GM2-gangliosidosis, AB variant is an extremely rare autosomal recessive inherited disorder caused by mutations in the GM2A gene that encodes
GM2 ganglioside activator
protein (GM2AP). GM2AP is necessary for solubilisation of
GM2 ganglioside in endolysosomes and its presentation to β-
hexosaminidase A. Conversely GM2AP deficiency impairs lysosomal catabolism of
GM2 ganglioside, leading to its storage in cells and tissues. We describe a 9-year-old child with an unusual juvenile clinical onset of GM2-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
GM2 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 GM2A: 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
GM2 ganglioside in the patient's fibroblasts was demonstrated by metabolic labeling with fluorescently labeled
GM1 ganglioside and by immunohistochemistry with anti-GM2 and anti-GM3
antibodies. Our observation expands the molecular and clinical spectrum of molecular defects linked to GM2-gangliosidosis and suggests novel diagnostic approach by whole exome sequencing and perhaps
ganglioside analysis in cultured patient's cells.