Seipinopathies: clinical variants of hereditary motor-sensory neuropathy and spastic paraplegia caused by mutations in the BSCL2 gene in patients from the Volga-Ural region
Background: Neuronal forms of seipinopathies are rare pathologies and are mainly caused by two pathogenic variants of the BSCL2 gene, p.269C>T (p.Ser90Leu) and p.263A>G (p.Asn88Ser). Incomplete penetrance and subclinical expression of these mutations make it difficult to establish the genetic etiology of such cases of the disease. In this regard, further studies of clinical and genetic features of seipinopathies and their prevalence in different populations are relevant. The aim of the study:To determine the genetic cause of the disease in patients with rare forms of hereditary motor-sensory neuropathies (HMSN) and hereditary spastic paraplegia (HSP) and to characterize the clinical phenotype of patients with mutations in the BSCL2 gene; to determine the frequency of identified mutations in samples of patients with HMSN and HSP from the Bashkortostan Republic (BR), one of the multinational regions of the Volga-Ural region. Materials and methods: In a family with НMSN II the search for the genetic cause of the disease was carried out by direct sequencing of the BSCL2 gene, in a family with НSP – by exome sequencing of the target gene panel. Screening for the presence/absence of identified mutations of the BSCL2 gene in samples from other 199 unrelated patients with НMSN and 62 patients with НSP-residents of the BR – was performed by the high-sensitivity melting curve analysis (HRM). Results: In four patients with НMSN II from one family, a heterozygous c.269C>T(p.Ser90Leu) mutation was identified in the BSCL2 gene. In all patients from this family, the clinical picture of the disease corresponded to the phenotype of Silver syndrome, including a combination of signs of pyramidal insufficiency, features of gait disturbance and hypotrophy of hand muscles. A c.263A>G (p.Asn88Ser) mutation was found in a patient with uncomplicated НSP, as well as in his father with subclinical manifestations of the disease. In other unrelated patients with HMSN and HSP from BR these mutations in the BSCL2 gene were not detected. Conclusion: The obtained data add to the data on clinical and genetic variants of seipinopathies, their genogeography and prevalence; they also emphasize the significant heterogeneity of two groups of neurodegenerative diseases – HMSN and HSP, revealing in their separate forms common mechanisms of pathogenesis and some clinical symptoms that may facilitate accurate diagnosis
Khidiyatova IM, Saifullina EV, Gaisina EV, et al. Seipinopathies: clinical variants of hereditary motor-sensory neuropathy and spastic paraplegia caused by mutations in the BSCL2 gene in patients from the Volga-Ural region. Research Results in Biomedicine. 2025;11(3):432-450. Russian. DOI: 10.18413/2658-6533-2025-11-3-0-3
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The equipment of the Regional Collective Use Centre «Agidel» of the UFIC RAS was used for the study. DNA samples for the study were taken from the «Human Biological Materials Collection» of the IBG UFITC RAS, supported by the Bioresource Collections Programme of FANO of Russia (Agreement No. 007-030164/2)