Tay-Sachs disease

テイ・サックス病 TSD

WordNet

1. an impairment of health or a condition of abnormal functioning
2. caused by or altered by or manifesting disease or pathology; "diseased tonsils"; "a morbid growth"; "pathologic tissue"; "pathological bodily processes" (同)morbid, pathologic, pathological
3. the 20th letter of the Roman alphabet (同)t
4. a branch of the Tai languages

PrepTutorEJDIC

1. (体の)『病気』,疾患 / (精神・道徳などの)病気,病弊
2. 女性の話術芸人 =diseur
3. 病気にかかった / 病的な,不健全な(morbid)
4. tritiumの化学記号
5. tantalumの化学記号

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/10/10 10:06:02」(JST)

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Tay–Sachs disease
Cherry-red spot as seen in Tay–Sachs disease: the fovea's center appears bright red because it is surrounded by a milky halo.
Classification and external resources
Specialty	Medical genetics
ICD-10	E75.0
ICD-9-CM	330.1
OMIM	272800 272750
DiseasesDB	12916
MedlinePlus	001417
eMedicine	ped/3016
Patient UK	Tay–Sachs disease
MeSH	D013661

Tay–Sachs disease (also known as GM2 gangliosidosis or hexosaminidase A deficiency) is a rare autosomal recessive genetic disorder. In its most common variant (known as infantile Tay–Sachs disease), it causes a progressive deterioration of nerve cells and of mental and physical abilities that begins around six months of age and usually results in death by the age of four. The disease occurs when harmful quantities of cell membrane components known as gangliosides accumulate in the brain's nerve cells, eventually leading to the premature death of the cells. A ganglioside is a form of sphingolipid, which makes Tay–Sachs disease a member of the sphingolipidoses. There is no known cure or treatment.

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

Research in the late 20th century demonstrated that Tay–Sachs disease is caused by a genetic mutation in the HEXA gene on (human) 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 that seen in Ashkenazi Jews, but carry a different mutation. Cajuns of southern Louisiana carry the same mutation that is seen most commonly in Ashkenazi Jews. HEXA mutations are rare and are most seen in genetically isolated populations. Tay–Sachs can occur from the inheritance of either two similar, or two unrelated, causative mutations in the HEXA gene.

As an autosomal recessive disorder, two Tay–Sachs alleles are required for an individual to exhibit symptoms of the disease. Carriers of a single Tay–Sachs allele do not exhibit symptoms of the disease but appear to be protected to some extent against tuberculosis. This accounts for the persistence of the allele in certain populations in that it confers a selective advantage—in other words, being a heterozygote is advantageous.

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 stimulus, known as the "startle response", because they are startled. 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 neurological symptoms.

• Infantile Tay–Sachs disease. Infants with Tay–Sachs disease appear to develop normally for the first six months after birth. Then, as neurons become distended with gangliosides, a relentless deterioration of mental and physical abilities begins. The child may become blind, deaf, unable to swallow, atrophied, and paralytic. Death usually occurs before the age of four.
• Juvenile Tay–Sachs disease. 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 develop cognitive and motor skill deterioration, dysarthria, dysphagia, ataxia, and spasticity. Death usually occurs between the age of five to fifteen years.
• Adult/Late-Onset Tay–Sachs disease. 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. People with late-onset Tay–Sachs may become full-time wheelchair users in adulthood.

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.

Genetics

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

The HEXA gene is located on the long (q) arm of human 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 with each pregnancy. The affected child would have received a mutated copy of the gene from each parent.

Tay–Sachs results from mutations in the HEXA gene on human chromosome 15, which encodes the alpha-subunit of beta-N-acetylhexosaminidase A, a lysosomal enzyme. By 2000, more than 100 different mutations had been identified in the human HEXA gene. These mutations have included single base insertions and deletions, splice phase mutations, missense mutations, and other more complex patterns. Each of these mutations alters the gene's protein product (i.e., the enzyme), sometimes severely inhibiting its function. In recent years, population studies and pedigree analysis have shown how such mutations arise and spread within small founder populations. Initial research focused on several 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.
• Cajun. 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.
• French Canadians. Two mutations, unrelated to the Ashkenazi/Cajun mutation, are absent in France but common among French Canadians living in eastern Quebec and Acadians from the Province of New Brunswick. Pedigree analysis suggests the mutations were uncommon before the late 17th century.

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. 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.

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.

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 wild-type alleles' dominance over nonfunctional mutant alleles in inborn errors of metabolism comes from how enzymes function. Enzymes are protein catalysts 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 abnormal phenotype. A heterozygote (heterozygous individual) has at least half of the normal enzyme activity level, due to expression by the wild-type allele. This level is normally enough to enable normal function and thus prevent phenotypic expression.

