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Background: This study presents the findings of a newborn screening (NBS) pilot project for 5q-spinal muscular atrophy (5q-SMA) in multiple regions across Russia for during the year 2022. The aim was to assess the feasibility and reproducibility of NBS for SMA5q in diverse populations and estimate the real prevalence of 5q-SMA in Russia as well as the distribution of patients with different number of SMN2 copies., Methods: The pilot project of NBS here was based on data, involving the analysis of 202,908 newborns. SMA screening assay was performed using a commercially available real-time polymerase chain reaction kit, the Eonis SCID-SMA., Results: In one year, 202,908 newborns were screened, identifying 26 infants with homozygous deletion of SMN1 exon 7, yielding an estimated 5q-SMA incidence of 1:7804 newborns. It was found that 38.46% had two SMN2 copies, 42.31% had three copies, 15.38% had four copies, and 3.85% had five copies of SMN2. Immediate treatment was proposed for patients with two or three SMN2 copies. Infants with four or more SMN2 copies warranted further investigation on management and treatment. Short-term monitoring after gene therapy showed motor function improvements. Delays in treatment initiation were observed, including the testing for adeno-associated virus 9 antibodies and nonmedical factors., Conclusions: The study emphasizes the need for a standardized algorithm for early diagnosis and management through NBS to benefit affected families. Overall, the NBS program for 5q-SMA in Russia demonstrated the potential to improve outcomes and transform SMA from a devastating disease to a chronic condition with evolving medical requirements., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andrey V. Marakhonov reports equipment, drugs, or supplies was provided by Novartis Pharma LLC. Andrey V. Marakhonov reports equipment, drugs, or supplies was provided by Skopinfarm LLC. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Newborn screening (NBS) for severe inborn errors of immunity (IEI), affecting T lymphocytes, and implementing measurements of T cell receptor excision circles (TREC) has been shown to be effective in early diagnosis and improved prognosis of patients with these genetic disorders. Few studies conducted on smaller groups of newborns report results of NBS that also include measurement of kappa-deleting recombination excision circles (KREC) for IEI affecting B lymphocytes. A pilot NBS study utilizing TREC/KREC detection was conducted on 202,908 infants born in 8 regions of Russia over a 14-month period. One hundred thirty-four newborns (0.66‰) were NBS positive after the first test and subsequent retest, 41% of whom were born preterm. After lymphocyte subsets were assessed via flow cytometry, samples of 18 infants (0.09‰) were sent for whole exome sequencing. Confirmed genetic defects were consistent with autosomal recessive agammaglobulinemia in 1/18, severe combined immunodeficiency - in 7/18, 22q11.2DS syndrome - in 4/18, combined immunodeficiency - in 1/18 and trisomy 21 syndrome - in 1/18. Two patients in whom no genetic defect was found met criteria of (severe) combined immunodeficiency with syndromic features. Three patients appeared to have transient lymphopenia. Our findings demonstrate the value of implementing combined TREC/KREC NBS screening and inform the development of policies and guidelines for its integration into routine newborn screening programs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Amyotrophic lateral sclerosis (ALS) is a sporadic disease in most of the cases; in 10-15% of cases genetic forms are recorded. A genetic form of ALS associated with the mutation in the ERBB4 gene (ALS19) has been reported in 2013. A protein encoded by the ERBB4 is probably involved in ubiquitous component of the pathogenesis of ALS. We present a case of ALS associated with a new pathogenic variant of the ERBB4 gene, with early bulbar onset and slow progression of the disease within 10 years.

Glutaric aciduria type 1 (GA1, deficiency of glutaryl CoA dehydrogenase, glutaric acidemia type 1) (ICD-10 code: E72.3; MIM 231670) is an autosomal recessive disease caused by mutations in the gene encoding the enzyme glutaryl CoA dehydrogenase (GCDH). Herein, we present the biochemical and molecular genetic characteristics of 51 patients diagnosed with GA1 from 49 unrelated families in Russia. We identified a total of 21 variants, 9 of which were novel: c.127 + 1G > T, с.471_473delCGA, c.161 T > C (p.Leu54Pro), c.531C > A (р.Phe177Leu), c.647C > T (p.Ser216Leu), c.705G > A (р.Gly235Asp), c.898 G > A (р.Gly300Ser), c.1205G > C (р.Arg402Pro), c.1178G > A (р.Gly393Glu). The most commonly detected missense variants were c.1204C > T (p.Arg402Trp) and с.1262C > T (р.Ala421Val), which were identified in 56.38% and 11.7% of mutated alleles. A heterozygous microdeletion of the short arm (p) of chromosome 19 from position 12,994,984-13,003,217 (8233 b.p.) and from position 12,991,506-13,003,217 (11,711 b.p.) were detected in two patients. Genes located in the area of imbalance were KLF1, DNASE2, and GCDH. Patients presented typical GA1 biochemical changes in the biological fluids, except one patient with the homozygous mutation p.Val400Met. No correlation was found between the GCDH genotype and glutaric acid (GA) concentration in the cohort of our patients.

