Sensory–Motor Polyneuropathy in an 11-year- old Girl with a Pathogenic Variant in SMC1A: A Case Report

Angelica De Luisa; Carlo A. Cesaroni; Marzia Pollazzon; Carlotta Spagnoli; Stefano G. Caraffi; Alberta Leon; Susanna Rizzi; Daniele Frattini; Anna Cavalli; Livia Garavelli; Carlo Fusco

doi:10.1055/a-2447-1508

Neuropediatrics, Table of Contents

Neuropediatrics 2025; 56(01): 056-060
DOI: 10.1055/a-2447-1508

Short Communication

Sensory–Motor Polyneuropathy in an 11-year- old Girl with a Pathogenic Variant in SMC1A: A Case Report

Angelica De Luisa

¹Child Neurology and Psychiatry Unit, Pediatric Neurophysiology Laboratory, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

,

Carlo A. Cesaroni

¹Child Neurology and Psychiatry Unit, Pediatric Neurophysiology Laboratory, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

,

Marzia Pollazzon

²Medical Genetics Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

,

Carlotta Spagnoli

¹Child Neurology and Psychiatry Unit, Pediatric Neurophysiology Laboratory, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

,

Stefano G. Caraffi

²Medical Genetics Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

,

Alberta Leon

³R & I Genetics, Italian National Health System, C.So Stati Uniti 4int.F, Padua, Italy

,

Susanna Rizzi

¹Child Neurology and Psychiatry Unit, Pediatric Neurophysiology Laboratory, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

,

Daniele Frattini

¹Child Neurology and Psychiatry Unit, Pediatric Neurophysiology Laboratory, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

,

Anna Cavalli

¹Child Neurology and Psychiatry Unit, Pediatric Neurophysiology Laboratory, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

,

Livia Garavelli

²Medical Genetics Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

,

Carlo Fusco

¹Child Neurology and Psychiatry Unit, Pediatric Neurophysiology Laboratory, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy

› Author Affiliations

Abstract

Pathogenic variants in the SMC1A gene are often dominant-negative and cause an X-linked form of Cornelia de Lange syndrome (CdLS) with growth retardation and typical facial features. However, rare SMC1A variants cause a developmental and epileptic encephalopathy (DEE) with intractable early-onset epilepsy that is absent in CdLS. Here we describe an 11-year-old girl with epilepsy, walking disorder, and neurodevelopmental disorder. A neurophysiological examination of nerve conduction velocity showed a mixed, sensory–motor, chronic 4-limb polyneuropathy. Whole-exome sequencing identified the variant c.3145C > T p.(Arg1049*) in SMC1A (NM_006306.3), which can be classified as pathogenic. To the best of our knowledge, among 79 individuals with SMC1A-related DEE reported in the literature, altered peripheral nerve conduction has never been described. In this article, we propose that severe sensory–motor polyneuropathy could be an expansion of the SMC1A-related phenotype.

Keywords

SMC1A - epilepsy - neurodevelopmental disorder - neuropathy

Full Text

References

References
1 Jansen S, Kleefstra T, Willemsen MH. et al. De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy-resistant epilepsy in females: expanding the phenotypic spectrum. Clin Genet 2016; 90 (05) 413-419
2 Symonds JD, Joss S, Metcalfe KA. et al. DDD Study. Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: detailed phenotyping of 10 new cases. Epilepsia 2017; 58 (04) 565-575
3 Pié J, Gil-Rodríguez MC, Ciero M. et al. Mutations and variants in the cohesion factor genes NIPBL, SMC1A, and SMC3 in a cohort of 30 unrelated patients with Cornelia de Lange syndrome. Am J Med Genet A 2010; 152A (04) 924-929
4 Gibellato E, Cianci P, Mariani M. et al. SMC1A epilepsy syndrome: clinical data from a large international cohort. Am J Med Genet A 2024; 194 (07) e63577
5 Richards S, Aziz N, Bale S. et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
6 Turner TN, Wilfert AB, Bakken TE. et al. Sex-based analysis of de novo variants in neurodevelopmental disorders. Am J Hum Genet 2019; 105 (06) 1274-1285
7 Martin HC, Gardner EJ, Samocha KE. et al. Deciphering Developmental Disorders Study. The contribution of X-linked coding variation to severe developmental disorders. Nat Commun 2021; 12 (01) 627
8 Bozarth XL, Lopez J, Fang H, Lee-Eng J, Duan Z, Deng X. Phenotypes and genotypes in patients with SMC1A-related developmental and epileptic encephalopathy. Genes (Basel) 2023; 14 (04) 852
9 Kaur M, Blair J, Devkota B. et al. Genomic analyses in Cornelia de Lange syndrome and related diagnoses: novel candidate genes, genotype-phenotype correlations and common mechanisms. Am J Med Genet A 2023; 191 (08) 2113-2131
10 Huisman S, Mulder PA, Redeker E. et al. Phenotypes and genotypes in individuals with SMC1A variants. Am J Med Genet A 2017; 173 (08) 2108-2125
11 Yatskevich S, Rhodes J, Nasmyth K. Organization of chromosomal DNA by SMC complexes. Annu Rev Genet 2019; 53: 445-482
12 Musio A. The multiple facets of the SMC1A gene. Gene 2020; 743: 144612
13 Remeseiro S, Cuadrado A, Losada A. Cohesin in development and disease. Development 2013; 140 (18) 3715-3718
14 Soardi FC, Machado-Silva A, Linhares ND. et al. Familial STAG2 germline mutation defines a new human cohesinopathy. NPJ Genom Med 2017; 2: 7
15 Lebrun N, Lebon S, Jeannet PY, Jacquemont S, Billuart P, Bienvenu T. Early-onset encephalopathy with epilepsy associated with a novel splice site mutation in SMC1A. Am J Med Genet A 2015; 167A (12) 3076-3081
16 Goldstein JH, Tim-Aroon T, Shieh J. et al. Novel SMC1A frameshift mutations in children with developmental delay and epilepsy. Eur J Med Genet 2015; 58 (10) 562-568
17 Schuldiner O, Berdnik D, Levy JM. et al. piggyBac-based mosaic screen identifies a postmitotic function for cohesin in regulating developmental axon pruning. Dev Cell 2008; 14 (02) 227-238
18 Cheng N, Li G, Kanchwala M, Evers BM, Xing C, Yu H. STAG2 promotes the myelination transcriptional program in oligodendrocytes. eLife 2022; 11: e77848