Abstract
Tay-Sachs disease (TSD) is a group of autosomal recessive lipid lysosomal storage disorders caused by mutations of the HEXA gene, which codes for the alpha subunit of the enzyme Hexosaminidase A, one of three enzymes responsible for the normal degradation of GM2 ganglioside, a substance found in high concentration in the plasma membrane of neuronal cells. The classic acute infantile form, discussed here, is a neurodegenerative disorder with onset at four to eight months of age in which acquired capabilities are lost and general neurologic deterioration occurs, with death by age two to four years. It occurs with highest frequency in the Ashkenazic Jewish and other select populations. Successful carrier testing and prenatal diagnosis is available. Treatment is symptomatic.
Tay-Sachs disease (TSD) is an autosomal recessive neurodegenerative disease and a lysosomal lipid storage disorder due to an abnormality of lipid metabolism caused by mutations of the gene coding for the alpha subunit of the enzyme Hexosaminidase A. Children with this condition appear clinically normal at birth but begin to display neurologic abnormalities that worsen over time. Eventually, overall deterioration, especially of respiratory function, leads to premature death.
The Enzyme
TSD is caused by an abnormal accumulation of GM2 ganglioside in the brain and other organs.
A ganglioside is a complex molecule composed of a glycosphingolipid (composed of a ceramide [a group of lipid molecules composed of sphingosine] [an 18 carbon amino alcohol] and a fatty acid)], plus an oligosaccharide [a sugar polymer containing from two to ten simple sugar residues]) and sialic acid (the most common of which is N-acetyl-neuraminic acid, a substituted monosaccharide with a nine carbon backbone) residues. They are found in the plasma membrane of cells, predominantly in the nervous system and are involved in modulating cell signal transduction events such as cell to cell contact, ion conductance, cellular recognition and cell to cell communication. The ganglioside involved in TSD is termed GM2. The “G” stands for “ganglioside”, the “M” indicates one (mono) sialic acid residue and the “2” indicates that it was the second monosialo-ganglioside described (Gravel, Kaback & Proia, 2001).
The enzymes responsible for the catabolism (breakdown or degradation) of GM2 ganglioside in the lysosomes are Hexosaminidase A, Hexosaminidase B and Hexosaminidase S. There are a number of different gene mutations that can cause abnormalities of GM2 degradation. In TSD, the enzyme Hexosaminidase A is affected. Hexosaminidase A is a dimer consisting of one alpha subunit and one beta subunit. In TSD, any of a number of mutations of the gene HEXA, the gene product of which is the alpha subunit of Hexosaminidase A, results in deficient or defective Hexosaminidase A. This results in accumulation of GM2 ganglioside in lysosomes, leading to formation of membranous cytoplasmic inclusion bodies (MCB’s) in neuronal cells. This in turn leads to unscheduled cell death and the symptoms of neurodegeneration described below (Kaback & Desnick, 2001).
There are several clinical disorders associated with mutations of the HEXA gene that are designated as types of TSD. These include the classic infantile acute, juvenile subacute, late infantile subacute-to-chronic and adult chronic forms. The remainder of this discussion will concern classic infantile acute TSD, also known as Type I GM2 gangliosidosis (Gravel et al., 2001).
Clinical Presentation
Classic infantile acute TSD is a neurodegenerative disease. It is particularly emotionally devastating because affected children seem quite normal at birth, only to begin showing neurologic manifestations at approximately three to five months of age that herald a progressive and inexorable downhill cause culminating in total dependency and death. Developmental milestones that have already been achieved, such as smiling, babbling, head lifting and reaching for objects, are performed less frequently until they are totally lost. New milestones are not achieved. Muscle weakness occurs. The patient becomes less and less interested in the environment. An increased sensitivity to sound, especially loud noises (hyperacusis), is characteristic of TSD. By the latter part of the first year of life, degeneration progresses more rapidly. Dysphagia (difficulty swallowing), blindness, seizures that are difficult to control, dementia and spasticity ensue. Death occurs on average between two and four years of age, usually from respiratory failure and pneumonia due to weakening of the diaphragm and other respiratory muscles (Kaback & Desnick, 2001).
Physical examination often reveals macrocephaly (increased head size) due to reactive cerebral gliosis (scarring and deposition of fibrous tissue due to the accumulation of GM2 ganglioside). Muscle spasticity (tightness) with joint contractures can be seen. The deep tendon reflexes (such as the patellar[knee] and Achilles tendon [ankle] reflexes are increased. Sustained ankle clonus (repeated beats of the foot after the Achilles tendon is tapped instead of one beat) may be seen. Funduscopic examination (examination of the back or fundus of the eye by looking through the pupil with an instrument called an ophthalmoscope) reveals a characteristic “cherry red spot”. This is located at the fovea, the central portion of the central vision area of the retina known as the macula. Actually, what is perceived as red is normal, but lipid filled ganglion cells form a grey-white halo around the fovea, making it appear more intensely red (Kaback & Desnick, 2001).
Genetics
TSD is an autosomal recessive condition. This means that either sex may be affected (autosomal) and that both parent s must pass on a mutated form of the HEXA gene in order to have an affected child (recessive).