Pathophysiology

Tay–Sachs disease is caused by insufficient activity of the enzyme hexosaminidase A. Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down glycolipids. When hexosaminidase A is no longer functioning properly, the lipids accumulate in the brain and interfere with normal biological processes. Hexosaminidase A specifically breaks down fatty 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 simple blood test that measures hexosaminidase A activity.

The hydrolysis of GM2-ganglioside requires three proteins. Two of them are subunits of hexosaminidase A; 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 ganglioside storage, primarily in the lysosomes of neurons. Tay–Sachs disease (along with AB-variant GM2-gangliosidosis and Sandhoff 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., the active site). Instead, they cause incorrect folding (disrupting function) or disable intracellular transport.

Diagnosis

In patients with a clinical suspicion for Tay–Sachs disease, with any age of onset, the initial testing involves an enzyme assay to measure the activity of hexosaminidase in serum, fibroblasts or leukocytes. 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. All patients with infantile onset Tay–Sachs disease have a "cherry red" macula in the retina, easily observable by a physician using an ophthalmoscope. This red spot is a retinal area that appears red because of gangliosides in the surrounding retinal ganglion cells. The choroidal circulation is showing through "red" in this foveal region where all retinal ganglion cells are pushed aside to increase visual 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. Unlike other lysosomal storage diseases (e.g., Gaucher disease, Niemann–Pick disease, and Sandhoff disease), hepatosplenomegaly (liver and spleen enlargement) is not seen in Tay–Sachs.

Prevention

Main article: Prevention of Tay–Sachs disease

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. 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.
• Preimplantation genetic diagnosis. By retrieving the mother's eggs for in vitro fertilization, it is possible to test the embryo for the disorder prior to implantation. Healthy embryos are then selected and transferred into the mother's womb, while unhealthy embryos are discarded. In addition to Tay–Sachs disease, preimplantation genetic diagnosis has been used to prevent cystic fibrosis and sickle cell anemia among other genetic disorders.
• 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.

Management

There is currently no cure or treatment for Tay–Sachs disease. Even with the best care, children with infantile Tay–Sachs disease die by the age of 4. Although experimental work is underway, no current medical treatment of the root cause yet exists. Patients receive supportive care to ease the symptoms or extend life. Infants are given feeding tubes when they can no longer swallow. Improvements in life-extending care have somewhat lengthened the survival of children with Tay–Sachs disease, but no current therapy is able to reverse or delay the disease's progress. 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, and risperidone) are associated with significant adverse effects. In 2011, researchers discovered that Pyrimethamine can increase ß-hexosaminidase activity, thus slowing down the progression of Late-Onset Tay–Sachs disease.

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. Two of the three founder populations are genetically distinct from the original population.

Ashkenazi Jews have a high incidence of Tay–Sachs and other lipid storage diseases. In the United States, about 1 in 27 to 1 in 30 Ashkenazi Jews are a recessive carrier. The disease incidence is about 1 in every 3,500 newborn among Ashkenazi Jews. 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. The incidence is approximately 1 in 320,000 newborns in the general population in United States.

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

• Heterozygote advantage. When applied to a particular allele, this theory posits that mutation carriers have a selective advantage, perhaps in a particular environment.
• Reproductive compensation. Parents who lose a child because of disease tend to "compensate" by having additional children to replace them. This phenomenon may maintain and possibly even increase the incidence of autosomal recessive disease.
• Founder effect. This hypothesis states that the high incidence of the 1278insTATC chromosomes is the result of an elevated allele frequency that existed by chance in an early founder 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 as linkage disequilibrium and coalescence analysis have brought an emerging consensus among researchers supporting the founder effect theory.

History

Main article: History of Tay–Sachs disease

Waren Tay and Bernard Sachs, two physicians, described the disease's progression and provided differential diagnostic criteria to distinguish it from other neurological disorders with similar symptoms.

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. 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.

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 doctors 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:

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.

In 1969, Shintaro Okada and John S. O'Brien showed that Tay–Sachs disease was caused by an enzyme defect; he also proved that Tay–Sachs patients could be diagnosed by an assay of hexosaminidase A activity. 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. 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.

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 and opened discussions about the proper scope of genetic testing for other disorders in Israel.

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) have or had a selective advantage. The presence of four different lysosomal storage disorders in the Ashkenazi Jewish population suggests a past selective advantage for heterozygous carriers of these conditions."

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

• 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 classical/balance controversy. The classical hypothesis of genetic variability, often associated with Hermann Muller, maintains that most genes are of a normal wild type, and that most individuals are homozygous for that wild type, while most selection is 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.
• Selectionists versus neutralists. In theoretical population genetics, selectionists emphasize the primacy of natural selection as a determinant of evolution and of variation within a population, while neutralists favor a form of Motoo Kimura's neutral theory of molecular evolution, which emphasizes the role of genetic drift.

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.

