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Tay–Sachs disease

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Tay–Sachs disease
SpecialtyPediatrics, neurology, medical genetics Edit this on Wikidata

Tay–Sachs disease (abbreviated TSD, also known as GM2 gangliosidosis or Hexosaminidase A deficiency) is an autosomal recessive genetic disorder. In its most common variant, known as infantile Tay–Sachs disease, it causes a relentless deterioration of mental and physical abilities that commences around six months of age and usually results in death by the age of four. It is caused by a genetic defect in a single gene with one defective copy of that gene inherited from each parent. The disease occurs when harmful quantities of cell membrane components known as gangliosides accumulate in the nerve cells of the brain, eventually leading to the premature death of those cells. There is no cure or treatment.

The disease is named after British ophthalmologist Warren Tay, who first described the red spot on the retina of the eye in 1881, and the American neurologist Bernard Sachs of Mount Sinai Hospital, New York who described the cellular changes of Tay–Sachs and noted an increased prevalence in the Eastern European Ashkenazi Jewish population in 1887.

Research in the late 20th century demonstrated that Tay–Sachs disease is caused by a genetic mutation 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 specific populations. French Canadians of southeastern Quebec have a carrier frequency similar to Ashkenazi Jews, but they carry a different mutation. Cajuns of southern Louisiana carry the same mutation that is most common in Ashkenazi Jews. HEXA mutations are rare, and do not occur in genetically isolated populations. The disease can occur from the inheritance of two unrelated mutations in the HEXA gene.

Signs and symptoms

Tay–Sachs disease is classified in variant forms, based on the time of onset of neurological symptoms.[1][2]

  • Infantile Tay–Sachs disease. Infants with Tay–Sachs disease appear to develop normally for the first six months after birth. Then, as nerve cells become distended with gangliosides, a relentless deterioration of mental and physical abilities occurs. The child becomes blind, deaf, unable to swallow, develops atrophy and paralysis. Death usually occurs before the age of four.[1]
  • Juvenile Tay–Sachs disease. Extremely rare, juvenile Tay–Sachs disease usually presents itself in children between two and 10 years of age. They develop cognitive and motor skill deterioration, dysarthria, dysphagia, ataxia, and spasticity. People with Juvenile Tay–Sachs disease usually die between five and fifteen years.[3]
  • Adult/Late Onset Tay–Sachs disease. A rare form of the disorder, known as Adult Onset Tay–Sachs disease or Late Onset Tay–Sachs disease, occurs in people in their 20s and early 30s. Late onset Tay–Sachs is frequently misdiagnosed, and is usually non-fatal. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of Late onset Tay–Sachs, which present in adolescence or early adulthood, include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly schizophrenic-like psychosis.[4]

Late onset Tay–Sachs

Until the 1970s and 1980s, when the molecular genetics of the disease became known, the juvenile and adult forms of the disease were not always recognized as variants of Tay–Sachs disease. Post-infantile Tay–Sachs was often mis-diagnosed as another neurological disorder, such as Friedreich ataxia.[5] People with Late onset Tay–Sachs frequently become full-time wheelchair users in adulthood. Psychiatric symptoms and seizures can be controlled with medication.[6]

Pathophysiology

Tay–Sachs disease is caused by insufficient activity of an enzyme called hexosaminidase A that catalyzes the biodegradation of fatty acid derivatives known as gangliosides. Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down phospholipids. When Hexosaminidase A is no longer functioning properly, the lipids accumulate in the brain and interfere with normal biological processes. 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.[1]

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 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 deactivates 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.[7]

Epidemiology

Founder effects occur when a small number of individuals from a larger population establish a new population. In this illustration, the original population is on the left with three possible founder populations on the right. Each founder population is genetically distinct from the original population.

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 being a carrier. In the general population, the incidence of carriers as heterozygotes is about 1 in 300.[2]

Three general classes of theories have been proposed to explain the high frequency of Tay–Sachs carriers in the Ashkenazi Jewish population:

  • Heterozygote advantage.[8] When applied to a particular allele, this theory posits that carriers of the mutation have a selective advantage, perhaps in a particular environment.[9]
  • Reproductive compensation. Parents who lose a child because of disease tend to "compensate" by having additional children to replace them. This may maintain and possibly even increase the incidence of autosomal recessive disease.[10]
  • Founder effect. This hypothesis states that the high incidence of the 1278insTATC chromosomes[9] are the result of genetic drift,[8] that existed by chance in an early founder population.[9]

Tay–Sachs disease was one of the first genetic disorders for which epidemiology was studied using new molecular data. Studies of Tay–Sachs disease mutations using new molecular techniques such as linkage disequilibrium and coalescence analysis has brought an emerging consensus among researchers in support of the founder effects theory.[11][12][13]

Genetics

Tay–Sachs disease is inherited in the autosomal recessive pattern, depicted above.
The HEXA gene is located on the long (q) arm of chromosome 15 between positions 23 and 24.

