Table of Contents - #272800

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#272800 ICD+
  • ICD10CM: E75.02,
  • SNOMEDCT: 111385000
 ICD10CM: E75.02, SNOMEDCT: 111385000
TAY-SACHS DISEASE; TSD

Alternative titles; symbols
GM2-GANGLIOSIDOSIS, TYPE I
B VARIANT GM2-GANGLIOSIDOSIS
HEXOSAMINIDASE A DEFICIENCY
HEXA DEFICIENCY

Other entities represented in this entry:
TAY-SACHS DISEASE, JUVENILE, INCLUDED
HEXOSAMINIDASE A DEFICIENCY, ADULT TYPE, INCLUDED
GM2-GANGLIOSIDOSIS, ADULT CHRONIC TYPE, INCLUDED
GM2-GANGLIOSIDOSIS, VARIANT B1, INCLUDED
TAY-SACHS DISEASE, VARIANT B1, INCLUDED
TAY-SACHS DISEASE, PSEUDO-AB VARIANT, INCLUDED

Phenotype Gene Relationships
Location Phenotype Phenotype
MIM number		 Gene/Locus Gene/Locus
MIM number
15q23 Tay-Sachs disease 272800 HEXA 606869
15q23 GM2-gangliosidosis, several forms 272800 HEXA 606869
15q23 [Hex A pseudodeficiency] 272800 HEXA 606869

Clinical Synopsis

TEXT
A number sign (#) is used with this entry because Tay-Sachs disease is caused by mutation in the alpha subunit of the hexosaminidase A gene (HEXA; 606869).

Description
Tay-Sachs disease is an autosomal recessive, progressive neurodegenerative disorder which, in the classic infantile form, is usually fatal by age 2 or 3 years.

Clinical Features
Classic Tay-Sachs disease is characterized by the onset in infancy of developmental retardation, followed by paralysis, dementia and blindness, with death in the second or third year of life. A gray-white area around the retinal fovea centralis, due to lipid-laden ganglion cells, leaving a central 'cherry-red' spot is a typical funduscopic finding. Pathologic verification is provided by the finding of the typically ballooned neurons in the central nervous system. An early and persistent extension response to sound ('startle reaction') is useful for recognizing the disorder.

Kolodny (1972), who studied the proband described by Okada et al. (1971), stated that visual function was retained and optic atrophy was not present at age 20 months. At death at 32 months, microscopic findings in the central nervous system were similar to those in Tay-Sachs disease. The patients showed normal results in tests that usually demonstrate the Tay-Sachs heterozygote.

Suzuki et al. (1970) and O'Brien (1972) reported non-Jewish patients with the Tay-Sachs variant of juvenile-onset GM2-gangliosidosis. Onset occurred with ataxia between ages 2 and 6 years. Thereafter deterioration to decerebrate rigidity took place. Blindness occurred late in the course in only some patients, unlike the situation in classic Tay-Sachs disease in which blindness is an invariable and early development. Death occurred between ages 5 and 15 years. The defect is a partial deficiency of hexosaminidase A.

Rapin et al. (1976) described a brother and 2 sisters of Ashkenazi extraction who had slowly progressive deterioration of gait and posture beginning in early childhood, muscle atrophy beginning distally, pes cavus, foot drop, spasticity, mild ataxia of limbs and trunk, dystonia, and dysarthria. Intelligence was little affected, vision and optic fundi were normal, and no seizures had occurred. One sister died at age 16 following a drug reaction. Autopsy showed diffuse neuronal storage with zebra bodies and increased GM2-ganglioside. Hexosaminidase A was decreased in the serum and leukocytes of the 2 living patients, and in their parents was in the range of carriers of Tay-Sachs disease. The 2 living sibs were 31 and 34 years old at the time of the report. This may be an allelic variety of Tay-Sachs disease. Kaback et al. (1978) described a similar but possibly distinct case. The son of an Ashkenazi couple was entirely normal until age 16 when slight leg muscle cramps began. Hex-A deficiency was found in a screening program at age 20. Both parents and a sister were heterozygotes. Heterokaryon complementation showed the development of Hex-A when the proband's cells were fused with Sandhoff cells, but showed no complementation with Tay-Sachs cells. Between ages 20 and 22, the patient showed dramatically progressive proximal muscle wasting, weakness, fasciculations, EMG abnormality, and elevated CPK. Ophthalmologic, audiologic and intellectual function remained normal. Muscle biopsy suggested anterior horn disease. Rectal ganglion cells showed ballooning and onion-skin cytoplasmic bodies.

Willner et al. (1981) reported 9 patients from 4 unrelated Ashkenazi Jewish families with a variant form of Hex-A deficiency masquerading as atypical Friedreich ataxia. They proposed that the affected individuals may be genetic compounds for the Tay-Sachs allele and another distinctive allele.

