Abstract
Lysosomal storage disorders (LSDs) are a large group of inborn errors of metabolism each caused by genetic mutations of a particular lysosomal protein encoding gene. These inherited conditions are characterized by lysosomal dysfunction with wide variety of organ impact sometimes organ failure with growing age. Neurological complications in LSD cases range from severe neurodegenerations in 70% cases to mild symptoms or absence of neuropathy in others. Each LSD is monogenic but heterogeneous from a molecular standpoint with a large number of mutations described in the respective gene. Some mutations are particular to specific populations, reflecting consequences of founder effect. Present study aimed to access the demographic and clinical profiles of forty-five LSD affected families enrolled during January 2018 to December 2019 at local hospitals to find out neurological symptoms in Pakistani LSD cases. Furthermore, molecular genetic analysis of Gaucher's disease affected families was performed to unveil underlying disease causing mutation/s. Neurological manifestations were present in twenty-eight families including eleven Mucopolysaccharidosis-1 (MPS-I), four Gaucher's disease (GD) and all MPS-II, MPS-III, Niemann-Pick, Griscelli and Chediak-Higashi cases. Neurological involvement was not found in eight MPS-I, one GD, all MPS-IV and Pycnodysostosis affected families. Screening of GBA gene in GD families revealed a reported missense mutation p.L483P in all analyzed families. Clinical heterogeneity of MPS-1 and GD is evident from literature however mutational analysis of all enrolled GD families depicted segregation of a reported missense variant p.L483P of GBA gene with disease phenotype in all families. Our findings highlight importance of homeostatic role of lysosomes in neuronal development as twenty eight out of forty families had neurological manifestations. Furthermore, identification of same mutation in GD patients with or without neuronal involvement may be related to some unknown differences in the expression of genetic modifiers or exposure to environmental triggers.