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Tay-Sachs Disease
Salim Banbahji, Jay Leb, Matthew Vorsanger
Tay-Sachs Disease is an autosomal recessive neurodegenerative disorder that is
typically fatal within the first two or three years of life. Its incidence is highest among
Ashkenazi Jews (Jews of Eastern European descent), approximately 100 times higher
than in the general population. Juvenile and adult onset variants of the disease exist, but
are extremely rare and will not be discussed here. The disease was characterized by two
doctors working independently, resulting in its hyphenated name; a British physician
named Warren Tay, and an American physician named Bernard Sachs. Tay, an
ophthalmologist was, in 1881, the first to notice the characteristic red spot on the eye that
is now considered a typical finding in the disease. Sachs, researching independently from
Tay, began to characterize this syndrome, noting its familial characteristics and
propensity to appear in Jewish children. In addition to the ophthalmologic findings made
by Tay, Sachs, in 1887, characterized the disease as involving a halt to mental
development, a deficiency in normal reflexes, progressive blindness, paresis, and
mortality at about two years of age.1
Symptomology
A thorough understanding of the symptoms of the disease is essential for the
physician in order to arrive at a correct diagnosis. Symptoms typically found include
retardation beginning early in infancy followed by dementia, blindness, and paralysis.
Infantile Tay-Sachs usually proves to be fatal by the age of three.2
A study done by Rapin et al. in 1976, assessed the condition of a brother and two
sisters of Ashkenazi descent who were diagnosed with Tay-Sachs. Early in childhood, the
children lost their ability to walk and maintain posture. Furthermore they showed loss of
muscle mass, foot drop, muscle spasms, as well as loss of coordination in their trunk and
extremities. Although the muscle atrophy began in the lower limbs, it soon reached the
upper body, causing stuttering due to the denervation of laryngeal muscles. Furthermore,
a characteristic "cherry-red" spot in the back of their retina was discovered as a
consequence of the neural degeneration in the CNS. Although displaying many of the
signs of classical Tay-Sachs, these children did not display the usual loss of optic acuity
and intelligence. After one of the children died, biochemical studies showed that this
family did indeed have an allelic variant of the disease.2
Diagnosis, Testing, and Prevention
Tay-Sachs is most prevalent in the Ashkenazi Jewish population with a carrier
rate of 1 in 25, as opposed to the rate of 1 in 250 in the general population. This high
carrier rate has caused the Jewish population, in both Israel and around the world, to
place more emphasis on genetic screening and testing. In fact, Tay-Sachs screening in the
Jewish community is one of the first successes for genetic screening for a specific genetic
disorder. Carrier detection and prevention programs have proven dramatically effective
and have established the paradigm for the prevention of recessive diseases. “Since 1970,
more than 1.4 million individuals worldwide have been screened voluntarily to determine
if they are carriers of the mutant gene for Tay Sachs Disease.” In the United States alone,
the incidence of Tay Sachs in the Jewish population has decreased by more than ninety
percent.3 The diagram below clearly shows the dramatic difference genetic testing has
had in eliminating this disease.4
50
40
30
Jewish
Non-Jewish
20
10
0
19
80
19
82
19
83
19
84
19
85
19
87
19
89
19
90
19
91
19
92
Number of Affected Children
Impact of Carrier Testing for Tay-Sachs
Disease
Years
Kaback, Int J Technol Assess Health Care. 10:592-603, 1994
Individuals carrying Tay Sachs mutations show a reduced level of the enzyme
Hexosaminidase A which is essential for breaking down fatty substances in neural tissue.
As a result these lipid molecules build up in the CNS and gradually destroy neural
structures. A routine and inexpensive carrier test is a blood test measuring the level of
hexosaminidase activity.5
Besides enzyme assays of hexosaminidase A acitivity, diagnosis can also be done
via genetic testing using polymerase chain reaction. The latter method is used when the
anscestry of both parents is known. This allows for the detection of specific genetic
markers. Although it is more specific, it is also much more expensive. Prenatal diagnosis
is done when both parents are known to be carriers to assess whether the fetus is
homozygous for the mutant alleles. This then allows the parents to decide whether they
want to terminate the pregnancy should the fetus test positive.3
Besides enzyme assay activity and genetic screening, eye exams can also help in
the diagnosis of Tay Sachs. As mentioned above, affected individuals have a
characteristic “cherry red” spot in the eye due to the displacement of the optic nerve into
the orbit.6 In 1968, a study by Balint, et al., showed that homozygous affected and
heterozygous individuals had reduced levels of the lipid sphingomyelin, in their red blood
cells. Therefore measuring levels of this lipid in the blood gives us yet another
biochemical tool for detecting carriers.7
In some orthodox Ashkenazi Jews, a special screening program called Dor
Yeshorim screens individuals for the common Tay-Sachs mutant alleles to determine if
there is any risk they could have a child with Tay-Sachs. A marriage between two carriers
would result in a 25% chance that their child would be affected with Tay-Sachs. Because
of this, Dor Yeshorim strongly recommends against marriage between individuals who
are both carriers.8
Disease Risks for Other Family Members
As mentioned above, Tay-Sachs is inherited in an autosomal recessive pattern.