Johnson et al. (1982) observed a 24-year-old Ashkenazi man with a 9-year history of progressive leg weakness and fasciculations. Other data were consistent with anterior horn cell disease. Hex-A was markedly decreased in the patient and partially decreased in both parents and a brother. A paternal relative had classic Tay-Sachs disease. The clinical picture, which suggested the Kugelberg-Welander phenotype, may have resulted, according to the suggestion of the authors, from a genetic compound state of the classic allele and a mild allele.

Griffin (1984) had a 31-year-old patient with hexosaminidase deficiency and marked cerebellar atrophy, dementia, and denervation motor neuron disease. Both parents showed a partial deficiency. In 3 patients in 2 unrelated families, Mitsumoto et al. (1985) described adult variants of hexosaminidase A deficiency. A 30-year-old non-Jewish proband in the first family had juvenile amyotrophic lateral sclerosis beginning at age 16 years and evolving to mild dementia, ataxia, and axonal (neuronal) motor-sensory peripheral neuropathy. A supposedly healthy brother, aged 32, had difficulty with memory in college but had obtained 2 degrees in 8 years and worked in an electronics company. He was dismissed from his job for poor memory and comprehension. He showed mild spasticity and ataxia but no evidence of motor neuron disease. In the second family, a 36-year-old man with Ashkenazi mother and Syrian Sephardic father had 'pure' spinal muscular atrophy; he had lifelong physical limitation with inability to run or throw a ball as a child. All 3 had marked cerebellar atrophy. Against artificial substrates, Hex-A activity was in the range of Tay-Sachs disease homozygotes but was higher when GM2 substrates were used. Hex-A activity in the parents was in the heterozygous range.

In a 34-year-old English Canadian man described by Parnes et al. (1985), the clinical picture was that of juvenile-onset spinal muscular atrophy. Atypical features were prominent muscle cramps, postural and action tremor, recurrent psychosis, incoordination, corticospinal and corticobulbar involvement, and dysarthria. With the report of a 24-year-old, non-Jewish man with dystonia, dementia, amyotrophy, choreoathetosis, and ataxia, Oates et al. (1986) emphasized that presumably allelic forms of Hex-A deficiency can take unusual clinical forms.

In Israel, Navon et al. (1986) identified 18 Hex-A-deficient adults by the end of 1985. All were Ashkenazi. The clinical picture varied between and within families and included spinocerebellar, various motor neuron, and cerebellar syndromes. The possibility exists that many of the affected persons are compound heterozygotes of the TSD allele with another rare allele. The relatively high frequency of the atypical adult disorder(s) in Ashkenazim is the result of the high frequency of the TSD allele to create genetic compounds.

Grebner et al. (1986) studied 3 clinically normal persons, aged 6 to 30 years, with absent serum Hex-A activity against artificial substrates and concluded that they were probably genetic compounds of the usual Tay-Sachs allele and a different mutant allele that in combination with it gave the abnormal phenotype. Karni et al. (1988) described a 39-year-old Israeli woman with proximal lower limb weakness and fasciculations as the only manifestations of Hex-A deficiency.

Bayleran et al. (1987) characterized the defective enzyme in 2 patients with Tay-Sachs disease and a high residual Hex-A activity. Clinical presentation was identical to that found among Ashkenazi patients. Both patients appeared to be heterozygous for the B1 phenotype, having virtually no capacity for hydrolysis of the sulfated HEXA substrate 4-methylumbelliferyl-beta-D-N-acetylglucosamine-6-sulfate (4MUGS).

Barnes et al. (1991) described a 42-year-old man of non-Jewish ancestry who in his 20s and 30s had the onset of slowly progressive gait disturbance, generalized weakness, dysarthria, clumsiness and tremor of his hands, and involuntary jerks. Two previously unreported features were clinically evident sensory neuropathy and internuclear ophthalmoplegia.

Perlman (2002) commented on late-onset Tay-Sachs disease as a Friedreich ataxia phenocopy.

Rucker et al. (2004) evaluated eye movements in 14 patients with late-onset Tay-Sachs disease (average age, 39 years). The main clinical features included childhood clumsiness or incoordination, proximal muscle weakness, ataxia, dysarthria, and tremor. All patients had normal visual function and normal optic fundi without cherry red spots. Saccades were hypometric and multistep with transient decelerations. Peak acceleration values of the saccades were normal, but decelerations occurred sooner and faster than in controls. Smooth pursuit was also impaired. Rucker et al. (2004) postulated a disruption in a 'latch circuit' that normally inhibits pontine 'omnipause' neurons to allow completion of eye movement. Saccade measurements may be a means of evaluating responses to treatment in patients with late-onset Tay-Sachs disease.

Neufeld (1989) provided a review of the disorders related to mutations in the HEXA (606869) and HEXB genes (606873).