Tay–Sachs disease is an autosomal recessive genetic disorder, meaning that when both parents are carriers, there is a 25% risk of giving birth to an affected child.[1] This also means that mutations can be passed down generations without manifesting as a genetic disorder.[14] Autosomal genes are chromosomal genes that are not located on one of the sex chromosomes. Every individual carries two copies of each autosomal gene, one copy from each parent. When both parents carry a mutation, the classic 25% Mendelian ratio determines the likelihood of disease.[1]

The disease results from mutations on chromosome 15 in the HEXA gene encoding the alpha-subunit of beta-N-acetylhexosaminidase A, a lysosomal enzyme. By 2000, more than 100 mutations had been identified in the HEXA gene.[15] These mutations have included single base insertions and deletions, splice site mutations, missense mutations, and other more complex patterns. Each of these mutations alters the protein product, and thus inhibits the function of the enzyme.[16] In recent years, population studies and pedigree analysis have shown how such mutations arise and spread within small founder populations. Initial research focused on such founder populations:

  • Ashkenazi Jews. 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.[17]
  • Cajun. The same mutation found among Ashkenazi Jews occurs in the Cajun population of southern Louisiana, an American ethnic group that has been isolated because of linguistic differences. Researchers have traced carriers from Louisiana families to a single founder couple, not known to be Jewish, that lived in France in the 18th century.[18]
  • French Canadians. A mutation that is unrelated to the predominant Ashkenazi mutation, a long sequence deletion, occurs with similar frequency in families with French Canadian ancestry, and has the same pathological effects. Like the Ashkenazi Jewish population, the French Canadian population grew rapidly from a small founder group, and remained isolated from surrounding populations because of geographic, cultural, and language barriers. In the early days of Tay–Sachs research, it was believed that mutations in these two populations were identical, that gene flow accounted for the prevalence of Tay–Sachs disease in eastern Quebec. Researchers claim that a prolific Jewish ancestor must have introduced the mutation into the French Canadian population. This theory became known as the "Jewish Fur Trader Hypothesis" among researchers in population genetics. However, subsequent research has demonstrated that the two mutations are unrelated, and pedigree analysis has traced the French Canadian mutation to a founding family that lived in southern Quebec in the late 17th century.[19][20]

In the 1960s and early 1970s, when the biochemical basis of Tay–Sachs disease was first becoming known, no mutations had been sequenced directly for genetic diseases. Researchers of that era did not yet know how common polymorphism would prove to be. The "Jewish Fur Trader Hypothesis," with its implication that a single mutation must have spread from one population into another, reflected the knowledge of the time. Subsequent research has proven that a large number of HEXA mutations can cause the disease. Because Tay–Sachs disease was one of the first genetic disorders for which widespread genetic screening was possible, it is one of the first genetic disorders in which the prevalence of compound heterozygosity was demonstrated.[21]

Compound heterozygosity ultimately explains the variability of the disease, including late-onset forms. The disease can potentially result from the inheritance of two unrelated mutations in the HEXA gene, one from each parent. Classic infantile Tay–Sachs disease 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. When a patient has at least one copy of the HEXA gene that still enables hexosaminidase A activity, a later onset form of the disease occurs. When disease occurs because of two unrelated mutations, the patient is said to be a compound heterozygote.[22]

Heterozygous carriers, individuals who inherit one mutant allele, show abnormal enzyme activity, but have no symptoms of the disease. Bruce Korf explains why carriers of recessive mutations generally do not manifest the symptoms of genetic disease: "The biochemical basis for the dominance of wild-type alleles over mutant alleles in inborn errors of metabolism can be understood by considering how enzymes function. Enzymes are proteins that catalyze chemical reactions, so only small quantities are required for a reaction to be carried out. In a person homozygous for a mutation in the gene encoding an enzyme, little or no enzyme activity is present, so he or she will manifest the abnormal phenotype. A heterozygous individual expresses at least 50% of the normal level of enzyme activity due to expression of the wild-type allele. This is usually sufficient to prevent phenotypic expression."[23]

