Atypical juvenile presentation of GM2 gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the GM2A gene

Abstract

G_M2-gangliosidosis, AB variant is an extremely rare autosomal recessive inherited disorder caused by mutations in the <i>GM2A</i> gene that encodes G_M2 ganglioside activator protein (GM2AP). GM2AP is necessary for solubilisation of G_M2 ganglioside in endolysosomes and its presentation to β-hexosaminidase A. Conversely GM2AP deficiency impairs lysosomal catabolism of G_M2 ganglioside, leading to its storage in cells and tissues. We describe a 9-year-old child with an unusual juvenile clinical onset of G_M2-gangliosidosis AB. At the age of 3 years he presented with global developmental delay, progressive epilepsy, intellectual disability, axial hypertonia, spasticity, seizures and ataxia, but without the macular cherry-red spots typical for G_M2 gangliosidosis. Brain MRI detected a rapid onset of diffuse atrophy, whereas whole exome sequencing showed that the patient is a compound heterozygote for two mutations in <i>GM2A</i>: a novel nonsense mutation, c.259G > T (p.E87X) and a missense mutation c.164C > T (p.P55L) that was recently identified in homozygosity in patients of a Saudi family with a progressive chorea-dementia syndrome. Western blot analysis showed an absence of GM2AP in cultured fibroblasts from the patient, suggesting that both mutations interfere with the synthesis and/or folding of the protein. Finally, impaired catabolism of G_M2 ganglioside in the patient's fibroblasts was demonstrated by metabolic labeling with fluorescently labeled G_M1 ganglioside and by immunohistochemistry with anti-G_M2 and anti-G_M3 antibodies. Our observation expands the molecular and clinical spectrum of molecular defects linked to G_M2-gangliosidosis and suggests novel diagnostic approach by whole exome sequencing and perhaps ganglioside analysis in cultured patient's cells.