Biochemical Features
Balint and Kyriakides (1968) demonstrated accumulation of a glycoprotein in red cells of patients with Tay-Sachs disease. The basic enzyme defect was shown by Okada and O'Brien (1969) to concern one component of hexosaminidase. Total hexosaminidase activity was normal but when components A (HEXA; 606869) and B (HEXB; 606873) were separated, component A was found to be absent. Hultberg (1969) confirmed the findings of Okada and O'Brien (1969). Okada et al. (1971) compared the findings in regard to hexosaminidases A and B in 3 forms of ganglioside GM2 storage disease--Tay-Sachs disease, Sandhoff disease (268800), and juvenile GM2-gangliosidosis.

Galjaard et al. (1974), Thomas et al. (1974), and Rattazzi et al. (1975) showed that Hex-A activity appears after fusion of Tay-Sachs and Sandhoff cells, suggesting genetic (or at least metabolic) complementation.

Beutler et al. (1975) concluded that Hex-A has the structure alpha-beta, whereas Hex-B is beta-beta; Tay-Sachs disease is an alpha-minus mutation, whereas Sandhoff disease is a beta-minus mutation; in the absence of beta subunits there is increased polymerization of alpha units to form Hex-S, which is a normal constituent of plasma and probably has a structure of alpha-6.

O'Brien (1978) made suggestions for nomenclature of the various hexosaminidase A and B mutations. Three loci were postulated: alpha, responsible for the alpha subunit, mapped to chromosome 15; beta, responsible for the beta subunit, mapped to chromosome 5; and an activator locus or loci determining the structure of one or more proteins that stimulate Hex-A to cleave GM2 and GA2 gangliosides.

Conzelmann et al. (1983) used a sensitive assay to demonstrate a correlation between level of residual activity and clinical severity: Tay-Sachs disease, 0.1% of normal; late infantile, 0.5%; adult GM2-gangliosidosis, 2-4%; healthy persons with 'low hexosaminidase,' 11% and 20%.

Several patients with a chronic type of Tay-Sachs disease were found by d'Azzo et al. (1984) to produce alpha-hexosaminidase A.

GM2-Gangliosidosis, B1 Variant

Patients with the GM2-gangliosidosis B1 variant produce hexosaminidase A, which appears catalytically normal when tested with substrates such as 4-methylumbelliferyl N-acetyl-glucosaminidase that are split by an active site of the beta subunit, but is catalytically defective against substrates that are hydrolyzed by the active site on the alpha subunit of normal hexosaminidase A, which is inactivated in patients' enzyme (Kytzia and Sandhoff, 1985).

Li et al. (1981) described a patient described as having a variant of type AB GM2-gangliosidosis but with a probable defect in beta-hexosaminidase A and not in the GM2 activator.

Inui et al. (1983) described a brother and sister from a consanguineous Puerto Rican marriage who had a juvenile-onset lipidosis first evident clinically at age 2.5 years by difficulties in motor function and delay in development. The sibs continued to deteriorate, showing muscle atrophy, spasticity, and loss of speech, and died at ages 7 and 8. Examination of the brains from these patients showed that the disorder was a GM2-gangliosidosis. HEXA and other lysosomal enzymes were normal and the GM2-activator protein was present in high normal concentrations in the liver. The defect in these patients appeared to reside in HEXA, which although normal in heat stability, electrophoretic mobility, and activity toward fluorogenic substrates, was resistant to activation, possibly because of defective binding to the activator. Inui et al. (1983) suggested that this be called the A(M)B variant of juvenile GM2-gangliosidosis to distinguish it from the disorder in patients missing the activator protein. (M = mutant.)

Sonderfeld et al. (1985) showed the expected complementation between the B (Tay-Sachs disease) and 0 (Sandhoff disease) variants and between the AB variant (activator deficiency) and any of the 3 variants: B, 0, and B1. Hex-A was shown to have 2 distinct catalytic sites. Complementation was demonstrated between B1 cells and variant 0 but not with variant B. Thus, the B1 cells must carry a mutation in the gene for the alpha subunit. Confirmation came from studies of the processing of immature enzyme in variant B1 cells showing the presence of alpha precursors and mature alpha chains but at a lower level than normal cells.

Pathogenesis
Through serial analysis of gene expression (SAGE), Myerowitz et al. (2002) determined gene expression profiles in cerebral cortex from a Tay-Sachs patient, a Sandhoff disease patient, and a pediatric control. Examination of genes that showed altered expression in both patients revealed molecular details of the pathophysiology of the disorders relating to neuronal dysfunction and loss. A large fraction of the elevated genes in the patients could be attributed to activated macrophages/microglia and astrocytes, and included class II histocompatibility antigens, the proinflammatory cytokine osteopontin (SPP1; 166490), complement components, proteinases and inhibitors, galectins, osteonectin (SPARC; 182120), and prostaglandin D2 synthase (PTGDS; 176803). The authors proposed a model of neurodegeneration that includes inflammation as a factor leading to the precipitous loss of neurons in individuals with these disorders.

