Tay–Sachs disease

Tay–Sachs disease
Specialty	Pediatrics, neurology, medical genetics

Tay-Sachs disease (abbreviated TSD, also known as "GM2 gangliosidosis") is a genetic disorder, fatal in its most common variant known as Infantile Tay-Sachs disease. TSD is inherited in an autosomal recessive pattern. The disease occurs when harmful quantities of a fatty acid derivative called a ganglioside accumulate in the nerve cells in the brain. Gangliosides are present in lipids, which are components of cellular membranes, and the ganglioside GM2, implicated in Tay-Sachs disease, is especially common in the nervous tissue of the brain.

The disease is named after the British ophthalmologist Warren Tay who first described the red spot on the retina of the eye in 1881, and the American neurologist Bernard Sachs who described the cellular changes of Tay-Sachs and noted an increased prevalence in the Eastern European Jewish (Ashkenazi) population in 1887. It has been suggested that carriers of Tay-Sachs (those with one defective version of HEXA and one normal gene) may have a selective advantage, but this has never been proven.

Research in the late 20th century demonstrated that Tay-Sachs disease is caused by mutations on the HEXA gene on chromosome 15. A large number of HEXA mutations have been discovered, and new ones are still being reported. These mutations reach significant frequencies in several populations. French Canadians of southeastern Quebec and Cajuns of southern Louisiana have a carrier frequency similar to Ashkenazi Jews, but they carry a different mutation. Most HEXA mutations are rare, and do not occur in genetically isolated populations. The disease can potentially occur from the inheritance of two unrelated mutations in the HEXA gene, one from each parent.

Symptoms

Tay-Sachs is classified in variant forms, based on the time of onset of neurological symptoms. The variant forms reflect diversity in the mutation base. All patients with Tay-Sachs have a "cherry-red" spot in the back of their eyes (the retina). Microscopic analysis of neurons shows that they are distended from excess storage of gangliosides.

• Infantile TSD. Infants with Tay-Sachs disease appear to develop normally for the first six months of life. Then, as nerve cells become distended with gangliosides, a relentless deterioration of mental and physical abilities occurs. The child becomes blind, deaf, and unable to swallow. Muscles begin to atrophy and paralysis sets in. Death usually occurs before the age of 3.

• Juvenile TSD. Extremely rare, Juvenile Tay-Sachs disease usually presents itself in children between 2 and 10 years of age. They develop cognitive, motor, speech, and swallowing difficulties; unsteadiness of gait (ataxia), and spasticity. Patients with Juvenile TSD usually die between 5-15 years.

• Adult/Late Onset TSD. A rare form of the disorder, known as Adult Onset Tay-Sachs disease or Late Onset Tay-Sachs disease (LOTS), occurs in patients in their 20s and early 30s. LOTS is frequently misdiagnosed, and is usually non-fatal. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of LOTS, which present in adolescence or early adulthood, include speech difficulties (dysarthria), swallowing difficulties (dysphagia), unsteadiness of gait (ataxia), spasticity, cognitive decline, and psychiatric illness, particularly schizophrenic-like psychosis. Patients with LOTS frequently become wheelchair-bound in adulthood, but many live full adult lives if psychiatric and physical difficulties are accommodated. Psychiatric symptoms and seizures can be controlled with medications.

Etiology and pathogenesis

Tay-Sachs disease is inherited in the autosomal recessive pattern, depicted above.

The condition is caused by insufficient activity of an enzyme called hexosaminidase A that catalyzes the biodegradation of fatty acid derivatives known as gangliosides. Gangliosides are made and biodegraded rapidly in early life as the brain develops. Patients and carriers of Tay-Sachs disease can be identified by a simple blood test that measures hexosaminidase A activity. TSD is a recessive genetic disorder, meaning that both parents must be carriers in order to give birth to an affected child. Even then, there is only a 25% chance with each pregnancy of having a child with TSD. Prenatal monitoring of pregnancies is available.

Hydrolysis of GM2-ganglioside requires three proteins. Two of them are subunits of hexosaminidase A, and the third is a small glycolipid transport protein, the GM2 activator protein (GM2A), which acts as a substrate specific cofactor for the enzyme. Deficiency in any one of these proteins leads to storage of the ganglioside, primarily in the lysosomes of neuronal cells. Tay-Sachs disease (along with GM2-gangliosidosis and Sandhoff disease) occurs because a genetic mutation inherited from both parents inactivates or inhibits this process. Most Tay-Sachs mutations appear not to affect functional elements of the protein. Instead, they cause incorrect folding or assembly of the enzyme, so that intracellular transport is disabled.

