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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]

Advent of new sequencing technologies and modern diagnostic procedures has opened the door for a deeper understanding of disorders about which little was known previously. Discovery of novel genes, new genetic variants in previously known genes and better techniques of functional validation has immensely contributed to unraveling the molecular basis of genetic disorders. Availability of knockout animal models like the zebrafish and gene editing tools like CRISPR-Cas9 has elucidated the function of many new genes and helped us to better understand the functional consequences of various gene defects. This has also led to better diagnosis and therapeutic interventions. In this context, a good body of research work has been done on X-linked recessive disorders with ocular findings. This review will focus on ocular and genetic findings of these rare disorders. To our knowledge, this is the first comprehensive review encompassing ocular and genomic spectrum of X-linked recessive disorders. [ABSTRACT FROM AUTHOR]

Epigenetics is a powerful regulator of gene expression. With advanced discoveries in underlying molecular mechanisms that can alter chromatin response to internal and external signals, epigenetic alterations have been implicated in various developmental pathways and human disorders. The extent to which this epigenetic effect contributes to eye development and progression of ocular disorders is currently less defined. However, emerging evidence suggests that epigenetic changes are relevant in the development of eye and ocular disorders like pterygium, age-related macular degeneration, glaucoma and more. This brief review will discuss the relevance of epigenetic mechanisms like DNA methylation, histone modifications, polycomb proteins and noncoding RNAs in the context of eye development and selected ocular disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)