Mapping
By study of somatic cell hybrids, Gilbert et al. (1975) suggested that a locus determining hexosaminidase A is on chromosome 7. Subsequently, Van Heyningen et al. (1975) found that the MPI (154550) and PK3 (179050) loci are on chromosome 15, and Lalley et al. (1975) concluded that MPI, PK3 and HEXA are syntenic.

Chern et al. (1976) studied heteropolymeric hexosaminidase A formed by human-mouse hybrid cells that contained an X-15 translocation chromosome but lacked human chromosome 5. Tests with specific antisera suggested that the hybrid molecule had human alpha units and mouse beta units. The findings are consistent with hexosaminidase A being composed of alpha and beta subunits coded by genes on chromosomes 15 and 5, respectively.

Formiga et al. (1988) reported 2 cases of interstitial deletion of chromosome 15. Assay of hexosaminidase A in 1 enabled them to confirm that the structural gene is located between 15q22 and 15q25 and is included in the deletion. By high resolution in situ hybridization, Takeda et al. (1990) narrowed the assignment to 15q23-q24. Using a cDNA clone for in situ hybridization, Nakai et al. (1991) assigned the HEXA gene to 15q23-q24.

Molecular Genetics
Myerowitz and Costigan (1988) demonstrated that the most frequent DNA lesion in Tay-Sachs disease in Ashkenazi Jews is a 4-bp insertion in exon 11 of the HEXA gene (606869.0001).

The gene responsible for the juvenile form has been shown by molecular analysis of the HEXA gene to be allelic to that responsible for the classic infantile form of Tay-Sachs disease (Paw et al., 1990). Whereas classic Tay-Sachs patients with complete deficiency of hexosaminidase A die before age 5 years, patients with the partial deficiency die by age 15 years.

Tanaka et al. (1990) studied 7 patients with the enzymologic characteristics of the B1 variant. All of the patients, except 1 from Czechoslovakia, carried the same arg178-to-his mutation referred to as DN (see 606869.0006). The Czechoslovakian patient had a mutation in the same codon: a change of nucleotide 532 from C to T resulting in an arg178-to-cys change in the protein (see 606869.0007). Site-directed mutagenesis and expression studies in COS-1 cells demonstrated that either of the point mutations abolished catalytic activity of the alpha subunit. The HEXA gene has 1 intron that is exceptionally large. Is it possible that it contains a sequence that codes for an unrelated protein, with an allelic form in linkage disequilibrium with the Tay-Sachs gene accounting for the high frequency of the gene in Ashkenazim?

Myerowitz (1997) stated that 78 mutations in the HEXA gene had been described, including 65 single-base substitutions, 1 large and 10 small deletions, and 2 small insertions.

Wicklow et al. (2004) described a child with severe subacute GM2-gangliosidosis who presented at age 22 months with classic cherry-red spots of the fundus but did not develop any neurologic deficit until almost age 4. They identified 3 mutations in the HEXA gene: 10T-C (S4P; 606869.0014) and 972T-A (V324V, 606869.0057) on the maternal allele, and 1A-T (M1L; 606869.0027) on the paternal allele. Because the delay in onset of neurologic symptoms indicated the presence of residual HEXA, Wicklow et al. (2004) analyzed the effects of the amino acid substitutions on HEXA expression in COS-7 cells and discovered that the 972T-A mutation created a new exon 8 donor site, causing a 17-bp deletion and destabilization of the resulting abnormal transcript. Wicklow et al. (2004) concluded that the remaining normal mRNA produced from the 972T-A allele must account for the delayed onset of symptoms in this child.

By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified a missense mutation in the HEXA gene (606869.0058) in a family (M165) in which first-cousin parents had 5 healthy children and 3 children with moderate intellectual disability and seizures.

Diagnosis
Balint et al. (1967) found that both homozygotes and heterozygotes show reduced sphingomyelin in red blood cells and suggested that this reduction is useful in carrier identification.

Triggs-Raine et al. (1990) compared DNA-based and enzyme-based screening tests for carriers of TSD among Ashkenazim. Among 62 Ashkenazi obligate carriers, 3 specific mutations, indicated as 606869.0001, 606869.0002, and 606869.0008 among the allelic variants, accounted for all but one of the mutant alleles (98%). In 216 Ashkenazi carriers identified by the enzyme tests, DNA analysis showed that 177 (82%) had 1 of the identified mutations. Of the 177, 79% had the exon 11 insertion mutation (606869.0001), 18% had the intron 12 splice junction mutation (606869.0002), and 3% had the less severe exon 7 mutation associated with adult-onset disease (606869.0008). The results of the enzyme tests in 39 subjects (18%) who were defined as carriers but in whom DNA analysis did not identify a mutant allele were probably false positive (although there remained some possibility of unidentified mutations). Of 152 persons defined as noncarriers by the enzyme-based test, 1 was identified as a carrier by DNA analysis (i.e., a false-negative enzyme-test result).

