• Lysosomal storage disease
• Ethnic variation in allele frequencies
• Genetic drift
• Population screening
Major Phenotypic Features
• Age at onset: Infancy through adulthood
• Retinal cherry-red spot
History and Physical Findings
R.T. and S.T., an Ashkenazi Jewish couple, were referred to the genetics clinic for evaluation of their risk for having a child with Tay-Sachs disease. S.T. had a sister who died of Tay-Sachs disease as a child. R.T. had a paternal uncle living in a psychiatric home, but he did not know what disease his uncle had. Both R.T. and S.T. had declined screening for Tay-Sachs carrier status as teenagers. Enzymatic carrier testing showed that both R.T. and S.T. had reduced hexosaminidase A activity. Subsequent molecular analysis for HEXA mutations predominant in Ashkenazi Jews confirmed that S.T. carried a disease-causing mutation, whereas R.T. had only a pseudodeficiency allele but no disease-causing mutation.
Disease Etiology and Incidence
Tay-Sachs disease (MIM 272800), infantile GM2 gangliosidosis, is a panethnic autosomal recessive disorder of ganglioside catabolism that is caused by a deficiency of hexosaminidase A (see Chapter 12). In addition to severe infantile-onset disease, hexosaminidase A deficiency causes milder disease with juvenile or adult onset.
The incidence of hexosaminidase A deficiency varies widely among different populations; the incidence of Tay-Sachs disease ranges from 1 in 3600 Ashkenazi Jewish births to 1 in 360,000 non–Ashkenazi Jewish North American births. French Canadians, Louisiana Cajuns, and Pennsylvania Amish have an incidence of Tay-Sachs disease comparable to that of Ashkenazi Jews. The increased carrier frequency in these four populations appears to be due to genetic drift, although heterozygote advantage cannot be excluded (see Chapter 9).
Gangliosides are ceramide oligosaccharides present in all cell surface membranes but most abundant in the brain. Gangliosides are concentrated in neuronal surface membranes, particularly in dendrites and axon termini. They function as receptors for various glycoprotein hormones and bacterial toxins and are involved in cell differentiation and cell-cell interaction.
Hexosaminidase A is a lysosomal enzyme composed of two subunits. The α subunit is encoded by the HEXA gene, and the β subunit is encoded by the HEXB gene. In the presence of activator protein, hexosaminidase A removes the terminal N-acetylgalactosamine from the ganglioside GM2. Mutations of the α subunit or the activator protein cause the accumulation of GM2 in the lysosome and thereby Tay-Sachs disease of the infantile, juvenile, or adult type. (Mutation of the β subunit causes Sandhoff disease [MIM 268800].) The mechanism by which the accumulation of GM2 ganglioside causes neuronal death has not been fully defined, although by analogy with Gaucher disease (see Chapter 12), toxic byproducts of GM2 ganglioside may cause the neuropathology.
The level of residual hexosaminidase A activity correlates inversely with the severity of the disease. Patients with infantile-onset GM2 gangliosidosis have two null alleles, that is, no hexosaminidase A enzymatic activity. Patients with juvenile- or adult-onset forms of GM2 gangliosidosis are usually compound heterozygotes for a null HEXA allele and an allele with low residual hexosaminidase A activity.
Phenotype and Natural History
Infantile-onset GM2 gangliosidosis is characterized by neurological deterioration beginning between the ages of 3 and 6 months and progressing to death by 2 to 4 years. Motor development usually plateaus or begins to regress by 8 to 10 months and progresses to loss of voluntary movement within the second year of life. Visual loss begins within the first year and progresses rapidly; it is almost uniformly associated with a cherry-red spot on funduscopic examination (Fig. C-43). Seizures usually begin near the end of the first year and progressively worsen. Further deterioration in the second year of life results in decerebrate posturing, swallowing difficulties, worse seizures, and finally an unresponsive, vegetative state.
FIGURE C-43 Cherry-red spot in Tay-Sachs disease. Right, Normal retina. The circle surrounds the macula, lateral to the optic nerve. Left, The macula of a child with Tay-Sachs disease. The cherry-red center is the normal retina of the fovea at the center of the macula that is surrounded by a macular retina made white by abnormal storage of GM2 in retinal neurons. See Sources & Acknowledgments.
