by Alexander Kurz

General outline

Sandhoff disease is an autosomal recessive neurodegenerative disorder characterised by an accumulation of GM2 gangliosides, particularly in neurons, and is clinically indistinguishable from Tay-Sachs disease.

The biochemical deficit is the absence of beta hexosaminidase A and B activity which results in the abnormal sotrage of GM2 gangliosides.

Neurodegeneration begins in infancy and leads to death generally by 4 – 6 years of age. The ganglioside, which is abnormally stored, is different from Tay-Sachs disease. There are infantile, late infantile, juvenile, and adult variants of generalised gangliosidosis.

Synonyms

GM2 gangliosidosis.

Symptoms and course

In the adult variant childhood development may be normal. In early adulthood patients may develop impairment in articulation or stuttering, and in limb coordination, hyperactive deep tendon reflexes, progressive dysarthria, moderate ataxia, and intention tremor. Intellectual impairment is usually mild.

Neurodegeneration begins in infancy and leads to death generally by 4 – 6 years of age.

Causes and risk factors

While Tay-Sachs disease results from a mutation in tha alpha subunit of the hexosaminidase gene (hex A), Sandhoff disease is caused by mutaion in the beta subunit of the hexosaminidase A (15q23-q24, leading to a partial deficit of the enzyme) and B (5q11) enzymes. Therefore, hxosaminidases A and B are both deficient in Sandhof disease.

Diagnostic procedures

The diagnosis is established by an enzymatic test.

Care and treatment

Most research effort has focused on strategies for augmenting enzyme levels to compensate for the underlying defect. These include bone marrow transplantation, enzyme replacementt, and gene therapy. An alternative strategy is substrate deprivation which aims at balancing the rate of ganglioside synthesis with the impaired rate of ganglioside breakdown. Studies in humans are planned.

Available services

Neurology and pediatrics departments.

References

• Bolhuis, P. A.; Oonk, J. G. W.; Kamp, P. E.; Ris, A. J.; Michalski, J. C.; Overdijk, B.; Reuser, A. J. J. : Ganglioside storage, hexosaminidase lability, and urinary oligosaccharides in adult Sandhoff's disease. Neurology 37: 75-81, 1987
• Chamoles, N. A.; Blanco, M.; Gaggioli, D.; Casentini, C. : Tay-Sachs and Sandhoff diseases: enzymatic diagnosis in dried blood spots on filter paper: retrospective diagnoses in newborn-screening cards. Clin. Chim. Acta 318: 133-137, 2002
• Myerowitz R, Lawson D, Mizukami H, Mi Y, Tifft CJ, Proia RL. Molecular pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene expression profiling. Hum Mol Genet. 2002;11(11):1343-50
• O'Brien, J. S. : Ganglioside storage diseases. In: Harris, H.; Hirschhorn, K. : Advances in Human Genetics. New York: Plenum Press (pub.) 3 1972. Pp. 39-98
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• Sandhoff K. The GM2-gangliosidoses and the elucidation of the beta-hexosaminidase system. Adv Genet. 2001;44:67-9
• Suzuki, K.; Suzuki, K.; Rapin, I.; Suzuki, Y.; Ishii, N. : Juvenile Gm(2)-gangliosidosis. Clinical variant of Tay-Sachs disease or a new disease. Neurology 20: 190-204, 1970