Unveiling an Uncommon Glucosylceramidase (GBA) Mutation: Gaucher Disease Due to p.Ser276Phe Substitution

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder resulting from pathogenic variants in the GBA1 gene, which encodes the enzyme glucocerebrosidase. We describe a child with neuropathic GD (type 3) associated with an uncommon GBA1 variant, p.Ser276Phe. A four-year-old girl, born to non-consanguineous parents, presented with gradually progressive neurological symptoms accompanied by systemic involvement. Examination revealed marked splenomegaly. Bone marrow biopsy demonstrated extensive infiltration by macrophages with characteristic wrinkled, fibrillary cytoplasm, partially replacing the marrow spaces, raising suspicion of GD. Antiepileptic therapy with levetiracetam resulted in partial improvement of neurological manifestations. Whole-exome sequencing identified a homozygous missense variant in exon 7 of the GBA1 gene, leading to the substitution of phenylalanine for serine at codon 276, within the PF07714 protein kinase domain. On follow-up at six months, the child continued to exhibit myoclonic jerks, progressive ataxia, and cognitive decline, consistent with a neuropathic disease course. While p.Leu483Pro is the most frequently reported mutation in the Indian population and is often associated with severe neurological disease in homozygous individuals, the p.Ser276Phe variant has been documented only rarely in the literature. This case highlights an uncommon GBA1 mutation and further illustrates the wide phenotypic variability and unpredictable clinical expression seen in neuropathic GD.