Tay-Sachs disease was one of the disorders used as a trial for preamplification DNA diagnosis of multiple disorders by Snabes et al. (1994). They applied single-cell whole-genome preamplification to PCR-based analysis of multiple disease loci from the same diploid cell. The method they described allowed diagnosis of multiple disease genes, analysis of multiple exons/introns within a gene, or corroborative embryo-sex assignment and specific mutation detection at sex-linked loci.

Although Tay-Sachs mutations are rare in the general population, non-Jewish individuals may be screened as spouses of Jewish carriers or as relatives of probands. To define a panel of alleles that might account for most mutations in non-Jewish carriers, Akerman et al. (1997) investigated 26 independent alleles from 20 obligate carriers and 3 affected individuals. Eighteen alleles were represented by 12 previously identified mutations, 7 that were newly identified and 1 that remained unidentified. They then investigated 46 enzyme-defined carrier alleles: 19 were pseudodeficiency alleles and 5 mutations accounted for 15 other alleles. An eighth new mutation was detected among enzyme-defined carriers. Eleven alleles remained unidentified, despite the testing for 23 alleles. Some may represent false positives for the enzyme test. The results indicated that predominant mutations, other than the 2 pseudodeficiency alleles (739C-T, 606869.0035 and 745C-T) and 1 disease allele (IVS9+1G-A; 606869.0033) do not occur in the general population. Thus, Akerman et al. (1997) concluded that determination of carrier status by DNA analysis alone is inefficient because of the large proportion of rare alleles. Notwithstanding the possibility of false positives inherent to enzyme screening, this method remains an essential component of carrier screening in non-Jews. DNA screening can be best used as an adjunct to enzyme testing to exclude known HEXA pseudodeficiency alleles, the IVS9+1G-A disease allele, and other mutations relevant to the subject's genetic heritage.

Bach et al. (2001) presented results strongly supporting the use of DNA testing alone as the most cost-effective and efficient approach to carrier screening for TSD in individuals of confirmed Ashkenazi Jewish ancestry.

Chamoles et al. (2002) described methods for the assay of hexosaminidase A activity in dried blood spots on filter paper for the screening of newborns.

Vallance et al. (2006) reported 2 clinically unaffected Ashkenazi Jewish brothers who had discrepant results on diagnosis of Tay-Sachs disease carrier status. Both had low-normal serum percent HexA enzyme activity above the cut-off for carrier detection, but leukocyte HexA activity was in the carrier range. DNA analysis showed that both brothers carried the common 4-bp insertion in the HEXA gene (1277_1278insTATC; 606869.0001) gene. Both also had 2 common polymorphisms in the HEXB gene: 619A-G (I207V) and a 2-bp deletion (delTG) in the 3-prime untranslated region. Genotyping of a larger sample of 72 Jewish and 104 non-Jewish alleles samples found that the HEXB variants were in strong linkage disequilibrium with haplotype frequencies of 9.7% and 7.7%, respectively. Three additional TSD carriers with the unusual biochemical phenotype (normal serum HexA activity and decreased leukocyte HexA activity) all carried the same HEXB I207V/delTG haplotype. Finally, analysis of a larger sample of 69 alleles found that the frequency of this HexB haplotype was significantly associated with low serum HexB activity. These findings indicated that this haplotype lowers HexB activity in serum, which has the effect of raising the percent of HexA activity as determined by heat inactivation methods of total Hex activity. This can result in masking of carrier status in carriers of TSD alleles that are measured solely by serum percentage of HexA activity. Vallance et al. (2006) noted that the high prevalence of this HexB haplotype may become clinically relevant in diagnosis of TSD carrier status, and that additional diagnostic methods should be used.

Prenatal Diagnosis

Conzelmann et al. (1985) performed prenatal diagnosis in a family with the pseudo-AB variant (B1 variant) of GM2-gangliosidosis. These patients have a late infantile form with nearly normal beta-hexosaminidase A levels when assayed with the usual synthetic substrate 4-methylumbelliferyl-N-acetyl-beta-D-glucosaminide. Since the enzyme is also inactive against another substrate that is thought to be hydrolyzed predominantly by Hex-A, the mutation is in the alpha subunit.

Population Genetics
Many aspects of Tay-Sachs disease and related disorders were discussed in the proceedings of a conference edited by Kaback et al. (1977). Tay-Sachs disease is approximately 100 times more common in infants of Ashkenazi Jewish ancestry (central-eastern Europe) than in non-Jewish infants (Kaback et al., 1977). Tay-Sachs disease and Sandhoff disease in French Canadians of Quebec was discussed by Andermann et al. (1977). Whether this represents an infusion of the Tay-Sachs gene from Jewish fur traders or an independent mutation was not known at that time, but was settled when the intragenic lesions were identified; see 606869.0003.

Petersen et al. (1983) concluded that proliferation of the TSD gene occurred among the antecedents of modern Ashkenazi Jewry after the second Diaspora (70 A.D.) and before the major migrations to regions of Poland and Russia (1100 A.D. and later). Among Moroccan Jews, the carriers of a Tay-Sachs mutation were estimated to have a frequency of 1 in 45 (Navon, 1990), a figure not greatly different from that found in North American Jews.

