Tay–Sachs disease
Tay–Sachs disease | |
---|---|
Other names | GM2 gangliosidosis, hexosaminidase A deficiency Supportive care, psychosocial support[2] |
Prognosis | Death often occurs in early childhood[1] |
Frequency | Rare in the general population[1] |
Named after |
Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord.[1] The most common form is infantile Tay–Sachs disease, which becomes apparent around the age of three to six months of age, with the baby losing the ability to turn over, sit, or crawl.[1] This is then followed by seizures, hearing loss, and inability to move, with death usually occurring by the age of three to five.[3][1] Less commonly, the disease may occur later in childhood, adolescence, or adulthood (juvenile or late-onset).[1] These forms tend to be less severe,[1] but the juvenile form typically results in death by age 15.[4]
Tay–Sachs disease is caused by a
The treatment of Tay–Sachs disease is
The disease is named after British ophthalmologist Waren Tay, who in 1881 first described a symptomatic red spot on the retina of the eye; and American neurologist Bernard Sachs, who described in 1887 the cellular changes and noted an increased rate of disease in Ashkenazi Jews.[6] Carriers of a single Tay–Sachs allele are typically normal.[2] It has been hypothesized that being a carrier may confer protection from tuberculosis, explaining the persistence of the allele in certain populations.[7] Researchers are looking at gene therapy or enzyme replacement therapy as possible treatments.[2]
Signs and symptoms
Tay–Sachs disease is typically first noticed in infants around 6 months old displaying an abnormally strong response to sudden noises or other stimuli, known as the "startle response". There may also be listlessness or muscle stiffness (hypertonia). The disease is classified into several forms, which are differentiated based on the onset age of
Infantile
Juvenile
Juvenile Tay–Sachs disease is rarer than other forms of Tay–Sachs, and usually is initially seen in children between two and ten years old. People with Tay–Sachs disease experience
Late-onset
A rare form of this disease, known as Adult-Onset or Late-Onset Tay–Sachs disease, usually has its first symptoms during the 30s or 40s. In contrast to the other forms, late-onset Tay–Sachs disease is usually not fatal as the effects can stop progressing. It is frequently misdiagnosed. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of late-onset Tay–Sachs – which typically begin to be seen in adolescence or early adulthood – include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly a schizophrenia-like psychosis.[11] Late-onset Tay–Sachs patients may become fully wheelchair-using.[12]
Until the 1970s and 1980s, when the disease's molecular genetics 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 misdiagnosed as another neurological disorder, such as Friedreich's ataxia.[13]
Genetics
Tay–Sachs disease is an
Tay–Sachs results from
- 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.[18]
- Cajuns. The same 1278insTATC mutation found among Ashkenazi Jews occurs in the Cajun population of southern Louisiana. Researchers have traced the ancestry of carriers from Louisiana families back to a single founder couple – not known to be Jewish – who lived in France in the 18th century.[19]
- French Canadians. Two mutations, unrelated to the Ashkenazi/Cajun mutation, are absent in France but common among certain French-Canadian communities living in southeastern Quebec and Acadians from the Province of New Brunswick. Pedigree analysis suggests the mutations were uncommon before the late 17th century.[20][21]
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 polymorphisms 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 at the time.[22] Subsequent research, however, has proven that a large variety of different HEXA mutations can cause the disease. Because Tay–Sachs 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 has been demonstrated.[23]
Compound heterozygosity ultimately explains the disease's variability, including the 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 stop the biodegradation of gangliosides. Late onset forms occur due to the diverse mutation base – people with Tay–Sachs disease may technically be heterozygotes, with two differing HEXA mutations that both inactivate, alter, or inhibit enzyme activity. When a patient has at least one HEXA copy that still enables some level of hexosaminidase A activity, a later onset disease form occurs. When disease occurs because of two unrelated mutations, the patient is said to be a compound heterozygote.[24]
Heterozygous carriers (individuals who inherit one mutant allele) show abnormal enzyme activity but manifest no disease symptoms. This phenomenon is called dominance; the biochemical reason for
Pathophysiology
Tay–Sachs disease is caused by insufficient activity of the enzyme
The
Diagnosis
In patients with a clinical suspicion for Tay–Sachs disease, with any age of onset, the initial testing involves an
Prevention
Three main approaches have been used to prevent or reduce the incidence of Tay–Sachs:
- Prenatal diagnosis. If both parents are identified as carriers, prenatal genetic testing can determine whether the fetus has inherited a defective gene copy from both parents.[31] Chorionic villus sampling (CVS), the most common form of prenatal diagnosis, can be performed between 10 and 14 weeks of gestation. Amniocentesis is usually performed at 15–18 weeks. These procedures have risks of miscarriage of 1% or less.[32][33]
- sickle cell anemia among other genetic disorders.[34]
- Pre-marriage screening. In Orthodox Jewish circles, the organization Dor Yeshorim carries out an anonymous screening program so that carriers for Tay–Sachs and other genetic disorders can avoid marrying each other.[35]
Management
As of 2010 there was no treatment that addressed the cause of Tay–Sachs disease or could slow its progression; people receive
Outcomes
As of 2010, even with the best care, children with infantile Tay–Sachs disease usually die by the age of 4. Children with the juvenile form are likely to die between the ages 5–15, while the lifespans of those with the adult form will probably not be affected.[36]
Epidemiology
Three general classes of theories have been proposed to explain the high frequency of Tay–Sachs carriers in the Ashkenazi Jewish population:
- Heterozygote advantage.[42] When applied to a particular allele, this theory posits that mutation carriers have a selective advantage, perhaps in a particular environment.[43]
- Reproductive compensation. Parents who lose a child because of disease tend to "compensate" by having additional children following the loss. This phenomenon may maintain and possibly even increase the incidence of autosomal recessive disease.[44]
- Founder effect. This hypothesis states that the high incidence of the 1278insTATC chromosomes[43] is the result of an elevated allele frequency[42] that existed by chance in an early founder population.[43]
Tay–Sachs disease was one of the first genetic disorders for which epidemiology was studied using molecular data. Studies of Tay–Sachs mutations using new molecular techniques such as
History
Waren Tay and Bernard Sachs were two physicians. They described the disease's progression and provided differential diagnostic criteria to distinguish it from other neurological disorders with similar symptoms.[6]
Both Tay and Sachs reported their first cases among Ashkenazi 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.[47] 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 other New York Neurological Society members.[48][49]
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
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.
