PROGRESSIVE CEREBELLAR-ATAXIA, PROXIMAL NEUROGENIC WEAKNESS AND OCULAR MOTOR DISTURBANCES - HEXOSAMINIDASE-A DEFICIENCY WITH LATE CLINICAL ONSET IN 4 SIBLINGS

Tay-Sachs disease is a genetically determined neurodegenerative disord er, resulting from mutations of the hexosaminidase (Hex) A gene coding for the alpha-subunit of beta-D-N-acetyl-hexosaminidase. Clinically, there is severe encephalomyelopathy leading to death within the first few years of life. Hex A activity is usually absent in tissue and body fluids of these patients. Juvenile and adult Hex A deficiencies are l ess severe but rare variants with some residual Hex A activity. All th ese variants are most prevalent among Ashkenazi Jews. We describe a no n-Jewish family in which four adult brothers and sisters had markedly reduced Hex A activities and onset of symptoms in the second decade of life. The phenotypical expression was remarkably homogeneous, consist ing in a combination of slowly progressive motor neuron disease, ataxi a and ocular motor disturbances. None of the patients were demented at this stage of their illness. Magnetic resonance studies showed severe cerebellar atrophy, but were otherwise normal. Hex A deficiency was e stablished by biochemical measurements in the serum and skin fibroblas ts using the fluorogenic substrates 4-MUG and 4-MUGS as well as by gel electrophoresis. Molecular genetic studies revealed that the patients are compound heterozygotes for the 'adult' mutation Gly(269) --> Ser and the 'infantile' 4-base insertion in exon 11 of the Hex A gene. (C) 1997 Elsevier Science B.V.