Juvenile-onset GM2 gangliosidosis manifests between 2 and 4 years and is characterized by neurological deterioration beginning with ataxia and uncoordination. By the end of the first decade, most patients experience spasticity and seizures; by 10 to 15 years, most develop decerebrate rigidity and enter a vegetative state with death generally occurring in the second decade. Loss of vision occurs, but there may not be a cherry-red spot; optic atrophy and retinitis pigmentosa often occur late in the disease course.
Adult-onset GM2 gangliosidosis exhibits marked clinical variability (progressive dystonia, spinocerebellar degeneration, motor neuron disease, or psychiatric abnormalities). As many as 40% of patients have progressive psychiatric manifestations without dementia. Vision is rarely affected, and results of the ophthalmological examination are generally normal.
The diagnosis of a GM2 gangliosidosis relies on the demonstration of both absent to nearly absent hexosaminidase A activity in the serum or white blood cells and normal to elevated activity of hexosaminidase B. Mutation analysis of the HEXA gene can also be used for diagnosis but is more typically only used to clarify carrier status and for prenatal testing.
Tay-Sachs disease is currently an incurable disorder; therefore, treatment focuses on the management of symptoms and palliative care. Nearly all patients require pharmacological management of their seizures. The psychiatric manifestations of patients with adult-onset GM2 gangliosidosis are not usually responsive to conventional antipsychotic or antidepressant medications; lithium and electroconvulsive therapy are most effective.
For potential parents without a family history of GM2 gangliosidosis, the empirical risk for having a child affected with GM2 gangliosidosis depends on the frequency of GM2 gangliosidosis in their ethnic groups. For most North Americans, the empirical risk for being a carrier is approximately 1 in 250 to 1 in 300, whereas individuals of Ashkenazi Jewish descent have an empirical carrier risk of 1 in 30. For couples who are both carriers, the risk for having a child with GM2 gangliosidosis is 25%.
Prenatal diagnosis relies on identification of the HEXA mutations or hexosaminidase A deficiency in fetal tissue such as chorionic villi or amniocytes. Effective identification of affected fetuses by HEXAmutation analysis usually requires that the mutations responsible for GM2 gangliosidosis in a family have already been identified.
Screening of high-risk populations for carriers and subsequent prevention has reduced the incidence of Tay-Sachs disease among Ashkenazi Jews by nearly 90% (see Chapters 12 and 18). Traditionally, such screening is performed by determining the serum activity of hexosaminidase A with an artificial substrate. This sensitive assay, however, cannot distinguish between pathological mutations and pseudodeficiency (reduced catabolism of the artificial substrate but normal catabolism of the natural substrate); therefore, carrier status is usually confirmed by molecular analysis of HEXA. Two pseudodeficiency alleles and more than 70 pathological mutations have been identified in the HEXA gene. Among Ashkenazi Jews who are positive by enzymatic carrier screening, 2% are heterozygous for a pseudodeficiency allele and 95% to 98% are heterozygous for one of three pathological mutations, two causing infantile-onset and one causing adult-onset GM2 gangliosidosis (see Chapter 12). In contrast, among non-Jewish North Americans who are positive by enzymatic carrier screening, 35% are heterozygous for a pseudodeficiency allele.
Questions for Small Group Discussion
1. Screening for what other diseases is complicated by pseudodeficiency?
2. What is genetic drift? What are causes of genetic drift? Name two other diseases that exhibit genetic drift.
3. Should population screening be instituted to identify carriers of other diseases?
4. What diseases are genocopies of adult-onset hexosaminidase A deficiency? Consider psychiatric disorders and adult-onset neuronal ceroid-lipofuscinosis. What diseases are genocopies of infantile-onset hexosaminidase A deficiency? Consider GM2 activator mutations. How would you distinguish between a genocopy and hexosaminidase A deficiency?
Bley AE, Giannikopoulos OA, Hayden D, et al. Natural history of infantile GM2 gangliosidosis. Pediatrics. 2011;128:e1233–e1241.
Kaback MM, Desnick RJ. Hexosaminidase A deficiency. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1218/.