Jewish immigration to the United States peaked in the period 1880–1924, with the immigrants arriving from Russia and countries in Eastern Europe; this was also a period of nativism (hostility to immigrants) in the United States. 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.[49]
In 1969, Shintaro Okada and John S. O'Brien showed that Tay–Sachs disease was caused by an enzyme defect; they also proved that Tay–Sachs patients could be diagnosed by an assay of hexosaminidase A activity.[51] The further development of enzyme assays demonstrated that levels of hexosaminidases A and B could be measured in patients and carriers, allowing the reliable detection of heterozygotes. During the early 1970s, researchers developed protocols for newborn testing, carrier screening, and pre-natal diagnosis.[35][52] By the end of 1979, researchers had identified three variant forms of GM2 gangliosidosis, including Sandhoff disease and the AB variant of GM2-gangliosidosis, accounting for false negatives in carrier testing.[53]
Society and culture
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 and opened discussions about the proper scope of genetic testing for other disorders in Israel.[54]
Because Tay–Sachs disease was one of the first autosomal recessive genetic disorders for which there was an
This controversy among researchers has reflected various debates among geneticists at large:[55]
- Dominance versus overdominance. In applied genetics (selective and agricultural breeding), this controversy has reflected the century-long debate over whether dominance or overdominance provides the best explanation for heterosis(hybrid vigor).
- The purifying selection that operates to eliminate deleterious alleles. The balancing hypothesis, often associated with Theodosius Dobzhansky, states that heterozygosity will be common at loci, and that it frequently reflects either directional selection or balancing selection.
- neutral theory of molecular evolution, which emphasizes the role of genetic drift.[56]
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 as well. The goal would be to replace the nonfunctional enzyme, a process similar to insulin injections for diabetes. However, in previous studies, the HEXA enzyme itself has been thought to be too large to pass through the specialized cell layer in the blood vessels that forms the blood–brain barrier in humans.[citation needed]
Researchers have also tried directly instilling the deficient enzyme hexosaminidase A into the cerebrospinal fluid (CSF) which bathes the brain. However, intracerebral neurons seem unable to take up this physically large molecule efficiently even when it is directly by them. Therefore, this approach to treatment of Tay–Sachs disease has also been ineffective so far.[57]
Jacob sheep model
Tay–Sachs disease exists in
Substrate reduction therapy
Other experimental methods being researched involve
Another metabolic therapy under investigation for Tay–Sachs disease uses
Increasing β-hexosaminidase A activity
As Tay–Sachs disease is a deficiency of β-hexosaminidase A, deterioration of affected individuals could be slowed or stopped through the use of a substance that increases its activity. However, since in infantile Tay–Sachs disease there is no β-hexosaminidase A, the treatment would be ineffective, but for people affected by Late-Onset Tay–Sachs disease, β-hexosaminidase A is present, so the treatment may be effective. The drug pyrimethamine has been shown to increase activity of β-hexosaminidase A.[66] However, the increased levels of β-hexosaminidase A still fall far short of the desired "10% of normal HEXA", above which the phenotypic symptoms begin to disappear.[66]
Cord blood transplant
This is a highly invasive procedure which involves destroying the patient's blood system with chemotherapy and administering cord blood. Of five people who had received the treatment as of 2008, two were still alive after five years and they still had a great deal of health problems.[67]
Critics point to the procedure's harsh nature—and the fact that it is unapproved. Other significant issues involve the difficulty in crossing the blood–brain barrier, as well as the great expense, as each unit of cord blood costs $25,000, and adult recipients need many units.[68]
Gene therapy
On 10 February 2022, the first ever gene therapy was announced, it uses an adeno-associated virus (AAV) to deliver the correct instruction for the HEXA gene on brain cells which causes the disease. Only two children were part of a compassionate trial presenting improvements over the natural course of the disease and no vector-related adverse events.[69][70][71]
References
- ^ a b c d e f g h i j k l m n o p q "Tay–Sachs disease". Genetics Home Reference. October 2012. Archived from the original on 13 May 2017. Retrieved 29 May 2017.
