Center for Jewish Genetic Diseases

Diseases: Tay-Sachs Disease

ay-Sachs disease is the most well known Jewish genetic disease, potentially affecting one in every 2,500 Ashkenazi Jewish newborns. Two forms of this disease occur in Ashkenazi Jews, the well known infantile-onset form and a lesser known, late-onset or adult form designated "chronic GM2-gangliosidosis".

Infantile Tay-Sachs Disease
This disease is characterized by the onset of severe mental and developmental retardation during the first four to eight months of life. An early sign of the disease is the cherry-red spot, an unusual abnormality in the retina of the eye observed only by use of an ophthalmoscope. The involvement of the central nervous system progresses rapidly and affected children become totally debilitated by two to five years of life. Affected children also develop seizures which are not controllable with anti-epileptic drugs. Death usually occurs by three to five years of life due to pneumonia or other infections.

Tay-Sachs disease is an inherited metabolic disorder. The basic defect in affected children is the deficiency of an enzyme, Beta-hexosaminidase A. This enzyme normally breaks down a naturally occurring fatty substance called GM2-ganglioside. The enzyme deficiency leads to a toxic accumulation of GM2-ganglioside in the cells of the nervous system. The gene for hexosaminidase A has been isolated on chromosome 15 and several specific mutations which cause infantile Tay-Sachs disease in Ashkenazi Jewish individuals have been identified.

Tay-Sachs disease is inherited in an autosomal recessive manner. Each parent of an affected child is a carrier of the disease. For such a "carrier couple," there is a 1 in 4 (25%) chance in each pregnancy to have an affected child. Although Tay-Sachs disease may occur in families of different ethnic backgrounds, it is significantly more common among Ashkenazi Jews. It is estimated that approximately 1 in 25 Ashkenazi Jews are carriers of Tay-Sachs disease. At present no treatment is available for Tay-Sachs disease. Therefore, emphasis has been placed on public education, carrier screening, and prenatal diagnosis for the prevention of this devastating disease.

Measurement of hexosaminidase A activity in plasma or white blood cells can reliably determine if an individual is a carrier of Tay-Sachs disease. In some instances it may also be important to confirm carrier status by performing gene mutation analysis. The ability to identify carriers reliably by both enzyme and gene mutation analyses has led to large-scale screening programs designed to prospectively (prior to pregnancy) identify carriers, and in particular, couples in which both spouses are carriers of gene mutations. Such carrier detection programs have become the prototype for prevention of genetic disease. To date, Tay-Sachs screening programs have detected over 38,000 carriers, or one in approximately every 25 Jewish individuals tested. More importantly, almost 1,100 carrier couples have been identified and counseled as to their 25% chance to have an affected child. Since prenatal diagnosis for this disease is available and quite reliable, these couples have the option to have unaffected children. Prenatal diagnosis is made possible by performing either CVS or amniocentesis. To date, over 2,500 pregnancies have been monitored.

Chronic GM2-gangliosidosis
A late-onset form of hexosaminidase A deficiency occurs in adolescents and adults of Ashkenazi Jewish ancestry. This disorder, called chronic (or adult) GM2-gangliosidosis, or late-onset Tay-Sachs disease (LOTS), has been detected in over 30 individuals from Ashkenazi Jewish families residing in both the United States and Israel. Onset of the disease occurs during childhood or adolescence and is characterized by poor coordination, tremor, and/or slurred speech. Because adult-onset Tay-Sachs may be confused with other disorders, some patients may have previously been misdiagnosed. These other disorders include Friedreich's ataxia, Kugelberg-Welander disease, and an amyotrophic lateral sclerosis-like disorder. With advancing age, patients develop neurologic symptoms including ataxia (inability to coordinate voluntary muscle movement), unsteady gait, muscle weakness, and slurred speech. In the fourth decade of life, mental and behavioral involvement may become evident.

Chronic GM2-gangliosidosis is inherited in an autosomal recessive manner The mutation in the hexosaminidase A gene that causes this form of the disease in Ashkenazi individuals has been identified. Carriers and affected individuals can be diagnosed by the deficiency of the enzyme, hexosaminidase A, or by demonstration of the specific gene mutation. Today most carriers for this form of hexosaminidase A deficiency are detected during mass-screening programs for infantile-onset Tay-Sachs disease.