Saturday 18 June 2005
Tay-Sachs disease, the most common form of GM2 gangliosidosis, results from mutations that affect the α-subunit locus on chromosome 15 and cause a severe deficiency of hexosaminidase A. This disease is especially prevalent among Jews, particularly among those of Eastern European (Ashkenazic) origin, in whom a carrier rate of 1 in 30 has been reported.
Tay-Sachs disease is caused by mutation in the alpha subunit of the hexosaminidase A gene (HEXA) (MIM.606869)
Tay-Sachs Disease (GM2 Gangliosidosis: Hexosaminidase α-Subunit Deficiency)
The hexosaminidase A is absent from virtually all the tissues that have been examined, including leukocytes and plasma, and so GM2 ganglioside accumulates in many tissues (e.g., heart, liver, spleen), but the involvement of neurons in the central and autonomic nervous systems and retina dominates the clinical picture.
On histologic examination, the neurons are ballooned with cytoplasmic vacuoles, each of which constitutes a markedly distended lysosome filled with gangliosides.
Stains for fat such as oil red O and Sudan black B are positive. With the electron microscope, several types of cytoplasmic inclusions can be visualized, the most prominent being whorled configurations within lysosomes composed of onion-skin layers of membranes.
In time, there is progressive destruction of neurons, proliferation of microglia, and accumulation of complex lipids in phagocytes within the brain substance. A similar process occurs in the cerebellum as well as in neurons throughout the basal ganglia, brain stem, spinal cord, and dorsal root ganglia and in the neurons of the autonomic nervous system.
The ganglion cells in the retina are similarly swollen with GM2 ganglioside, particularly at the margins of the macula. A cherry-red spot thus appears in the macula, representing accentuation of the normal color of the macular choroid contrasted with the pallor produced by the swollen ganglion cells in the remainder of the retina. This finding is characteristic of Tay-Sachs disease and other storage disorders affecting the neurons.