Diagnosis

The development of improved testing methods has allowed neurologists to diagnose Tay–Sachs and other neurological diseases with greater precision. All patients with Tay–Sachs disease have a "cherry red" macula, easily observable by a physician using an ophthalmoscope, in the retina.[1][24] This red spot is the area of the retina which is accentuated because of gangliosides in the surrounding retinal ganglion cells. The choroidal circulation is showing through "red" in this region of the fovea where all of the retinal ganglion cells are normally pushed aside to increase visual acuity. Thus, the cherry-red spot is the only normal part of the retina seen. Microscopic analysis of neurons shows that they are distended from excess storage of gangliosides. Without molecular diagnostic methods, only the cherry red spot, characteristic of all GM2 gangliosidosis disorders, provides a definitive diagnostic sign.[25] Unlike other lysosomal storage diseases (i.e. Gaucher disease, Niemann-Pick disease, Sandhoff disease), hepatosplenomegaly is not a feature of Tay–Sachs disease.[26]

Prevention

Main article: Prevention of Tay–Sachs disease

Three main approaches have been used to prevent or reduce the incidence of Tay–Sachs disease:

  • Prenatal diagnosis. If both parents are identified as carriers, prenatal genetic testing can determine whether the fetus has inherited a defective copy of the gene from both parents. Couples may be willing to terminate the pregnancy, although abortion may raise ethical issues.[27] Chorionic villus sampling (CVS), can be performed after the 10th week of gestation. It is the most common form of prenatal diagnosis. Both CVS and amniocentesis present developmental risks to the fetus that have to be balanced with the possible benefits, especially in cases where the carrier status of only one parent is known.[28]
  • Mate selection. In Orthodox Jewish circles, the organization Dor Yeshorim carries out an anonymous screening program so that couples with Tay–Sachs or another genetic disorder can avoid conception.[29] Nomi Stone of Dartmouth College describes this approach as Orthodox Jewish high school students are given blood tests to determine if they have the Tay–Sachs gene. Instead of receiving the results directly as to their carrier status, each person is given a six-digit identification number. Couples can call a hotline. If both are carriers, they will be deemed as 'incompatible.' Individuals are not told if they are carriers directly to avoid possibility of stigmatization or discrimination. She states: "If the information were released, carriers could potentially become unmarriageable within the community."[30]
  • Preimplantation genetic diagnosis. By retrieving the mother's eggs for in vitro fertilization, it is possible to test the embryo prior to implantation. The healthy embryos are selected and transferred into the mother's womb. In addition to Tay–Sachs disease, Preimplantation genetic diagnosis has been used to prevent cystic fibrosis, sickle cell anemia, among other genetic disorders.[31]

History

Main article: History of Tay–Sachs disease

With development and acceptance of the germ theory of disease in the 1860s to the 1870s,[32] the possibility that science could explain, prevent or cure illness prompted medical doctors to undertake more precise description and diagnosis of disease.[33] Warren Tay and Bernard Sachs, two physicians, described the progression of the disease and provided differential diagnostic criteria to distinguish it from other neurological disorders with similar symptoms.

Both Tay and Sachs reported their first cases among Jewish families. Tay reported his observations in 1881 in the first volume of the proceedings of the British Ophthalmological Society, of which he was a founding member.[34] By 1884, he had seen three cases in a single family. Years later, Bernard Sachs, an American neurologist, reported similar findings when he reported a case of "arrested cerebral development" to members of the New York Neurological Society.[35]

Sachs, who recognized that the disease had a familial basis, proposed that the disease should be called amaurotic familial idiocy. However, its genetic basis was still poorly understood. Although Gregor Mendel had published his article on the genetics of peas in 1865, Mendel's paper was largely forgotten for more than a generation, not rediscovered by other scientists until 1899. Thus, the Mendelian model for explaining Tay–Sachs was unavailable to scientists and medical practitioners of the time. The first edition of the Jewish Encyclopedia, published in 12 volumes between 1901 and 1906, described what was then known about the disease:[36]

It is a curious fact that amaurotic family idiocy, a rare and fatal disease of children, occurs mostly among Jews. The largest number of cases has been observed in the United States—over thirty in number. It was at first thought that this was an exclusively Jewish disease, because most of the cases at first reported were between Russian and Polish Jews; but recently there have been reported cases occurring in non-Jewish children. The chief characteristics of the disease are progressive mental and physical enfeeblement; weakness and paralysis of all the extremities; and marasmus, associated with symmetrical changes in the macula lutea. On investigation of the reported cases, they found that neither consanguinity nor syphilitic, alcoholic, or nervous antecedents in the family history are factors in the etiology of the disease. No preventive measures have as yet been discovered, and no treatment has been of benefit, all the cases having terminated fatally.

