| Tay–Sachs disease | |
|---|---|
| Other names | GM2 gangliosidosis, hexosaminidase A deficiency[1] |
 | |
| Cherry-red spot as seen in theretina in Tay–Sachs disease. Thefovea's center appears bright red because it is surrounded by a whiter-than-usual area. | |
| Specialty | Medical genetics |
| Symptoms | Initially: Decreased ability to turn over, sit, or crawl[1] Later:Seizures,hearing loss, inability to move[1] |
| Usual onset | Three-to-six months of age[1] |
| Duration | Long term[2] |
| Types | Infantile, juvenile, late-onset[2] |
| Causes | Genetic (autosomal recessive)[1] |
| Diagnostic method | Testing bloodhexosaminidase A levels,genetic testing[2] |
| Differential diagnosis | Sandhoff disease,Leigh syndrome,neuronal ceroid lipofuscinoses[2] |
| Treatment | 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 aninheritedlysosomal storage disease that results in the destruction of nerve cells in thebrain andspinal 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 infant losing the ability to turn over, sit, or crawl.[1] This is then followed byseizures,hearing loss, andinability 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 the age of 15.[4]
Tay–Sachs disease is caused by agenetic mutation in theHEXA gene onchromosome 15, which codes asubunit of thehexosaminidaseenzyme known as hexosaminidase A.[1] It is inherited in anautosomal recessive manner.[1] The mutation disrupts the activity of the enzyme, which results in the build-up of the moleculeGM2 ganglioside within cells, leading to toxicity.[1] Diagnosis may be supported by measuring the blood hexosaminidase A level orgenetic testing.[2] Tay–Sachs disease is a type ofGM2 gangliosidosis andsphingolipidosis.[5]
The treatment of Tay–Sachs disease issupportive in nature.[2] This may involve multiple specialties as well as psychosocial support for the family.[2] The disease is rare in the general population.[1] InAshkenazi Jews,French Canadians of southeasternQuebec, theOld Order Amish ofPennsylvania, and theCajuns of southernLouisiana, the condition is more common.[2][1] Approximately 1 in 3,600 Ashkenazi Jews at birth are affected.[2]
The disease is named after British ophthalmologistWaren Tay, who in 1881 first described a symptomatic red spot on theretina of the eye; and American neurologistBernard Sachs, who described in 1887 thecellular changes and noted an increased rate of disease in Ashkenazi Jews.[6] Carriers of a single Tay–Sachsallele are typically normal.[2] It has been hypothesized that being a carrier may confer protection fromtuberculosis, explaining the persistence of the allele in certain populations.[7] Researchers are looking atgene therapy orenzyme replacement therapy as possible treatments.[2]
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 ofneurologicalsymptoms.[8][9]
Infants with Tay–Sachs disease appear to develop normally for the first six months afterbirth. Then, asneurons become distended with GM2 gangliosides, a relentlessdeterioration of mental and physical abilities begins. The child may becomeblind,deaf, unable toswallow,atrophied, andparalytic. Death usually occurs before the age of four.[8]
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 experiencecognitive andmotor skill deterioration,dysarthria,dysphagia,ataxia, andspasticity.[10] Death usually occurs between the ages of five and fifteen years.[4]
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 ofgait and progressive neurological deterioration. Symptoms of late-onset Tay–Sachs – which typically begin to be seen inadolescence or earlyadulthood – includespeech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly aschizophrenia-likepsychosis.[11] Late-onset Tay–Sachs patients may become fullywheelchair-bound.[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 asFriedreich's ataxia.[13]
Tay–Sachs disease is anautosomal recessive genetic disorder, meaning that when both parents arecarriers, there is a 25% risk of giving birth to an affected child with each pregnancy. The affected child would have received a mutated copy of the gene from each parent.[8][14] A person with one mutated copy and one normal copy is a carrier, like the parent they received the mutant copy from. Tay–Sachs carriers are known to be more resistant to infections ofmycobacteria, includingtuberculosis, compared to a person with two normal copies of the gene.[14]
Tay–Sachs results frommutations in theHEXA gene onchromosome 15, which encodes the alpha-subunit ofbeta-N-acetylhexosaminidase A, alysosomalenzyme. By 2000, more than 100 different mutations had been identified in the humanHEXA gene.[15] These mutations have included single base insertions and deletions,splice phase mutations,missense mutations, and other more complex patterns. Each of these mutations alters thegene's protein product (i.e., the enzyme), sometimes severely inhibiting its function.[16] In recent years, population studies and pedigree analysishave shown how such mutations arise and spread within smallfounder populations.[17][18] Initial research focused on several such founder populations:
In the 1960s and early 1970s, when thebiochemical basis of Tay–Sachs disease was first becoming known, no mutations had beensequenced directly for genetic diseases. Researchers of that era did not yet know how commonpolymorphisms 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.[23] Subsequent research, however, has proven that a large variety of differentHEXA 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 ofcompound heterozygosity has been demonstrated.[24]