Petersen et al. (1983) found a TSD carrier frequency in 46,304 North American Jews to be 0.0324 (1 in 31). Jews with Polish and/or Russian ancestry constituted 88% of this sample and had a carrier frequency of 0.0327. No carrier was found among the 166 Jews of Near Eastern origins. Relative to Jews of Polish and Russian origins, there was a 2-fold increase in carrier frequency in Jews of Austrian, Hungarian, and Czechoslovakian origins. Among U.S. Jews originating from Austria, a carrier frequency of 0.1092 was observed.

Yokoyama (1979) concluded that it is unlikely that drift alone was responsible for the high frequency of Tay-Sachs disease in Ashkenazim. Heterozygote advantage was considered a likely additional factor. Spyropoulos et al. (1981) showed that proportionally the grandparents of Tay-Sachs disease carriers died from the same causes as grandparents of noncarriers. They suggested that the finding indirectly supports the notion that the high frequency of the TSD gene in Ashkenazim is 'caused by a combination of founder effect, genetic drift, and differential immigration patterns.'

Diamond (1988) defended selective advantage as the cause of the high frequency of the TS gene in Ashkenazi Jews.

Paw et al. (1990) analyzed the frequency of 3 HEXA mutations among heterozygotes identified in a Tay-Sachs screening program: the 4-nucleotide insertion in exon 11 (606869.0001), the G-to-C transversion at the 5-prime splice site in intron 12 (606869.0002), and the gly269-to-ser mutation in exon 7 (606869.0008). Mutation analysis included PCR amplification of the relevant regions followed by allele-specific oligonucleotide (ASO) hybridization and, in the case of the exon 11 insertion, the formation of heteroduplex PCR fragments of low electrophoretic mobility. The percentage distribution of the exon 11, intron 12, exon 7, and unidentified mutant alleles was 73:15:4:8 among 156 Jewish carriers of HEXA deficiency and 16:0:3:81 among 51 non-Jewish carriers. Regardless of the mutation, the ancestral origin of the Jewish carriers was primarily eastern and (somewhat less often) central Europe, whereas for non-Jewish carriers it was western Europe.

Among 148 Ashkenazi Jews carrying the Tay-Sachs gene, Grebner and Tomczak (1991) found that 108 had the insertion mutation (606869.0001), 26 had the splice junction mutation (606869.0002), 5 had the adult mutation (606869.0008), and 9 had none of the 3. Among 28 non-Jewish carriers tested, most of whom were obligate carriers, 4 had the insertion mutation, 1 had the adult mutation, and the remaining 23 had none of the 3. The 2 patients with the asp258-to-his type of B1 allele (606869.0038) had infantile TSD with serum and fibroblasts containing heterozygote levels of HEXA.

Risch et al. (2003) postulated that geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift, rather than selection, as the mechanism of unusually high frequency of conditions such as TSD. Zlotogora and Bach (2003) provided a rebuttal in support of selection as the determining factor. They stated that the occurrence of several mutations in the same gene or mutations in different genes responsible for the high prevalence of some genetic diseases in relatively small populations is most easily explained by selection, and pointed out that Bardet-Biedl syndrome (209900) has a high frequency among the Bedouins of the Negev, owing to mutations in 3 different genes. They pointed to the occurrence of the high frequency of 4 lysosomal storage diseases among Ashkenazim--TSD, Gaucher disease type I (230800), Niemann-Pick disease (see 257200), and mucolipidosis type IV (252650)--in which the mutations are in genes that encode enzymes from a common biochemical pathway. In all 4, the main storage substances are sphingolipids. A further indication of a nonrandom process is the number of mutations responsible for each disorder. In almost all of the nonlysosomal disorders, 1 mutation is prevalent, and, if more than 1 mutation is found in a given population, its frequency is significantly less than 10% of the first mutation. This is true for almost all the nonlysosomal disorders, except cystic fibrosis (219700), in which a selection process had been suggested, and factor XI deficiency (612416). On the other hand, in all 4 lysosomal disorders among Ashkenazim, the second allele is more than 10% prevalent, when compared with the frequency of the major mutation. Risch and Tang (2003) presented counterarguments.

History
Fernandes Filho and Shapiro (2004) reviewed the early history of Tay-Sachs disease.