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.

Jacob sheep model

Tay–Sachs disease exists in Jacob sheep. 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. Sequencing of the HEXA gene cDNA of affected Jacobs sheep reveal an identical number of nucleotides and exons as in the human HEXA gene, and 86% nucleotide sequence identity. A missense mutation (G444R) was found in the HEXA 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) via splicing. The Tay–Sachs model provided by the Jacob sheep is the first to offer promise as a means for gene therapy clinical trials, which may prove useful for disease treatment in humans.

Substrate reduction therapy

Other experimental methods being researched involve substrate 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. One experiment has demonstrated that using the enzyme sialidase 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.

Another metabolic therapy under investigation for Tay–Sachs disease uses miglustat. This drug is a reversible inhibitor of the enzyme glucosylceramide synthase, which catalyzes the first step in synthesizing glucose-based glycosphingolipids like GM2 ganglioside.

Increasing β-hexosaminidase A activity

As Tay–Sachs disease is a deficiency of β-hexosaminidase A, by getting a substance that increases its activity, people affected will not be deteriorating as fast or not at all. While for infantile Tay–Sachs disease, there is no β-hexosaminidase A so then the treatment would be ineffective. However, for people affected by Late-Onset Tay–Sachs disease, they still have β-hexosaminidase A. The drug Pyrimethamine has been shown to increase activity of β-hexosaminidase A. 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.

References

External links

• GeneReviews/NCBI/NIH/UW entry on hexosaminidase A deficiency, Tay–Sachs disease
• NINDS Tay–Sachs Disease Information Page
• Tay–Sachs disease at NLM Genetics Home Reference
• Tay–Sachs on NCBI

UpToDate Contents

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• 1. アシュケナージ系ユダヤ人集団における遺伝的疾患の出生前スクリーニング prenatal screening for genetic disease in the ashkenazi jewish population
• 2. 先天性代謝異常：疫学、病因、および臨床的特徴 inborn errors of metabolism epidemiology pathogenesis and clinical features
• 3. 遺伝性運動失調の概要 overview of the hereditary ataxias
• 4. 筋萎縮性側索硬化症およびその他の運動ニューロン疾患の診断 diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease
• 5. 先天性代謝異常：分類 inborn errors of metabolism classification

English Journal

• Genetic testing behavior and reporting patterns in electronic medical records for physicians trained in a primary care specialty or subspecialty.

• Ronquillo JG, Li C, Lester WT.SourceLaboratory of Computer Science, Massachusetts General Hospital, Boston, Massachusetts, USA.
• Journal of the American Medical Informatics Association : JAMIA.J Am Med Inform Assoc.2012 Apr 17. [Epub ahead of print]
• ObjectiveTo characterize important patterns of genetic testing behavior and reporting in modern electronic medical records (EMRs) at the institutional level.Materials and methodsRetrospective observational study using EMR data of all 10 715 patients who received genetic testing by physicians train
• PMID 22511017

• Lysosomal Dysfunction in a Mouse Model of Sandhoff Disease Leads to Accumulation of Ganglioside-Bound Amyloid-β Peptide.

• Keilani S, Lun Y, Stevens AC, Williams HN, Sjoberg ER, Khanna R, Valenzano KJ, Checler F, Buxbaum JD, Yanagisawa K, Lockhart DJ, Wustman BA, Gandy S.SourceDepartments of Neurology and Psychiatry, Alzheimer's Disease Research Center, and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, Amicus Therapeutics, Cranbury, New Jersey 08512, Amicus Therapeutics, La Jolla, California 92037, Institute of Molecular and Cellular Pharmacology, UMR7275 CNRS/Université de Nice-Sophia Antipolis, "Fondation Pour la Recherche Médicale" and "Laboratory of excellence (DISTALZ)" Team, 06560 Valbonne, France, and Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522, Japan.
• The Journal of neuroscience : the official journal of the Society for Neuroscience.J Neurosci.2012 Apr 11;32(15):5223-5236.
• Alterations in the lipid composition of endosomal-lysosomal membranes may constitute an early event in Alzheimer's disease (AD) pathogenesis. In this study, we investigated the possibility that GM2 ganglioside accumulation in a mouse model of Sandhoff disease might be associated with the accumulatio
• PMID 22496568

Japanese Journal

• Identification of two HEXA mutations causing infantile-onset Tay-Sachs disease in the Persian population

• HAGHIGHI Alireza,REZAZADEH Jamileh,SHADMEHRI Azam Ahmadi,HAGHIGHI Amirreza,KORNREICH Ruth,DESNICK Robert J
• Journal of human genetics 56(9), 682-684, 2011-09-01
• NAID 10030661076

• Identification of two HEXA mutations causing infantile-onset Tay-Sachs disease in the Persian population

• Hanghighi Alireza,Rezazadeh Jamileh,Shadmehri Azam Ahmadi [他]
• Journal of human genetics 56(9), 682-684, 2011-09
• NAID 40018996986

Related Links

• テイ＝サックス病 - Wikipedia

Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients. ... Based in part on the 'Tay-Sachs Disease Information Page' of the National Institute of Neurological Disorders and Stroke ...