The World War I time was a period of nativism of hostility to immigrants. Jewish immigration to the United States peaked in the period 1880–1924, with the immigrants arriving from Russia and countries in Eastern Europe. Opponents of immigration often questioned whether immigrants from southern and eastern Europe could be assimilated into American society. Reports of Tay–Sachs disease contributed to a perception among nativists that Jews were an inferior race. Reuter writes, "The fact that Jewish immigrants continued to display their nervous tendencies in America where they were free from persecution was seen as proof of their biological inferiority and raised concerns about the degree to which they were being permitted free entry into the US."[37]

In 1969, John S. O'Brien showed that Tay–Sachs disease was caused by a defect in a enzyme. He also proved that Tay–Sachs disease patients could be diagnosed by enzyme assay of hexosaminidase A.[38] Further development of enzyme assay testing demonstrated that levels of both hexosaminidases A and B could be measured in patients and carriers, allowing reliable detection of heterozygotes. During the early 1970s, researchers developed protocols for newborn testing, carrier screening, and pre-natal diagnosis.[39][40] By the end of the 1970s, researchers had identified three variant forms of GM2 gangliosidosis, including Sandhoff disease and GM2-gangliosidosis, AB variant, accounting for false negatives in carrier testing.[41]

Society and culture

Main article: Sociological and cultural aspects of Tay–Sachs disease

Since carrier testing for Tay–Sachs began in 1971, millions of Ashkenazi Jews have been screened as carriers. Jewish communities embraced the cause of genetic screening from the 1970s on. The success with Tay–Sachs disease has led Israel to become the first country that offers free genetic screening and counseling for all couples. Israel has become a leading center for research on genetic disease. Both the Jewish, Arab, and Palestinian populations in Israel contain ethnic and religious minority groups, and Israel's success with Tay–Sachs disease has led to the development of screening programs for other diseases. The success also opened discussions and debates about the proper scope of genetic testing for other disorders.[42]

Neil Risch is the principal author of a study which analyzes the geographic distributions of mutations among Ashkenazi Jews. Risch found "compelling support for random genetic drift."[11]

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, and researchers sought evidence of a selective process. A continuing controversy is whether heterozygotes (carriers) has selective advantage. Neil Risch writes: "The anomalous presence of four different lysosomal storage disorders in the Ashkenazi Jewish population has been the source of long-standing controversy. Many have argued that the low likelihood of four such diseases — particularly when four are involved in the storage of glycosphingolipids — must reflect past selective advantage for heterozygous carriers of these conditions."[11]

This controversy among researchers has reflected three debates among geneticists at large:

Research directions

Enzyme replacement therapy

Enzyme replacement therapy techniques have been investigated for lysosomal storage disorders, and could potentially be used to treat Tay–Sachs disease. The goal would be to replace the missing enzyme, a process similar to insulin injections for diabetes. However, the HEXA enzyme has proven to be too large to pass through the blood into the brain through the blood-brain barrier. 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.[44]

Gene therapy

Options for gene therapy have been explored for Tay–Sachs and other lysosomal storage diseases. If the defective genes could be replaced throughout the brain, Tay–Sachs could theoretically be cured. However, researchers 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. Use of a viral vector, promoting an infection as a means to introduce new genetic material into cells, has been proposed as a technique for genetic diseases in general. Hematopoetic stem cell therapy (HSCT), another form of gene therapy, uses cells that have not yet differentiated and taken on specialized functions. Yet another approach to gene therapy uses stem cells from umbilical cord blood in an effort to replace the defective gene. Although the stem cell approach has been effective with Krabbé disease.[45]

Tay–Sachs disease exists in flocks of Jacob sheep.[46] The biochemical mechanism for this disease in the Jacob sheep is virtually identical to that observed in humans. Diminished activity of hexosaminidase A resulted in increased concentrations of GM2 ganglioside.[47] Sequencing of the cDNA of the HEXA gene of affected Jacobs reveals an identical number of nucleotides and exons as in the human HEXA gene, and 86% identity in nucleotide sequence.[46] A missense mutation, referred to as the G444R mutation[48] was found in the HEXA cDNA of the affected sheep caused by a single nucleotide change at the end of exon 11 resulting in skipping of exon 11. This model of Tay–Sachs disease provided by the Jacob sheep is the first to offer promise as a means for trials of gene therapy which may eventually prove to be useful in the treatment of the disease in humans.[46]

Substrate reduction therapy

Other experimental methods being researched involve Substrate reduction therapy, the aim of which is to use alternative enzymes to increase the brain's catabolism of GM2 gangliosides to a point where residual degradative activity is sufficient to prevent substrate accumulation.[49][50] 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.[51] Metabolic therapies under investigation for Late-Onset Tay–Sachs disease include treatment with the drug OGT 918 (Zavesca).[52]

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