Animal Model
Taniike et al. (1995) produced a mouse model of Tay-Sachs disease by targeted disruption of the HEXA gene. The mice were devoid of beta-hexosaminidase A activity, accumulated GM2 ganglioside in the central nervous system, and displayed neurons with membranous cytoplasmic bodies identical to those of Tay-Sachs disease in humans. Unlike human Tay-Sachs disease in which all neurons store GM2 ganglioside, no storage was evident in the olfactory bulb, cerebellar cortex, or spinal anterior horn cells of these mice. Sango et al. (1995) likewise found that disruption of the Hexa gene in mouse embryonic stem cells resulted in mice that showed no neurologic abnormalities, although they exhibited biochemical and pathologic features of the disease. In contrast, mice in whom the Hexb gene was disrupted as a model of Sandhoff disease were severely affected. The authors suggested that the phenotypic differences between the 2 mouse models was the result of differences in the ganglioside degradation pathway between mice and humans. The authors postulated that alternative ganglioside degradative pathway revealed by the hexosaminidase-deficient mice may be significant in the analysis of other mouse models of the sphingolipidoses, as well as suggest novel therapies for Tay-Sachs disease.

Cohen-Tannoudji et al. (1995) used gene targeting in embryonic stem (ES) cells to disrupt the mouse Hexa gene. Mice homozygous for the disrupted allele mimicked some of the biochemical and histologic features of human Tay-Sachs disease. They displayed, for example, total deficiency of Hexa activity and membranous cytoplasmic inclusions typical of GM2-gangliosidoses found in the cytoplasm of their neurons. However, while the number of storage neurons increased with age, it remained low compared with that found in the human, and no apparent motor or behavioral disorders could be observed. This suggested that beta-hexosaminidase A is not an absolute requirement for ganglioside degradation in mice. Nonetheless, the authors stated that animal models should be useful for the testing of new forms of therapy.

Phaneuf et al. (1996) likewise found that mice with disruption of the Hexa gene suffered no obvious behavioral or neurologic deficit whereas those homozygous for a disruption of the Hexb gene developed a fatal neurodegenerative disease with spasticity, muscle weakness, rigidity, tremor, and ataxia. They proposed that homozygous Hexa-deficient mice escaped disease through particle catabolism of accumulated G(M2) via G(A2) through the combined action of sialidase and beta-hexosaminidase B.

In a mouse model of Tay-Sachs disease, Platt et al. (1997) evaluated a strategy for treatment of the disorder based on N-butyldeoxynojirimycin, an inhibitor of glycosphingolipid (GSL) biosynthesis. When Tay Sachs mice were treated with this agent, the accumulation of GM2 in the brain was prevented, with the number of storage neurons and the quantity of ganglioside stored per cell markedly reduced. Thus, the authors concluded that limiting the biosynthesis of the substrate for the defective Hexa enzyme prevented GSL accumulation and the neuropathology associated with its storage in lysosomes.

Guidotti et al. (1999) determined the in vivo strategy leading to the highest Hexa activity in the maximum number of tissues in Hexa-deficient knockout mice. They demonstrated that intravenous coadministration of adenoviral vectors coding for both alpha- and beta-subunits, resulting in preferential liver transduction, was essential to obtain the most successful results. Only the supply of both subunits allowed for Hexa overexpression, leading to massive secretion of the enzyme in serum, and full or partial restoration of enzymatic activity in all peripheral tissues tested. These results emphasized the need to overexpress both subunits of heterodimeric proteins in order to obtain a high level of secretion in animals defective in only 1 subunit. Otherwise, the endogenous nondefective subunit is limiting.

See Also:
Ainsworth and Coulter-Mackie (1992); Akalin et al. (1992); Akerman et al. (1992); Akli et al. (1993); Akli et al. (1991); Akli et al. (1993); Aronson et al. (1960); Arpaia et al. (1988); Ben-Yoseph et al. (1985); Boustany et al. (1991); Brady (1970); Brown and Mahuran (1993); Charrow et al. (1985); Chern et al. (1977); Coulter-Mackie (1994); De Braekeleer et al. (1992); De Gasperi et al. (1996); dos Santos et al. (1991); Dreyfus et al. (1975); Drucker and Navon (1993); Drucker et al. (1992); Fernandes et al. (1992); Fernandes et al. (1997); Goebel et al. (1989); Gordon et al. (1988); Greenberg and Kaback (1982); Hanhart (1954); Hechtman et al. (1992); Hechtman et al. (1990); Hellkuhl et al. (1978); Higami et al. (1976); Hou et al. (1996); Johnson et al. (1980); Kappler et al. (1990); Keats et al. (1987); Kelly et al. (1975); Kelly et al. (1976); Koeslag and Schach (1984); Korneluk et al. (1986); Landels et al. (1992); Landels et al. (1993); Lane et al. (1980); Lau and Neufeld (1989); McDowell et al. (1992); McDowell et al. (1989); Meek et al. (1984); Momoi et al. (1978); Mules et al. (1991); Mules et al. (1992); Mules et al. (1992); Myerowitz (1988); Myerowitz and Hogikyan (1986); Myerowitz and Hogikyan (1987); Myerowitz et al. (1985); Myerowitz and Proia (1984); Nakano et al. (1988); Nakano et al. (1990); Navon et al. (1976); Navon et al. (1990); Navon and Proia (1989); Navon and Proia (1991); Nishimoto et al. (1991); O'Brien and Geiger (1979); O'Brien et al. (1970); O'Brien et al. (1971); O'Brien et al. (1978); Ohman et al. (1971); Ohno and Suzuki (1988); Ohno and Suzuki (1988); Ohno and Suzuki (1988); Paw et al. (1989); Paw et al. (1991); Petroulakis et al. (1998); Proia et al. (1990); Proia and Neufeld (1982); Proia and Soravia (1987); Raghavan et al. (1985); Rattazzi et al. (1976); Schneck et al. (1964); Seldin et al. (1991); Shore et al. (1992); Sloan and Fredrickson (1972); Strasberg et al. (1997); Suzuki and Suzuki (1970); Tanaka et al. (1988); Tanaka et al. (1990); Thomas et al. (1982); Thurmon (1993); Tomczak et al. (1993); Triggs-Raine et al. (1991); Triggs-Raine and Gravel (1990); Triggs-Raine et al. (1992); Trop et al. (1992); Trop et al. (1990); Van Cong et al. (1975); Volk (1964); Whitley et al. (1992); Yaffe et al. (1979); Zlotogora (1993); Zokaeem et al. (1987)