Only homozygotes for the mutant allele display the phenotype of Tay-Sachs. For a TaySachs child to be born, both parents have to be carriers of the mutant allele. If this is the
case, there is a 25% chance that this couple will have an affected child. However, two
thirds of the healthy children from these parents will still be heterozygous i.e. carriers for
the mutant allele. When a couple has a Tay-Sachs child, this indicates the presence of
mutant allele their family’s gene pool. This knowledge has a great effect on many
members of the family. The parents must be made aware that for each child there is a new
25% chance that the baby will have the disease. Furthermore, if each parent is a carrier
that means that this mutant allele can be found in one of their parents. So one of the
maternal grandparents and one of the paternal grandparents are carriers for the mutant
allele. Once we know that one grandparent from each set is a carrier we can then turn our
attention to all the aunts and uncles. Each aunt and uncle has a 50% chance of being a
carrier as they have a 50% chance of inheriting the mutant allele from their heterozygous
parent. This can affect their children if their mate is also a carrier. This knowledge can
prove crucial in family planning.
Biochemistry and Genetics
Tay-Sachs is classified as a lysosomal storage disease. The normal function of the
affected protein, β-hexosaminidase A, is to degrade a compound called GM2-ganglioside,
a fatty-acid derivative. Without this degradation, GM2-ganglioside builds up in the
lysosomes of neuronal tissue, leading to the neurodegenerative effects of the disease.
While massive neuronal apoptosis is observed in patients with Tay-Sachs, the exact
method through which the GM2-gangliosides cause this has yet to be determined. Gene
expression profiles in diseased individuals demonstrate the presence of an intense
inflammatory process. It is hypothesized that astrocytes and microglia become activated
in response to the initial neuronal damage to release inflammatory cytokines which
trigger the apoptosis present in this disorder.9
In the form of Tay-Sachs found in Ashkenazi Jews, the major defect is an
insertion in the α-chain of the gene for β-hexosaminidase A, also known as HEXA. The
disease is inherited in an autosomal recessive manner with the carriers displaying no
visible disease phenotype. As an autosomal recessive disease, the risk for two carrier
parents to have an affected child is one in four. Thanks to rigorous testing among the
Ashkenazi population, the number of affected children born to Ashkenazi families has
actually dropped below the number of affected children born to non-Ashkenazi families.
The high incidence of the mutation in the Ashkenazi Jewish population would seem to
indicate a founder effect, and in fact a single mutation appears to account for 70% of the
carriers in this population. This defect introduces a premature termination signal,
resulting in a deficiency of HEXA mRNA in affected individuals, most likely due to
nonsense-mediated decay.10 Unlike other recessive diseases with a high incidence in a
certain population (i.e. sickle cell anemia) no selective advantage of the heterozygous
state has been conclusively proven. However, some believe that the heterozygous state
may confer some resistance to tuberculosis.11 The underlying reason for the current
incidence and distribution of Tay-Sachs in the Ashkenazi Jewish population has
provoked a large amount of debate in the field. Some argue that the geographical
distribution of the disease is no different from any other disorder showing the signs of
founder effect and genetic drift.12 There are others who cite the high frequency of other
lysosomal storage disease among the Ashkenazi Jews as indirect proof that there must be
some selection advantage conferred by this trait.13
Treatment
At the present time there is no successful cure or treatment to halt the rapid
progression of Tay-Sachs disease. A number of different therapies are being evaluated;
however, none have proven effective in curing this devastating illness. Some of the
potential therapies currently under study are enzyme replacement, bone marrow
transplant, and gene therapy.