The HEXA gene locus (position) is at 15q23-q24. This means that the gene is located on the long (“q”) arm of chromosome number 15 at the bands designated as 23 and 24. Every normal human has two chromosomes numbered 1 to 22 (the autosomes or non-sex chromosomes), plus two sex chromosomes (X and Y in a male, X and X in a female), for a total of 46 (the diploid number), in all nucleated cells of the body, with the exception of mature sperm and egg cells. Since genes are carried on the chromosomes, each parent has a pair of genes for each trait or gene product. Through the process of meiosis, a reduction division occurs whereby each mature sperm and egg cell has only one member of each chromosome (and thus gene) pair, for a total of 23 (the haploid number). When fertilization ((joining of a sperm and egg cell) occurs, the diploid number (46) of chromosomes is restored in the zygote (which becomes an embryo, fetus and newborn). Therefore, each parent, contributing only one chromosome number 15 to their child, contributes only one copy of the HEXA gene. In TSD, as in all autosomal recessive conditions, each parent carries one abnormal (mutated) gene for the condition. Because the condition is recessive, however, meaning that two abnormal genes (alleles, or members of a gene pair) are necessary in order to manifest the condition, the carrier parent does not manifest any signs of the disease. Since each parent will contribute only one chromosome number 15 and thus one HEXA allele, each parent has a 50 % chance to pass on the mutant allele of the HEXA gene. The chance that both parents pass on the mutant allele in the same pregnancy is 50 % x 50 % or 25 %. Therefore, when each parent is a TSD carrier, there is a ¼ chance with each pregnancy of having an affected child (Kaback & Desnick, 2001).
The HEXA gene measures 35 kb (35,000 base pairs). Over 100 mutations of this gene have been described, 70 % of which cause the classic acute infantile form of TSD. In this form, there is virtually no Hexosaminidase A enzyme activity (0.1% of normal). In the most common mutations, virtually none of the enzyme is produced (as opposed to other mutations with which the enzyme is produced but is misshapen and functionally inactive) (Chin, Bean, Coffee & Hegde, 2009).
Historically, TSD was thought of as a disease of mainly the Ashkenazic (Eastern European) Jewish population, with the carrier frequency for a mutated HEXA gene being 1/25 to 1/30 (as compared with a general population carrier frequency of 1/283), with an incidence of TSD of between1/2,500 to 1/3,600 pregnancies (as compared with an incidence of 1/320,000 in the general population). This is calculated as follows: the chance that both parents are carriers, based upon the general population carrier frequency, is 1/25 x 1/25 = 1/625, multiplied by ¼ (the chance of a mutated allele being passed on by both parents in any given pregnancy) = 1/2,500 (a similar calculation using a carrier frequency of 1/30 gives an incidence of 1/3,600). When the Ashkenazic community recognized the burden of this uniformly fatal condition, a concerted effort was made to identify carriers (see below for a discussion of carrier testing). This effort resulted in a reduction of TSD incidence of 90 % (Langlois & Wilson, 1998).
Further study revealed that it was not only the Ashkenazic Jewish population that had a carrier frequency significantly increased above that of the general population. The carrier frequency among French Canadians of the eastern St. Lawrence River Valley region of the province of Quebec, Louisiana Cajuns, certain ethnic groups of the Cordoba region of Argentina and the Pennsylvania Dutch are similar or higher than that seen in the Ashkenazic population (Langlois & Wilson, 1998).
Carrier Testing
Carrier testing is recommended for Ashkenazic Jews and members of other high-risk populations. This can be accomplished by measuring Hexosaminidase A activity in serum in males and in females who are not pregnant and who are not taking oral contraceptives (serum levels are affected by pregnancy and oral contraceptives). For pregnant women or those using oral contraceptives, carrier testing can be accomplished by measuring enzyme activity in white blood cells (this is also done for individuals whose enzyme activity levels are in the inconclusive range in serum). Approximately 50 % of carriers can be detected by measuring enzyme activity, but when this testing is couple with DNA mutation analysis, the rate increases to 98 %. In these individuals, DNA studies to identify the mutation should be done, as well as to identify so-called “pseudodeficiency alleles” (which show decreased enzyme activity against the artificial substrate used in testing but normal activity against actual GM2 ganglioside in the brain) that do not cause disease. Prenatal diagnosis can be offered when both members of a couple are found to be carriers and can be performed in amniocytes and chorionic villus cells (Langlois & Wilson, 1998).
Diagnosis
The diagnosis of TSD can be strongly suspected based upon ethnic background and the characteristic onset of neurodegeneration at three to five months of age. The diagnosis can be confirmed by Hexosaminidase A enzyme activity testing and mutation analysis of the HEXA gene. MRI scanning of the brain may show atrophy of the cerebellum. Electromyography (EMG) shows atrophy of muscle due to loss of innervations. A rectal biopsy will show membranous cytoplasmic body (MCB) accumulation with swelling of ganglion cells (Gravel et al., 2001).
Treatment
There is no specific treatment or cure for TSD. Enzyme replacement has not been successful so far. Treatment is aimed at symptoms. Nutrition and hydration should be maintained. Seizure medications should be used, although they may become ineffective later in the course of the disease. The airway should be kept clear of secretions and antibiotics should be used for respiratory and other infections (Gravel et al., 2001).
References
Chin, E., Bean, L., Coffee, B. & Hegde, M.R. (2009). Novel human pathological mutations.
Gene symbol: HEXA. Disease: Tay-Sachs disease. Human Genetics, 126, 329.
Gravel, R.A., Kaback, M.M. & Proia, R.L. (2001). The GM2 gangliosidoses. In C.R. Scriver,
A.L. Beaudet & W.S. Sly (Eds.), The metabolic and molecular bases of inherited disease (Vol. 3) (8th ed.) (pp. 3827-3876). New York, NY: McGraw-Hill.
Kaback, M.M. & Desnick, R.J. (2001). Tay-Sachs disease: from clinical description to molecular
defect. Advances in Genetics, 44, 1-9.
Langlois, S. & Wilson, R.D. (1998). Carrier screening for genetic disorders in individuals of
Ashkenazi Jewish descent. Journal of Obstetrics and Gynaecology Canada, 28, 324-342.