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Contributors: Ada Hamosh - updated : 1/6/2012
Cassandra L. Kniffin - updated : 1/4/2010
Cassandra L. Kniffin - updated : 4/6/2005
Cassandra L. Kniffin - updated : 12/15/2004
Marla J. F. O'Neill - updated : 6/30/2004
Victor A. McKusick - updated : 8/11/2003
George E. Tiller - updated : 2/24/2003
Victor A. McKusick - updated : 1/22/2003
Cassandra L. Kniffin - reorganized : 5/7/2002
Cassandra L. Kniffin - updated : 5/7/2002
Victor A. McKusick - updated : 2/21/2001
Victor A. McKusick - updated : 5/18/1999
Victor A. McKusick - updated : 9/9/1998
Victor A. McKusick - updated : 9/4/1998
Victor A. McKusick - edited : 2/24/1998
Victor A. McKusick - updated : 10/10/1997
Victor A. McKusick - updated : 8/27/1997
Victor A. McKusick - updated : 6/16/1997
Victor A. McKusick - updated : 5/8/1997
Victor A. McKusick - updated : 4/17/1997
Perseveranda M. Cagas - updated : 11/6/1996
Orest Hurko - updated : 11/6/1996
Stylianos E. Antonarakis - updated : 6/29/1996
Orest Hurko - updated : 6/13/1995
Creation Date: Victor A. McKusick : 6/4/1986
Edit History: carol : 01/09/2012
terry : 1/6/2012
wwang : 2/16/2010
ckniffin : 1/4/2010
carol : 11/4/2009
carol : 11/4/2009
carol : 11/2/2009
terry : 3/25/2009
carol : 11/20/2008
terry : 8/26/2008
terry : 8/26/2008
terry : 8/26/2008
carol : 10/1/2007
carol : 11/18/2005
wwang : 4/20/2005
wwang : 4/15/2005
ckniffin : 4/6/2005
carol : 3/3/2005
tkritzer : 12/21/2004
ckniffin : 12/15/2004
carol : 7/1/2004
terry : 6/30/2004
tkritzer : 8/18/2003
terry : 8/11/2003
carol : 8/1/2003
carol : 2/27/2003
cwells : 2/24/2003
cwells : 1/29/2003
tkritzer : 1/22/2003
carol : 5/7/2002
carol : 5/7/2002
carol : 5/7/2002
ckniffin : 5/6/2002
carol : 5/6/2002
ckniffin : 4/30/2002
carol : 3/2/2001
cwells : 2/27/2001
terry : 2/21/2001
mcapotos : 8/4/2000
mgross : 5/25/1999
terry : 5/18/1999
carol : 10/14/1998
dkim : 9/10/1998
alopez : 9/10/1998
terry : 9/9/1998
carol : 9/8/1998
terry : 9/4/1998
terry : 8/13/1998
terry : 7/24/1998
terry : 6/4/1998
mark : 3/3/1998
terry : 2/24/1998
mark : 2/11/1998
alopez : 1/13/1998
jenny : 10/17/1997
terry : 10/10/1997
jenny : 9/5/1997
terry : 8/27/1997
terry : 6/23/1997
terry : 6/16/1997
mark : 6/10/1997
mark : 5/8/1997
alopez : 5/6/1997
mark : 4/17/1997
terry : 4/14/1997
mark : 4/2/1997
terry : 3/31/1997
terry : 1/17/1997
mark : 11/6/1996
mark : 11/6/1996
terry : 10/23/1996
carol : 6/29/1996
carol : 6/27/1996
carol : 5/29/1996
mark : 2/14/1996
mark : 2/9/1996
terry : 2/9/1996
terry : 1/31/1996
mark : 12/20/1995
mark : 10/30/1995
carol : 9/21/1994
davew : 8/31/1994
jason : 7/12/1994
warfield : 4/20/1994