Rare Variant of GM2 Gangliosidosis due to Activator Protein Deficiency: A Case Report
Introduction: Disorders of degradation of GM2 gangliosides, as seen in Sandhoff and Tay–Sachs disease, are mainly caused by loss of function of hexosaminidase A or the hexosaminidases A + B. However, in rare cases, deficits of the GM2 activator protein encoded by the GM2AP gene, which is essential for the catalytic function of the hexosaminidases,1 have been identified as etiological factor.2 We report the case of a patient with the rare AB-variant of the disease and a genetic mutation (c.262_264delAAG p.Lys88del) showing a clinical course similar to infantile Tay–Sachs disease.
Case Report: A 16-month-old female patient, the first child of consanguineous parents of Turkish origin, was presented with ataxia and developmental stagnation since the age of 9 months. Cranial MRI (age, 14 months) and initial investigations of metabolic diseases showed no pathologic results apart from mildly elevated AST and LDH as well as mild hepatomegaly. History and clinical findings showed developmental regression. Visual- and auditory-evoked potentials confirmed pathologic sensory functions. Ophthalmologic examination revealed the landmark finding of a macular cherry red spot. Follow-up cMRI showed periventricular dysmyelinization. Enzyme activity of both hexosaminidase A and total hexosaminidase activity was normal. At the age of 20 months, the patient developed audiogenic cloni characteristic to Tay–Sachs disease. An analysis of the GM2AP gene revealed a homozygous deletion in exon 3 resulting in loss of a single lysin at position 88 and leading to impaired processing of the GM2 activator protein.
Currently, at the age of 23 months, the course of the encephalopathy in our patient is rapidly progressive with severe muscular hypotonia and visual loss.
Conclusion: Characteristic clinical findings of infantile Tay–Sachs disease, for example, audiogenic cloni and macular cherry red spot, may indicate to rare variants of the disease and should be considered in the broad differential diagnosis of progressive encephalopathy.
Keywords: GM2-gangliosidosis, AB variant, GM2 activator protein, Tay-Sachs' disease, macular cherry red spot, audiogenic.
References1 Sandhoff K, Harzer K. Gangliosides and gangliosidoses: principles of molecular and metabolic pathogenesis. J Neurosci 2013;33(25):10195–10208
2 Schepers U, Glombitza G, Lemm T, et al. Molecular analysis of a GM2-activator deficiency in two patients with GM2-gangliosidosis AB variant. Am J Hum Genet 1996;59(5):1048–1056