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A rare disorder characterized by accumulation of G2 gangliosides due to hexosaminidase A deficiency.
ORPHA:845Classification level: Disorder
The prevalence of the disease is 1 case per 320 000 live births.
Three variants have been described according to age of onset. The infantile form (type 1) begins between 3 and 6 months of age. The earliest sign is an incessant startle response to noise. Psychomotor retardation appears after the age of 8 months with hypotonia, amaurosis, and megalencephaly. A cherry-red macular spot may be found but is not specific. Muscular weakness progresses and leads to paralysis. The disorder degenerates into a state of decerebration and is fatal during childhood. Enzymatic activity of the hexosaminidase A is either extremely low or totally absent in leucocytes and cultured in fibroblasts obtained by skin biopsy. In the juvenile form (type 2), onset is between ages 2 and 6 with locomotor ataxia, behavioural disorders, and progressive loss of intellectual capacities, leading to a state of decerebration and death at around the age of 15. The decrease in hexosaminidase A activity is less pronounced than in the infantile form. The adult or chronic form (type 3) may begin around the age of 10, but often the disorder is not diagnosed until adulthood. Two different clinical forms exist. The first is similar to atypical Friedreich disease, with spinocerebellar ataxia but no cardiac or osseous signs, such as scoliosis or flat feet. The second is that of juvenile spinal amyotrophy resembling Kugelberg-Welander's syndrome. Mental capacities and behaviour may or may not be affected. Hexosaminidase A deficiency is found.
The causative gene (HEXA) encodes the alpha subunit of hexosaminidase A and is located on chromosome 15(15q23).
Screening of heterozygous individuals is available and recommended in populations at increased risk of this disorder (individuals of Ashkenazi Jewish descent). Two variants of the disease have been reported. In GM2 gangliosidosis, variant B1, clinical signs are identical to those found in the juvenile and adult forms of variant B. Hexosaminidase A deficiency can only be detected with a specific artificial substrate, which differs from the one used for the B variant. GM2 gangliosidosis variant AB is Tay-Sachs-like, but hexosaminidase A activity is normal. The enzyme activator required for hydrolysing GM2 is deficient. The gene encoding this protein is located on chromosome 5 (5q31).
Prenatal diagnosis is available and recommended in populations at increased risk of this disorder.
Tay-Sachs disease is transmitted as an autosomal recessive trait.
Management and treatment
There is no efficient treatment for Tay-Sachs disease, but anti-epileptics can be prescribed. A treatment aimed at inhibiting gangliosides synthesis (Miglustat) is currently being investigated for the slowly progressive forms.
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