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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Giant axonal neuropathy (GAN) is a severe and rare autosomal recessive neurodegenerative disorder of childhood affecting both the peripheral and central nervous systems (CNS). It is caused by mutations in the GAN (gigaxonin) gene linked to chromosome 16q24. Here, we present a 15-year-old male patient with GAN from a consanguineous family of Poonch, Jammu and Kashmir (J&K)-India. Whole-exome sequencing (WES) was employed to unravel the genetic cause of GAN in the proband. Pathogenic variant identified with WES was confirmed in other affected sibling using Sanger sequencing. Magnetic resonance imaging (MRI) and detailed clinical investigation was also carried out on proband. WES revealed a novel homozygous stopgain GAN mutation (NM_022041, c.C1028G, p.S343X) in the patient. MRI of brain displayed bilateral symmetrical confluent areas of deep white matter signal changes affecting periventricular regions (with sparing of subcortical U-fibers), posterior limbs of internal capsules, thalami, external capsules, and semioval centers. The patient was initially suspected to be a case of metachromatic leukodystrophy. However, WES analysis revealed a pathogenic variant in GAN gene as causative. No other pathogenic variant relevant to any other type of dystrophy was reported in WES. Our findings extend the geographical distribution of GAN to even a very remote region in India, extend the mutational and imaging spectrum of GAN and substantiate the need for introducing genetic testing and counselling in primary referral centers/district hospitals in India. [ABSTRACT FROM AUTHOR]

Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is a rare neurodegenerative disorder characterized by the triad of early-onset cerebellar ataxia, peripheral sensorimotor neuropathy, and lower limb spasticity. Here, we present a 28-year-old male patient with symptoms of ARSACS and mild intellectual disability from a consanguineous family of tribal J&K, India. Whole exome sequencing unraveled a novel homozygous frameshift SACS mutation (Cys2869ValfsTer15) in the patient. In addition to the well-established ARSACS imaging features, MRI revealed T2 hyperintense rim around the thalami ("bithalamic stripes") demonstrating that this feature might serve as an additional supportive diagnostic imaging marker for ARSACS. Moreover, retinal nerve fiber layer thickening which has recently been proposed as a diagnostic biomarker for ARSACS was present on routine optic coherence tomography (OCT) also in this patient, indicating that it might indeed present a relatively universal diagnostic biomarker for ARSACS. In sum, our findings extend the geographical distribution of ARSACS to even very remote tribal regions in Asia (such as the Rajouri region of J&K, India) and extend the mutational and imaging spectrum of ARSACS. They provide further support that brain imaging and OCT markers might serve as diagnostic biomarkers for ARSACS in patients with novel SACS mutations, applicable even in remote regions of the world to identify and confirm ARSACS disease. [ABSTRACT FROM AUTHOR]