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Description
A 47-year-old Caucasian man of non-consanguineous parents presented with a slowly progressive gait disorder and falls. Disease manifestations were present since early childhood with mild motor and mental retardation. Slowly progressive cerebellar ataxia, proximal muscle weakness and atrophy, mild cognitive decline and incomplete ophthalmoplaegia developed in late adolescence. At the time of presentation, he was still able to walk unaided for short distances. MRI of the brain (figure 1A, B) revealed marked cerebellar atrophy. The brainstem appeared unaltered. There were no white matter abnormalities. Nerve conduction studies were normal. Electromyography (EMG; figure 1C) and muscle biopsy revealed signs of chronic denervation reminiscent of lower motor neuron degeneration (or anterior horn disease). Neurological examination and magnetic motor test evoked potentials revealed accompanying pyramidal tract dysfunction. The β-hexosaminidase A activity was detectable, but significantly reduced (0.02 E405 nm/106 cells; normal activity >0.3 E405 nm/106 cells). Genetic testing revealed two known mutations in the β-hexosaminidase A (HEXA)-gene (c.805G>A; p.G269S and c.1274_1277dupTATC; p.Y427lfsX5,1–2), confirming the diagnosis of late onset Tay-Sachs disease (or GM2 gangliosidosis, variant B). Compound heterozygosity was verified by genetic testing of the neurologically healthy mother and sister, who carried one of the two mutations each. Late-onset Tay-Sachs disease/GM2 gangliosidosis is frequently accompanied by psychiatric disease, which was absent in the present case.3 In adults with cerebellar atrophy and signs of anterior horn disease, diagnostic considerations should include late-onset Tay-Sachs disease/GM2 gangliosidosis even in the absence of Ashkenazi Jewish ancestry and psychiatric disease.
Learning points
In adults with cerebellar atrophy and signs of anterior horn disease, diagnostic considerations should include late-onset Tay-Sachs disease/GM2 gangliosidosis.
Late-onset Tay-Sachs disease/GM2-gangliosidosis can occur without any considerable psychiatric symptoms and outside Jewish populations.
Acknowledgments
The authors thank Professor Dr Ingeborg Krägeloh-Mann, Department of Paediatric Neurology, University Children’s Hospital, Tübingen, Germany, for analysis of the β-hexosaminidase activity; Dr Saskia Biskup, CeGaT GmbH, Tübingen, Germany, for performing the genetic testing and commenting on the manuscript; and Dr Matthias Synofzik, Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany, for helpful discussion of the case and commenting on the manuscript.
Footnotes
Contributors KMS was responsible for design and conceptualisation of the study and drafting the manuscript. JB and SG were involved in acquisition of data and revising the manuscript. DT was responsible for acquisition of data; conceptualisation and supervision of the study; revising the manuscript.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.