 spinal muscular atrophies and 180 primary immunodeficiencies. Effective treatment and dispensary follow-up methods have been developed so far for all the screened nosologies. Thus, the introduction of the neonatal screening made it possible to initiate therapy for most of the identified patients at preclinical stages reducing the overall infant mortality and improving the quality of life for such patients and their caretakers.

Duchenne/Becker muscular dystrophy (DMD/BMD) is the most common form of muscular dystrophy, accounting for over 50% of all cases. In this regard, in Russia we carry out a program of selective screening for DMD/BMD, which mainly involves male patients. The main inclusion criteria are an increase in the level of creatine phosphokinase (>2000 U/L) or an established clinical diagnosis. At the first stage of screening, patients are scanned for extended deletions and duplications in the DMD gene using multiplex ligase-dependent probe amplification (MLPA SALSA P034 and P035 DMD probemix, MRC-Holland). The second stage is the search for small mutations using a custom NGS panel, which includes 31 genes responsible for various forms of limb-girdle muscular dystrophy. In a screening of 1025 families with a referral Duchenne/Becker diagnosis, pathogenic and likely pathogenic variants in the DMD gene were found in 788 families (in 76.9% of cases). In the current study, we analyzed the mutation spectrum of the DMD gene in Russian patients and noted certain differences between the examined cohort and the multi-ethnic cohort. The analysis of the DMD gene mutation spectrum is essential for patients with DMD/BMD because the exact mutation type determines the application of a specific therapeutic method.

Ataxia with oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive, PNKP-related disorder delineated in 2015 in Portugal. We diagnosed AOA4 by next generation sequencing (NGS) followed by Sanger's sequencing in three boys from two unrelated Belarusian families. In both families, one of the heterozygous PNKP mutations was c.1123G>T, common in Portuguese patients; biallelic mutations, c.1270_1283dup14 and c.1029+2T>C, respectively, were novel. These are the first reported AOA4 Slavic cases and the first with a “Portuguese” PNKP mutation outside Portugal. Distinction in two brothers was microcephaly but their disease was not severe in contrast to PNKP-related “microcephaly, seizures, and developmental delay” and reported cases with features of both phenotypes.