The disease results from mutations on chromosome 15 in the HEXA gene encoding the alpha-subunit of the lysosomal enzyme beta-N-acetylhexosaminidase A. More than 90 mutations have been identified to date in the HEXA gene, and new mutations are still being reported. These mutations have included base pair insertions and deletions, splice site mutations, point mutations, and other more complex patterns. Each of these mutations alter the protein product, and thus inhibit the function of the enzyme in some manner.

For example, a four base pair insertion in exon 11 (1278insTATC) results in an altered reading frame for the HEXA gene. This mutation is the most prevalent mutation in the Ashkenazi Jewish population, and leads to the infantile form of Tay-Sachs disease. An unrelated mutation in exon 11, a single point transposition of C to G, occurs with similar frequency in families with French Canadian and Cajun ancestry, and has the same effect.

Disease can potentially occur from the inheritance of two unrelated mutations in the HEXA gene, one from each parent. Classic infantile TSD results when a child has inherited mutations from both parents that completely inactivate the biodegradation of gangliosides. Late onset forms of the disease occur because of the diverse mutation base. Patients may technically be heterozygotes, but with two different HEXA mutations that both inactivate, alter, or inhibit enzyme activity in some way. When a patient has at least one copy of the HEXA gene that still enables some hexosaminidase A activity, a later onset form of the disease occurs.

Testing

In populations with a high carrier frequency for TSD, genetic counseling is recommended so genetic testing can be done to detect carriership. Preimplantation genetic diagnosis can be considered in couples where both are carriers. In countries where selective abortion is legal, this method can be contemplated.

In Orthodox Jewish circles, the organisation Dor Yeshorim carries out an anonymous screening program, preventing the stigma of carriership while decreasing the rate of homozygosity in this population.

Proactive testing has been quite effective in eliminating Tays-Sachs occurrence amongst Ashkenazi Jews. Of the 10 babies born with Tay-Sachs in North America in 2003, none were Jews. In Israel, only one child was born with Tay-Sachs in 2003, and preliminary results from early 2005 indicated that none were born with it in 2004.

Therapy

There is currently no cure or treatment for TSD. Even with the best care, children with Infantile TSD die by the age of 5, and the progress of Late-Onset TSD can only be slowed, not reversed. However, research is ongoing. Several methods of treatment are being investigated, although significant hurdles remain before any of them pass the experimental stages.

• Enzyme replacement therapy. The goal would be to replace the missing enzyme, a process similar to insulin injections for diabetes. However, the enzyme has proven to be too large to pass through the blood into the brain through the blood-brain barrier. Blood vessels in the brain develop junctions so small that many toxic (or large) molecules cannot enter into nerve cells and cause damage. Researchers have also tried instilling the enzyme into cerebrospinal fluid, which bathes the brain. However, neurons are unable to take up the large enzyme efficiently even when it is placed next to the cell, so the treatment is still ineffective.

• Gene therapy. The most recent option explored by scientists has been gene therapy. However, scientists working in this field believe that they are years away from the technology to transport the genes into neurons, which would be as difficult as transporting the enzyme. Currently, most research involving gene therapy involves developing a method of using a viral vector to transfer new DNA into neurons. If the defective genes were to be replaced throughout the brain, Tay Sachs could theoretically be cured.

• Metabolic therapy. Other highly experimental methods being researched involve manipulating the brain's metabolism of GM2 gangliosides. One experiment has demonstrated that, by using the enzyme sialidase, the genetic defect can be effectively bypassed and GM2 gangliosides can be metabolized so that they become almost inconsequential. If a safe pharmacological treatment can be developed, one that causes the increased expression of lysosomal sialidase in neurons, a new form of therapy, essentially curing the disease, could be on the horizon. Metabolic therapies under investigation for Late-Onset TSD include treatment with the drug OGT 918 (Zavesca).

Epidemiology

Historically, Eastern European people of Jewish descent (Ashkenazi Jews) have a high incidence of Tay-Sachs and other lipid storage diseases. Documentation of Tay-Sachs in this Jewish population reaches back to 15th century Europe. In the United States, about 1 in 27 to 1 in 30 Ashkenazi Jews is a recessive carrier. French Canadians and the Cajun community of Louisiana have an occurrence similar to the Ashkenazi Jews. Irish Americans have a 1 in 50 chance of a person being a carrier. In the general population, the incidence of carriers (heterozygotes) is about 1 in 300.