Enzyme replacement seems to be a logical solution to this problem and has
recently received a great deal of attention. As mentioned earlier, Tay-Sachs leads to the
storage of gangliosides, primarily in the lysosomes of neuronal cells. If the defective
enzymes in the CNS could be replaced, this abnormal storage of gangliosides should be
reduced. As simple as this may appear, it is far from an easy feat to accomplish. To be
successful, this therapy would require not only that catalytically active HEXA reach CNS
neurons, but also that defective cells be able to clear out the gangliosides that have
already accumulated to recover a normal phenotype.14 While effective in nonneurological diseases of lysosome storage, enzyme replacement therapy is still not a
viable option for Tay-Sach.15
Bone marrow transplant is another therapy that shows promise in treating TaySachs disease. Like enzyme replacement therapy, it has been able to correct similar
enzymatic defects in visceral tissue, but the same problem remains with targeting the
therapy to the CNS.16
Another option that is currently being investigated is gene therapy. Gene therapy
studies on mice with Sandhoff disease, which involves the loss of the β-chain of HEXA,
have shown promise in decreasing inflammation and GM2-ganglioside buildup in the
brain.17
With no cure currently available for Tay Sachs, treatment is restricted to
supportive care and the maintenance of comfort, by ensuring adequate nutrition and
hydration, treatment of infection, and control of seizures. In severe cases bowel
management is also a frequent problem.18
References
1. Filho JAF, Shapiro BE. Tay-Sachs disease. Arch Neurol 2004;61:1466-1468.
2. Rapin I, Suzuki K, Suzuki K, Valsamis MP. Adult (chronic) Gm2 gangliosidosis.
Arch. Neurol 1976;33:120-130.
3. Kaback MM. Population-based genetic screening for reproductive counseling: the
Tay-Sachs disease model. Eur J Pediatr 2000;159 Suppl 3:S192-5.
4. Kaback MM. Perspectives in genetic screening: principles and implications. Int J
Technol Assess Health Care 1994;10:592-603.
5. Chamoles NA, Blanco M, Gaggioli D, Casentini C. Tay-Sachs and Sandhoff
diseases: enzymatic diagnosis in dried blood spots on filter paper: retrospective
diagnoses in newborn-screening cards. Clin Chim Acta 2002;318:133-137.
6. Kivlin JD, Sanborn GE, Myers GG. The cherry-red spot in Tay-Sachs and other
storage diseases. Ann Neurol 1985;17:356-60.
7. Balint JA, Kyriakides EC. Studies of red cell stromal proteins in Tay-Sachs
disease. J Clin Invest 1968;47:1858-64.
8. Hall J, Fiebig DG, King MT, Hossain I, Louviere JJ. J Health Econ 2006;25:52037.
9. Myerowitz R, Lawson D, Mizukami H, Mi Y, Tifft CJ, Proia RL. Molecular
pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene
expression profiling. Hum Mol Genet 2002;11:1343-50.
10. Myerowitz R, Costigan FC. The major defect in Ashkenazi Jews with Tay-Sachs
disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase.
J Biol Chem 1988;263:18587-9.
11. Spyropoulos B. Tay-Sachs carriers and tuberculosis resistance. Nature
1988;331:666.
12. Risch N, Tang H, Katzenstein H, Ekstein J. Geographic distribution of disease
mutations in the Ashkenazi Jewish population supports genetic drift over
selection. Am J Hum Genet 2003;72:812-22.
13. Zlotogora J, Bach G. The possibility of a selection process in the Ashkenazi
Jewish population. Am J Hum Genet 2003;73:438-40.
14. Chavany C, Jendoubi M. Biology and potential strategies for the treatment of
GM2 gangliosidoses. Mol. Med. Today 1998;4:158–165.
15. Sakuraba H, Sawada M, Matsuzawa F, Aikawa S, Chiba Y, Jigami Y, Itoh K.
Molecular pathologies of and enzyme replacement therapies for lysosomal
diseases. CNS Neurol Disord Drug Targets 2006;5:401-13.
16. Walkley SU, Dobrenis K. Bone marrow transplantation for lysosomal diseases.
Lancet 1995;345:1382–1383.
17. Cachon-Gonzalez MB, Wang SZ, Lynch A, Ziegler R, Cheng SH, Cox TM.
Effective gene therapy in an authentic model of Tay-Sachs-related diseases.
Proc Natl Acad Sci USA 2006;103:10373-8.
18. The Online Metabolic and Molecular Bases of Inherited Disease.
Chapter 153 – Therapy.