Tay Sachs Disease

Tay-Sachs disease exemplifies GM2 gangliosidosis. The disease has a predilection for the Ashkenazi Jewish population. Distinct clinical features are a fine complexion; regression of psychomotor functions; visual impairment, rapidly progressing to blindness; a cherry red spot at the macula; startle reactions, particularly to sound; seizures; and macrocephaly in the late course of the

TABLE 9.3.

GM2 Gangliosidosis

Diseases

Enzyme Deficiency

Gene Symbol

Gene Locus

Tay-Sachs disease variant B Sandhoff's disease variant O

Variant AB

Hex A-a-subunit Hex A-P-subunit Hex B-P-subunit GM2 Activator-protein

HEX A HEX B

Chromosome S

Hex A, hexosaminidase A; Hex B, hexosaminidase B.

Tay Sachs Lamellar Bodies

FIGURE 9.2

Tay-Sachs disease. A first-born infant girl of healthy Ashkenazi Jewish parents developed normally up to 6 months of age, when she became listless and unresponsive to her environment. A few months later, cherry red spot of the macula was diagnosed. She startled in response to all stimuli and developed seizures. She steadily regressed to a vegetative state and, at 20 months of age, she died. A. The brain is large, weighing 1,400 g. B. Frozen section of the cerebral cortex shows accumulation of glycolipids in the neurons (oil-red O stain). C. Cerebellum shows Purkinje cell losses and expansion of empty-appearing dendrites due to extraction of lipids during tissue processing (Bodian stain). D. Autonomic ganglia in rectal mucosa contain lipid material (Oil-red O). E. Schematic drawing of concentric lamellar bodies, the EM appearance of storage material.

disease. MRI may demonstrate hyperintensities in the basal ganglia and thalami in early stage of the disease. By the age of 18 to 36 months, the disease is inevitably fatal.

The rare late infantile, juvenile, and adult variants of GM2 gangliosidosis present with psychomotor regres sion; mental decline, slowly progressing to dementia; seizures; and neurologic deficits. The clinical course is protracted.

Pathology: Grossly, the brain is large and heavy, weighing 1,200 to 1,400 g (Fig. 9.2). The ventricles are enlarged, and the central hemispheric white matter is soft. Histologically, the neurons throughout the nervous system are markedly swollen, ballooned with the Nissl substance, and the nucleus displaced to the periphery. The stored material stains positively for lipids with oil-red O and Luxol fast blue, and for sugar with PAS reagent. Under the electron microscope, the stored material appears as concentric membranous cytoplasmic bodies (MCBs) with a homogenous or finely granular center (see Fig. 9.2). In time, the distended neurons burst and disintegrate, leaving empty spaces. Macrophages remove the debris while reactive astrocytes replace the neuronal losses. The hemispheric white matter shows variable degrees of failure of myelination and/or demyelination.

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