A continuing controversy is whether heterozygotes, individuals who are carriers of one copy of the gene but do not actually develop the disease, have some selective advantage. The classic case of heterozygote advantage is sickle cell anemia, and some researchers have argued that there must be some evolutionary benefit to being a heterozygote for Tay-Sachs as well. Four different theories have been proposed to explain the high frequency of Tay-Sachs carriers in the Ashkemazi Jewish population:

• Heterozygote advantage with tuberculosis resistance. Being a Tay-Sachs carrier may serve as a form of protection against tuberculosis. TB's prevalence in the European Jewish population was very high, in part because Jews were forced to live in crowded conditions. However, several statistical studies have demonstrated that grandparents of Tay-Sachs died proportionally from the same causes as non-carriers.
• Heterozygote advantage because of higher intelligence. Another theory (attributed to Gregory Cochran) proposes that Tay-Sachs and the other lipid storage diseases that are prevalent in Ashkenazi Jews may enhance dendrite growth and promote higher intelligence when present in carrier form, thus providing a selective advantage at a time when Ashkenazi Jews were restricted to intellectual occupations. (See Ashkenazi intelligence.)
• Reproductive compensation. Parents who lose a child because of disease tend to "compensate" by having additional children to replace them, and this may increase the incidence of autosomal recessive disease.
• Founder effect. This hypothesis states that the high incidence of the 1278insTATC mutation is the result of genetic drift, which amplified a high frequency that existed by chance in an early founder population.

Because Tay-Sachs disease was one of the first autosomal recessive genetic disorders for which there was an enzyme assay test (prior to polymerase chain reaction testing methods), it was intensely studied as a model for all such diseases. The researchers of the 1970s often favored theories of heterozygote advantage, but failed to find much evidence for them in human populations. They were also unaware of the diversity of the Tay-Sachs mutation base.

DNA sequencing techniques using PCR have since been applied to many genetic disorders, and in other human populations. Several broad genetic studies of the Ashkenazi population (not related to genetic disease) have demonstrated that the Ashkenazi Jews are the descendants of a small founder population, which may have gone through additional population bottlenecks. These studies also correlate well with historical information about Ashkenazi Jews. Thus, a preponderence of the recent studies have supported the founder effects theory.

References

• Fernandes Filho JA, Shapiro BE (2004). "Tay-Sachs disease". Arch Neurol. 61 (9): 1466–8. PMID 15364698.
• Frisch A, Colombo R, Michaelovsky E, Karpati M, Goldman B, Peleg L. (2004). "Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis". Human Genetics. 114 (4): 366–76. PMID 14727180.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Johns Hopkins University. "Online Mendelian Inheritance in Man: Tay-Sachs disease". Retrieved Jul 26. {{cite web}}: Check date values in: |accessdate= (help); Unknown parameter |accessyear= ignored (|access-date= suggested) (help)
• Johns Hopkins University. "Online Mendelian Inheritance in Man: Hexoamidase A". Retrieved Jul 26. {{cite web}}: Check date values in: |accessdate= (help); Unknown parameter |accessyear= ignored (|access-date= suggested) (help)
• National Institutes of Health, National Center for Biotechnology Information. "NCBI: Tay-Sachs". Retrieved Jul 26. {{cite web}}: Check date values in: |accessdate= (help); Unknown parameter |accessyear= ignored (|access-date= suggested) (help)
• National Institute of Neurological Disorders and Stroke. "Tay-Sachs Disease Information Page". Retrieved July 26. {{cite web}}: Check date values in: |accessdate= (help); Unknown parameter |accessyear= ignored (|access-date= suggested) (help)
• Tel Aviv University, Department of Human Genetics, Bioinformatics Unit. "Genedis: Human Genetics Disease Database". Retrieved July 26. {{cite web}}: Check date values in: |accessdate= (help); Unknown parameter |accessyear= ignored (|access-date= suggested) (help)CS1 maint: multiple names: authors list (link)

External links

• Jewish Genetic Diseases, a Mazornet Guide. Tay Sachs Disease
• Late Onset Tay-Sachs Foundation
• National Tay-Sachs and Allied Diseases
• Tay-Sachs and Canavan Diseases
• Your Genes, Your Health, on Tay-Sachs