Expanding the phenotypic spectrum of LAMA2-related disorders: Axonal neuropathy in the absence of muscular dystrophy.

The LAMA2 gene encodes the alpha-2 chain of laminin-2, a key component of the basement membrane that maintains muscle fiber stability and integrity. Mutations in this gene are linked with LAMA2-related muscular dystrophies, which includes congenital muscular dystrophy type 1 A (MDC1A) and limb-girdle muscular dystrophy autosomal recessive 23 (LGMDR23). Here, we present two siblings from one of 200 unrelated Iranian Charcot-Marie-Tooth (CMT) families, exhibiting axonal sensorimotor polyneuropathy, without any clinical signs of muscular dystrophy, carrying a homozygous variant in the LAMA2 gene. Following clinical and paraclinical assessments of the patients, genomic DNA was extracted from peripheral blood samples. Whole-exome sequencing (WES) was employed to identify potential genetic variants, and Sanger sequencing was subsequently used to confirm the detected variant. In silico prediction tools were further applied to evaluate the potential pathogenicity and functional impact of the identified variant. A homozygous missense variant in the LAMA2 gene, c.2916 T > G; p.Phe972Leu, was identified and co-segregated with the disease status within the family, whose neurological assessments confirmed axonal sensorimotor polyneuropathy. So far, only two studies have reported LAMA2 variants in patients only manifesting a neuropathy phenotype. None of these studies reported the detailed clinical data of their cases. However, our study provides further evidence of the association between LAMA2 mutations and neuropathy, and includes comprehensive clinical and paraclinical characterization of the affected individuals. Our findings underscore the importance of comprehensive genomic testing in diagnosing neuromuscular disorders and expand the phenotypic spectrum associated with LAMA2 mutations.