Tuberous sclerosis (TS) is a rare autosomal-dominant genetic disease. TS is manifested by the development of multiple hamartomas, which affect brain, kidneys, retina, skin and other organs. This study aimed to reveal specific features of molecular epidemiology of TS in Russia. Blood DNA samples from 61 patients with definite (n = 53) or probable (n = 8) clinical diagnosis of TS were tested for mutations in TSC1 and TSC2 genes using Sanger sequencing and MLPA analysis. Five TSC1/2 mutation-negative patients were further analyzed by exome sequencing. TSC1/2 mutations were detected in 53/61 patients (87%): 39 (74%) carried mutations in the TSC2 and 14 (26%) in the TSC1. Large rearrangements (exon deletions/duplications) affected exclusively TSC2, accounting for 15% of lesions of this gene. 6/8 (75%) patients with incomplete clinical manifestation of TS carried TSC1/2 gene lesion. Overall, 96% of detected germline TSC1/2 mutations occurred de novo. Patients with no mutation identified (NMI) differed from TSC1/2 mutation carriers, being lacking cortical tubers and subependymal nodules but having higher frequencies of renal angiomyolipomas, rhabdomyomas, and lymphangioleiomyomatosis. Exome sequencing failed to identify overt disease-causing mutation candidates among NMI patients. Russian patients with TS have increased frequency of TSC2 large gene rearrangements and TSC1/2 mutations occurring de novo as compared to other studies. Patients with suspected TS diagnosis but NMI status may represent a distinct disease entity.

The authors present a case-report of 13 year-old girl with L-2-hydroxyglutaric aciduria [MIM#236792], a rare autosomal/recessive metabolic disorder caused by mutations in the L-encoding 2-hydroxyglutarate dehydrogenase (L2HGDH, 14q21.3). Clinical signs of the disease are presented by predominantly neurological symptoms (epilepsy, cerebellar ataxia, cognitive impairment). The distinctive feature is the specific multifocal lesion of the white matter detected on MRI. The characteristic neuroimaging picture and positive results of biochemical and molecular genetic diagnosis were identified.

Background: Hereditary motor-sensory neuropathy 1X (НМСН 1X) is the second frequent form of hereditary motor-sensory neuropathies caused by mutations in the GJB1 gene (gap junction B1 type). The authors have established earlier that the с.259C>G (р.P87A) mutation is the most frequent cause of НМСН 1Х (92%) in patients from the Republic of Bashkortostan., Aim: To study in details the territorial ethnic distribution and clinical manifestations of the с.259C>G (р.P87A) in the GJB1 gene in patients with НМСН 1Х from the Republic of Bashkortostan., Material and Methods: Clinical/neurological data were assessed in 52 patients (32 men and 20 women) from 13 families with this НМСН 1Х mutation in accordance to the diagnostic criteria of the European neuromuscular center. Twenty-three patients underwent standard electroneuromyographic study ('Nicolet Viking quest') using cutaneous electrodes. Data analysis was performed with Statistica ver.6.0 ('Stat Soft, Inc.', 2003) software., Results: The с.259C>G (р.P87A) mutation was more frequent in Bashkir (61%) and Russian (31%) families from 6 areas of the Republic of Bashkortostan. The age-at-onset was 13.24±4.33 years in men. In women, the age-at-onset varied from 7 to 45 years, it was difficult to detect this parameter in several patients due to the absence of complaints and symptoms of disease. A comparative analysis revealed the higher degree of peripheral nerve lesions in men compared to women. There was the distinct difference in electrophysiological parameters (excitation spreading velocity and M-response amplitude) along motor fibers of the middle nerves between men and women that indicated the predominantly demyelinating character of the pathological process in men and the axonal character in women., Conclusion: Clear clinical/electrophysiological sex differences (intra- and inter family) were shown in patients with НМСН IX with the с.259C>G (р.P87A) mutation in the GJB1 gene. The disease was less severe and often with the absence of symptoms in women. Genetic testing for mutations in the GJB1 gene, including the с.259C>G (р.P87A) mutation, can be recommended to female patients with excitation spreading velocity >38m/s.

Hereditary spastik paraplegias (HSP) are a group of neurodegenerative disorders with primary lesion of the pyramidal tract. The most frequent autosomal dominant form of the disease in Europeans is HSP associated with mutations in the spastin gene (SPG4). Analysis of the gene SPG4 was carried out in 52 unrelated families with HSP from Bashkortostan by SSCP and following sequencing. Previously undescribed frameshift mutations c.322del29 (p.Val108SerfsX18) and c.885del10 (p.Thr295ThrfsX16) were detected in two unrelated families. Clinical studies have shown that, in both families, the disease corresponds to an uncomplicated form of hereditary spastic paraplegia, a main feature of which is the lower spastic paraparesis without any other symptoms.

Hereditary motor and sensory neuropathy (HMSN) type IIA is caused by mutations in the mitofusin type-2 (MFN2) gene and represents one of the most common axonal forms of HMSN. We determined the spectrum and frequency of MFN2 gene mutations in patients from the Bashkortostan Republic (BR). Four different mutations were revealed in 5 out of 170 unrelated patients, i.e., c.2113G>A (p.Val705Ile) (1.2% among all types of H MSN in the total sample of patients and 2% among patients of Tatar ethnicity). This mutation was described previously; c.775C>T (p.Arg259Cys) (0.6%, in the total sample of patients and 2% among the patients of Tatar ethnicity); c.776G>A (p.Arg259His) (0.6% in the total sample of patients and 1.5% among the patients of Russians ethnicity); and c.2171T>C (p.Leu724Pro) (1.2% in the total sample of patients and 7.4% among the patients of Bashkirs ethnicity). These are new mutations that were not observed among healthy family members and in control samples of healthy subjects. Five identified nucleotide substitutions represent single nucleotide polymorphisms of the gene, including c.892G>A (p.Gly298Arg), c.957C>T (Gly319Gly), and c1039-222t>c, which were described previously, while c.175+28c>t and c.2204+15t>c represent new nucleotide substitutions in the intron regions of the gene.