• Tay–Sachs disease - Wikipedia, the free encyclopedia

Tay–Sachs disease (also known as GM2 gangliosidosis or hexosaminidase A deficiency) is a rare autosomal recessive genetic disorder. In its most common variant (known as infantile Tay–Sachs disease), it causes a progressive deterioration ...

Related Pictures

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★リンクテーブル★

リンク元	「テイ・サックス病」「ヘキソサミニダーゼA」「チェリーレッドスポット」「TSD」
拡張検索	「AB variant Tay-Sachs disease」
関連記事	「disease」「T」「Ta」

「テイ・サックス病」

　　[★]

英

Tay-Sachs disease

同

テイ-サックス病、(国試)Tay-Sachs病

βヘキソサミニダーゼA欠損症 β-hexosaminidase A deficiency、家族性黒内障性白痴 amaurotic familial idiocy, AFI

GM2ガングリオシドーシスI型 GM2 gangliosidosis type I

関

リソソーム蓄積症、スフィンゴ脂質蓄積症。サンドホフ病。スフィンゴリピドーシス、ガングリオシド、スフィンゴ脂質

• first aid step1 2006 p.99

概念

• 家族性黒内障白痴のinfantile form。
• 乳児期に発病し、重度の精神運動発達遅延を呈する。

視力障害、精神運動発育遅延、筋トーヌス亢進、球麻痺、小脳失調などが進行し、痙攣発作などをきたし、除脳硬直に至って死亡する。

• 黄斑部にチェリーレッドスポットが出現
• βヘキソサミニダーゼαサブユニット遺伝子(15q23-24)の異常によるβヘキソサミニダーゼAの欠損症

病因

• 欠損酵素：hexosaminidase A
• 蓄積する物質：G_M2 ganglioside

病型

• 乳児型GM2-ガングリオシドーシス(古典的テイ-サックス病)、家族性黒内障性白痴
• 若年型GM2-ガングリオシドーシス
• 慢性・成人型GM2-ガングリオシドーシス

臨床病型 (PED.311)

		乳児型	若年型	慢性・成人型
発症年齢		3-5ヶ月	2-10歳	様々
経過		2-4歳で死亡	15歳頃までに死亡	様々
中枢神経症状	発達遅滞・退行	＋	＋	－
	精神症状	－	－	＋
	錐体路症状	＋	＋	－
	錐体外路症状	－	－	＋
	失調症状	－	－	＋
	痙攣	＋	＋	－
眼底所見	cherry red spot	＋	±	－

疫学

• アシュケナージ系ユダヤ人(Ashkenazi Jews)に多い

遺伝形式

• 常染色体劣性遺伝

症状

• 精神遅滞、盲目、muscular weakness、生後3年以内の死亡

progressive neurodegeneration, developmental delay, cherry-red spot, lysozymes with onion skin

治療

• 根治療法無し

予後

• 3歳くらいまでに死亡

「ヘキソサミニダーゼA」

　　[★]

英

hexosaminidase A

• 欠損によりテイ・サックス病を呈するGM2ガングリオシド分解酵素
• ガングリオシドGM2　－(hexosaminidase A)→ ガングリオシドGM3

臨床関連

• テイ・サックス病 Tay-Sachs disease

「チェリーレッドスポット」

　　[★]

英

cherry-red　spot

同

さくらんぼ赤色斑、桜実紅斑

関

[[]]

• 網膜中心動脈閉塞症 central retinal artery occlusion
• テイ・サックス病 Tay-Sachs disease
• ニーマン-ピック病 Niemann-Pick disease

「TSD」

　　[★] テイ・サックス病 Tay-Sachs disease

「AB variant Tay-Sachs disease」

　　[★]

AB型テイ・サックス病、AB型Tay-Sachs病

「disease」

　　[★]

• n.

疾患：illnessより厳密な概念。「ある臓器に明確な障害が確認され、それによって症状が出ているとはっきり説明できる場合」 (PSY.9)

特定の原因、病態生理、症状、経過、予後、病理組織所見が全てそろった場合 (PSY.9)

• something that is very wrong with people's attitudes, way of life or with society.

関

ail、ailment、disease entity、disorder、ill、illness、malady、sick、sickness

• 注意

disease ≠ illness ≠ disorder

　 　 　

「T」

　　[★]

• T波 T wave
• チミン thymine
• ツイスト数
• スレオニントレオニン threonine

　 　

「Ta」

　　[★]

タンタル

関

tantalum