- ^ a b c d e f g h i j k l "Tay Sachs Disease". NORD (National Organization for Rare Disorders). 2017. Archived from the original on 20 February 2017. Retrieved 29 May 2017.
- ^ "Tay-Sachs disease - Symptoms and causes". Mayo Clinic.
- ^ ISBN 978-3-527-33189-5.
- ISBN 9781461595649. Archivedfrom the original on 2017-11-05.
- ^ ISBN 9781404206977.
- ISBN 9783662033562. Archivedfrom the original on 2017-11-05.
- ^ a b c d e "Tay–Sachs disease Information Page". National Institute of Neurological Disorders and Stroke. 14 February 2007. Archived from the original on 27 November 2011. Retrieved 10 May 2007.
- ^ a b McKusick, Victor A; Hamosh, Ada. "Online Mendelian Inheritance in Man". United States National Institutes of Health. Archived from the original on 4 January 2016. Retrieved 24 April 2009.
- S2CID 19301606.
- PMID 7635850.
- PMID 32295606.
- S2CID 27305940.
- S2CID 5808156.
- S2CID 22587938.
- ISBN 978-1-119-97731-5.
- PMID 22981120.
- from the original on 17 April 2014.
- PMID 1307230.
- S2CID 23770703.
- S2CID 19278804.
- PMID 897699.
- (PDF) from the original on 26 September 2007. Retrieved 11 May 2007.
- ^ from the original on 2014-01-16.
- ISBN 978-0-632-04425-2.
- PMID 10571007.
- PMID 8397824.
- PMID 5947589.
- PMID 19820796.
- PMID 21810694.
- PMID 10182027.
- ^ "Chorionic Villus Sampling and Amniocentesis: Recommendations for Prenatal Counseling". United States, Center for Disease Control. Archived from the original on 14 July 2009. Retrieved 18 June 2009.
- PMID 22216843.
- ^ Marik, J J (13 April 2005). "Preimplantation Genetic Diagnosis". eMedicine.com. Archived from the original on 31 January 2009. Retrieved 10 May 2007.
- ^ )
- ^ PMID 20393311.
- S2CID 86246245.
- S2CID 37096876.
- PMID 11500789.
- ^ "1,000 New York Irish to get tested for Tay Sachs disease gene". Irish Central. 13 August 2014. Retrieved 13 February 2020.
- ^ GM2 Gangliosidoses – Introduction And Epidemiology Archived 2012-04-20 at the Wayback Machine at Medscape. Author: David H Tegay. Updated: Mar 9, 2012
- ^ PMID 677122.
- ^ S2CID 10768286.
- S2CID 23470984.
- ^ PMID 12612865.
- PMID 15208782.
- ^ Tay, Waren (1881). "Symmetrical changes in the region of the yellow spot in each eye of an infant". Transactions of the Ophthalmological Society. 1: 55–57.
- hdl:10192/32703.
- ^ S2CID 143784985.
- ^ "Amaurotic Idiocy". The Jewish Encyclopedia. New York: Funk and Wagnalls. 1901–1906. Archived from the original on 3 March 2012. Retrieved 7 March 2009.
- S2CID 8473726.
- PMID 4986776.
- ^ O'Brien, John S (1983). "The Gangliosidoses". In Stanbury, J B; et al. (eds.). The Metabolic Basis of Inherited Disease. New York: McGraw Hill. pp. 945–969.
- S2CID 31003675.
- ISBN 978-0-08-049030-4.
- ISBN 978-0-521-23109-1.
- PMID 21487393.
- ^ PMID 20817517.
- S2CID 6106101.
- ^ Kolodny E, Horak F, Horak J (2011). "Jacob sheep breeders find more Tay–Sachs carriers". ALBC Newsletter. Archived from the original on 20 March 2012. Retrieved 5 May 2011.
- PMID 9103204.
- S2CID 5625586.
- PMID 10332044.
- ^ "Pharmacokinetics, Safety and Tolerability of Zavesca (Miglustat) in Patients With Infantile Onset Gangliosidosis: Single and Steady State Oral Doses". 5 May 2008. Archived from the original on 13 February 2012. Retrieved 10 April 2012.
- S2CID 221872176.
- ^ PMID 21185210.
- PMID 18587012.
- ^ William Hathaway (May 16, 2006). "Umbilical Cord Blood Is Child's Last Hope, Stem Cells Could Halt Tay–Sachs Damage". Hartford Courant. Archived from the original on 2018-07-05. Retrieved 2018-05-20.
- S2CID 246748772.
- ^ Sena-Esteves, Miguel (14 February 2022). "First gene therapy for Tay-Sachs disease successfully given to two children". The Conversation. Retrieved 2022-03-07.
- ^ "Parents spark breakthrough gene therapy for children with Tay-Sachs disease". The Independent. 2022-02-18. Retrieved 2022-03-07.