GM2-Activator Deficiency Mimics Tay–Sachs Disease
Clinical Case: We report the case of a 14-month-old girl of consanguineous parents who primarily showed normal development after uneventful ICSI pregnancy. From the age of 10 months onward, development stagnated with no signs of locomotion nor speech. Neurological examination showed muscular hypotonia, reduced facial expression and adynamia, but normal tendon reflexes; length, weight, and head-circumference were normal. The girl then developed audiogenic startles, severe epilepsy, and developmental regression resulting in loss of motor and cognitive abilities.
Diagnosis: Abdominal ultrasound, an initial EEG and blood tests including levels of lysosomal enzymes were normal. Cerebral MRI showed a slight hyperintension of basal ganglia and thalamus. Fovea centralis of the retina showed a cherry red spot. Clinical features were suspicious for GM2 gangliosidosis, particularly for an infantile Tay–Sachs disease (TSD), alternatively for Sandhoff disease, but enzyme activities for Hex A and Hex B were normal, and no pathogenic mutation of the corresponding genes were found. Diagnosis was done by detection of a homozygous mutation (c.369_371delinsATTAA p.Pro124Leufs*48) in the GM2A gene (5q33.1), coding for the intralysosomal glycoprotein (GM2 activator) that is required for the degradation of GM2 ganglioside. Activator-deficient TSD (AB variant) is an extremely rare form of infantile GM2 ganglioside storage disorder.
Conclusion: The phenotype of activator-deficient TSD is identical to that of classic TSD. If the clinical symptoms and MRI findings suggest the diagnosis of TSD or Sandhoff disease, but the enzyme levels of Hex A and Hex B are normal, molecular genetic investigation of the GM2A gene should be performed.
Keywords: GM2 gangliosidosis, Tay–Sachs disease, Hex A deficiency, GM2 activator deficiency, GM2A gene.