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 theHEXA gene, one from each parent. Classic infantile Tay–Sachs disease results when a child has inherited mutations from both parents that completely stop thebiodegradation ofgangliosides. Late-onset forms occur due to the diverse mutation base – people with Tay–Sachs disease may technically be heterozygotes, with two differingHEXA mutations that both inactivate, alter, or inhibit enzyme activity. When a patient has at least oneHEXA copy that still enables some 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.[25]
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 forwild-type alleles' dominance over nonfunctional mutant alleles ininborn errors of metabolism comes from howenzymes function. Enzymes areproteincatalysts for chemical reactions; as catalysts, they speed up reactions without being used up in the process, so only small enzyme quantities are required to carry out a reaction. Someone homozygous for a nonfunctional mutation in the enzyme-encoding gene has little or no enzyme activity, so will manifest the abnormalphenotype (i.e. will develop full-blown disease). A normal: mutated heterozygote (heterozygous individual, also known as a 'carrier') has at least half of the normal enzyme activity level, due to the expression of the wild-type allele. This level is normally enough to enable normal functioning and thus prevent phenotypic expression (i.e. a normal: mutated carrier will not become ill).[26]
Tay–Sachs disease is caused by insufficient activity of the enzymehexosaminidase A. Hexosaminidase A is a vitalhydrolytic enzyme, found in thelysosomes, that breaks downsphingolipids. When hexosaminidase A is no longer functioning properly, the lipids accumulate in the brain and interfere with normal biological processes. Hexosaminidase A specifically breaks downfatty acid derivatives called gangliosides; these are made and biodegraded rapidly in early life as the brain develops. Patients with and carriers of Tay–Sachs can be identified by a simpleblood test that measures hexosaminidase A activity.[8]
Thehydrolysis of GM2-ganglioside requires three proteins. Two of them are subunits of hexosaminidase A; the third is a smallglycolipid transport protein, the GM2 activator protein (GM2A), which acts as a substrate-specificcofactor for the enzyme. Deficiency in any one of these proteins leads to ganglioside storage, primarily in thelysosomes ofneurons. Tay–Sachs disease (along withAB-variant GM2-gangliosidosis andSandhoff disease) occurs because a mutation inherited from both parents deactivates or inhibits this process. Most Tay–Sachs mutations probably do not directly affect protein functional elements (e.g., theactive site). Instead, they cause incorrectfolding (disrupting function) or disable intracellular transport.[27]
In patients with a clinical suspicion of Tay–Sachs disease, with any age of onset, the initial testing involves anenzyme assay to measure the activity of hexosaminidase inserum,fibroblasts, orleukocytes. Total hexosaminidase enzyme activity is decreased in individuals with Tay–Sachs as is the percentage of hexosaminidase A. After confirmation of decreased enzyme activity in an individual, confirmation by molecular analysis can be pursued.[28] All patients with infantile-onset Tay–Sachs disease have a "cherry red"macula in theretina, easily observable by a physician using anophthalmoscope.[8][29] This red spot is a retinal area that appears red because of gangliosides in the surrounding retinal ganglion cells. Thechoroidal circulation is showing through "red" in thisfoveal region where allretinal ganglion cells are pushed aside to increasevisual acuity. Thus, this cherry-red spot is the only normal part of the retina; it shows up in contrast to the rest of the retina. Microscopic analysis of the retinal neurons shows they are distended from excess ganglioside storage.[30] Unlike other lysosomal storage diseases (e.g.,Gaucher disease,Niemann–Pick disease, andSandhoff disease),hepatosplenomegaly (liver and spleen enlargement) is not seen in Tay–Sachs.[31]
Three main approaches have been used to prevent or reduce the incidence of Tay–Sachs:
As of 2010, no treatment addressed the cause of Tay–Sachs disease or could slow its progression; people receivesupportive care to ease the symptoms and extend life by reducing the chance of contracting infections.[37] Infants are given feeding tubes when they can no longer swallow.[38] In late-onset Tay–Sachs, medication (e.g.,lithium for depression) can sometimes control psychiatric symptoms and seizures, although some medications (e.g.,tricyclic antidepressants,phenothiazines,haloperidol, andrisperidone) are associated with significant adverse effects.[25][39]
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 of 5–15, while the lifespans of those with the adult form will probably not be affected.[37]
Ashkenazi Jews have a high incidence of Tay–Sachs and otherlipid storage diseases. In theUnited States, about 1 in 27 to 1 in 30Ashkenazi Jews is a recessive carrier. The diseaseincidence is about 1 in every 3,500 newborns among Ashkenazi Jews.[40]French Canadians and theCajun community ofLouisiana have an occurrence similar to the Ashkenazi Jews.Irish Americans have a 1 in 50 chance of being a carrier.[41] In the general population, the incidence of carriers asheterozygotes is about 1 in 300.[9] The incidence is approximately 1 in 320,000 newborns in the general population in the United States.[42]
Three general classes of theories have been proposed to explain the high frequency of Tay–Sachs carriers in the Ashkenazi Jewish population:
