RESUMO
BACKGROUND: Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder caused by a deficiency of Arylsulfatase A (ARSA) enzyme activity. Its clinical manifestations include progressive motor and cognitive decline. ARSA gene mutations are frequent in MLD. METHODS AND RESULTS: In the present study, whole exome sequencing (WES) was employed to decipher the genetic cause of motor and cognitive decline in proband's of two consanguineous families from J&K (India). Clinical investigations using radiological and biochemical analysis revealed MLD-like features. WES confirmed a pathogenic variant in the ARSA gene. Molecular simulation dynamics was applied for structural characterization of the variant. CONCLUSION: We report the identification of a pathogenic missense variant (c.1174 C > T; p.Arg390Trp) in the ARSA gene in two cases of late infantile MLD from consanguineous families in Jammu and Kashmir, India. Our study utilized genetic analysis and molecular dynamics simulations to identify and investigate the structural consequences of this mutation. The molecular dynamics simulations revealed significant alterations in the structural dynamics, residue interactions, and stability of the ARSA protein harbouring the p.Arg390Trp mutation. These findings provide valuable insights into the molecular mechanisms underlying the pathogenicity of this variant in MLD.