This is an autosomal recessive disease, mostly of Jewish infants of eastern European (Ashkenazic) background. The first description came from Tay, a British ophthalmologist, in 1881, and Sachs, an American neurologist, in 1887; they called it amaurotic family idiocy. The disease becomes apparent in the first weeks and months of life, almost always by the fourth month. The first manifestations are a regression of motor activity and an abnormal startle to acoustic stimuli, accompanied by listlessness, irritability, and poor reactions to visual stimuli. These are followed by a progressive delay in psychomotor development or regression (by 4 to 6 months), with inability to roll over and sit. At first, axial hypotonia is prominent, but later spasticity and other corticospinal tract signs and visual failure become evident. Degeneration of the macular cells exposes the underlying red vascular choroid surrounded by a whitish gray ring of retinal cells distended with ganglioside. The resulting appearance is of the cherry-red spot with optic atrophy (Fig. 36-1). These are observed in the retinas in more than 90 percent of patients (but are also characteristic of other storage diseases—see Table 36-4). In the second year, there are tonic-clonic or minor motor seizures and an increasing size of the head and diastasis of sutures with relatively normal-size ventricles; in the third year, the clinical picture is one of dementia, decerebration, and blindness. Cachexia becomes increasingly severe and death occurs at 2 to 4 years. The electroencephalogram (EEG) becomes abnormal in the early stages (paroxysmal slow waves with multiple spikes). Occasionally, one can find basophilic granules in leukocytes and vacuoles in lymphocytes. There are no visceral, skeletal, or bone marrow abnormalities by light microscopy.
The basic enzymatic abnormality is a deficiency of beta hexosaminidase A, which normally cleaves the
N-acetylgalactosamine from gangliosides. As a result of this deficiency, GM2 ganglioside accumulates in the cerebral cortical neurons, Purkinje cells, retinal ganglion cells, and, to a lesser extent, larger neurons of the brainstem and spinal cord. The enzymatic defect can be found in the serum, white blood cells, and cultured fibroblasts from the skin or amniotic fluid, the latter giving parents the option of abortion to prevent a presently untreatable and fatal disease. Testing for hexosaminidase A also permits the detection of heterozygote carriers of the gene defect. Detection of this enzyme defect is complicated by the fact that more than 50 mutations of the HEXA gene have been isolated, coding for alpha subunit of the beta hexosaminidases and the enzyme itself is normal in one form of activator enzyme deficiency. Only three mutations account for 98 percent of the form that is common in individuals of Jewish ancestry.
The brain is large, sometimes twice the normal weight. In addition, there is a loss of neurons and a reactive gliosis; remaining nerve cells throughout the CNS are distended with glycolipid. Biopsies of the rectal mucosa disclose glycolipid distention of the ganglion cells of the Auerbach plexus. In the past, this was used as a diagnostic method but has been obviated by prenatal and neonatal screening. Under the electron microscope, the particles of stored material appear as membranous cytoplasmic bodies. Retinal ganglion cells are distended with the same material and, together with fat-filled histiocytes, cause the whitish gray rings around the fovea, where there are no nerve cells, as noted above.
Tay-Sachs disease is untreatable but can be prevented by testing all individuals of Jewish origin for the recessive trait. Where screening has been instituted the disease has become virtually eliminated.
In Sandhoff disease, which affects infants of non-