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 aslinkage disequilibrium andcoalescence analysis have brought an emerging consensus among researchers supporting the founder effect theory.[44][46][47]
Waren Tay andBernard Sachs were two physicians. They described the disease's progression and provideddifferential 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.[48] 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.[49][50]
Sachs, who recognized that the disease had a familial basis, proposed that the disease should be calledamaurotic familial idiocy. However, its genetic basis was still poorly understood. AlthoughGregor 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 doctors of the time. The first edition of theJewish Encyclopedia, published in 12 volumes between 1901 and 1906, described what was then known about the disease:[51]
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 inEastern Europe; this was also a period ofnativism (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.[50]
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.[52] 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 prenatal diagnosis.[36][53] By the end of 1979, researchers had identified three variant forms ofGM2 gangliosidosis, including Sandhoff disease and the AB variant of GM2-gangliosidosis, accounting for false negatives in carrier testing.[54]
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 ledIsrael to become the first country that offers free genetic screening andcounseling for all couples and opened discussions about the proper scope of genetic testing for other disorders in Israel.[55]
Because Tay–Sachs disease was one of the first autosomal recessive genetic disorders for which there was anenzyme assay test (beforepolymerase chain reaction testing methods), it was intensely studied as a model for all such diseases, and researchers sought evidence of aselective process. A continuing controversy is whetherheterozygotes (carriers) have or had a selective advantage. The presence of four differentlysosomal storage disorders in theAshkenazi Jewish population suggests a past selective advantage for heterozygous carriers of these conditions."[46]
This controversy among researchers has reflected various debates among geneticists at large:[56]
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 toinsulin injections fordiabetes. However, in previous studies, theHEXA enzyme itself has been thought to be too large to pass through the specialized cell layer in the blood vessels that form theblood–brain barrier in humans.[citation needed]
Researchers have also tried directly instilling the deficient enzyme hexosaminidase A into thecerebrospinal fluid (CSF) which bathes the brain. However, intracerebral neurons seem unable to take up this physically largemolecule efficiently even when it is directly by them. Therefore, this approach to treatment of Tay–Sachs disease has also been ineffective so far.[58]
Tay–Sachs disease exists inJacob sheep.[59] The biochemical mechanism for this disease in the Jacob sheep is virtually identical to that in humans, wherein diminished activity of hexosaminidase A results in increased concentrations of GM2 ganglioside in the affected animal.[60] Sequencing of theHEXA genecDNA of affected Jacobs sheep reveal an identical number ofnucleotides andexons as in the humanHEXA gene, and 86% nucleotide sequenceidentity.[59] A missense mutation (G444R)[61] was found in theHEXA cDNA of the affected sheep. This mutation is a single nucleotide change at the end of exon 11, resulting in that exon's deletion (before translation) viasplicing. The Tay–Sachs model provided by the Jacob sheep is the first to offer promise as a means for gene therapyclinical trials, which may prove useful for disease treatment in humans.[59]
Other experimental methods being researched involvesubstrate reduction therapy, which attempts 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.[62][63] One experiment has demonstrated that using the enzymesialidase allows the genetic defect to be effectively bypassed, and as a consequence, GM2 gangliosides are metabolized so that their levels become almost inconsequential. If a safe pharmacological treatment can be developed – one that increases expression of lysosomal sialidase in neurons without other toxicity – then this new form of therapy could essentially cure the disease.[64]
Another metabolic therapy under investigation for Tay–Sachs disease usesmiglustat.[65] This drug is a reversibleinhibitor of the enzymeglucosylceramide synthase, which catalyzes the first step in synthesizing glucose-basedglycosphingolipids like GM2 ganglioside.[66]
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 drugpyrimethamine has been shown to increase activity of β-hexosaminidase A.[67] 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.[67]
This is a highly invasive procedure that involves destroying the patient's blood system with chemotherapy and administeringcord 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.[68]
Critics point to the procedure's harsh nature—and the fact that it is unapproved. Other significant issues involve the difficulty in crossing theblood–brain barrier, as well as the great expense, as each unit of cord blood costs $25,000, and adult recipients need many units.[69]
On 10 February 2022, the first-ever gene therapy was announced, it uses anadeno-associated virus (AAV) to deliver the correct instruction for theHEXA 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-relatedadverse events.[70][71][72]
