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Neurological manifestations in Pakistani lysosomal storage disorders patients and molecular characterization of Gaucher disease

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.