GenomeNet

Database: OMIM
Entry: 272800
LinkDB: 272800
MIM Entry: 272800
Title:
  #272800 TAY-SACHS DISEASE; TSD
  ;;GM2-GANGLIOSIDOSIS, TYPE I;;
  B VARIANT GM2-GANGLIOSIDOSIS;;
  HEXOSAMINIDASE A DEFICIENCY;;
  HEXA DEFICIENCY
  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
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-gangiosidosis. 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.
  
  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 mucolipodosis 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 (1991); Navon and Proia (1989); 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)
References:
  1. Ainsworth, P. J.; Coulter-Mackie, M. B.: A double mutation in
  exon 6 of the beta-hexosaminidase alpha subunit in a patient with
  the B1 variant of Tay-Sachs disease. Am. J. Hum. Genet. 51: 802-809,
  1992.
  
  2. Akalin, N.; Shi, H.-P.; Vavougios, G.; Hechtman, P.; Lo, W.; Scriver,
  C. R.; Mahuran, D.; Kaplan, F.: Novel Tay-Sachs disease mutations
  from China. Hum. Mutat. 1: 40-46, 1992.
  
  3. Akerman, B. R.; Natowicz, M. R.; Kaback, M. M.; Loyer, M.; Campeau,
  E.; Gravel, R. A.: Novel mutations and DNA-based screening in non-Jewish
  carriers of Tay-Sachs disease. Am. J. Hum. Genet. 60: 1099-1106,
  1997.
  
  4. Akerman, B. R.; Zielenski, J.; Triggs-Raine, B. L.; Prence, E.
  M.; Natowicz, M. R.; Lim-Steele, J. S. T.; Kaback, M. M.; Mules, E.
  H.; Thomas, G. H.; Clarke, J. T. R.; Gravel, R. A.: A mutation common
  in non-Jewish Tay-Sachs disease: frequency and RNA studies. Hum.
  Mutat. 1: 303-309, 1992.
  
  5. Akli, S.; Chelly, J.; Kahn, A.; Poenaru, L.: A null allele frequent
  in non-Jewish Tay-Sachs patients. Hum. Genet. 90: 614-620, 1993.
  
  6. Akli, S.; Chelly, J.; Lacorte, J.; Poenaru, L.; Kahn, A.: Seven
  novel Tay-Sachs mutations detected by chemical mismatch cleavage of
  PCR-amplified cDNA fragments. Genomics 11: 124-134, 1991.
  
  7. Akli, S.; Chomel, J.-C.; Lacorte, J.-M.; Bachner, L.; Poenaru,
  A.; Poenaru, L.: Ten novel mutations in the HEXA gene in non-Jewish
  Tay-Sachs patients. Hum. Molec. Genet. 2: 61-67, 1993.
  
  8. Andermann, E.; Scriver, C. R.; Wolfe, L. S.; Dansky, L.; Andermann,
  F.: Genetic variants of Tay-Sachs disease and Sandhoff's disease
  in French-Canadians, juvenile Tay-Sachs disease in Lebanese Canadians,
  and a Tay-Sachs screening program in the French-Canadian population.In:
  Kaback, M. M.; Rimoin, D. L.; O'Brien, J. S.: Tay-Sachs Disease:
  Screening and Prevention.  New York: Alan R. Liss (pub.)  1977.
  Pp. 161-168.
  
  9. Aronson, S. M.; Valsamis, M. P.; Volk, B. W.: Infantile amaurotic
  family idiocy: occurrence, genetic considerations and pathophysiology
  in the non-Jewish infant. Pediatrics 26: 229-242, 1960.
  
  10. Arpaia, E.; Dumbrille-Ross, A.; Maler, T.; Neote, K.; Tropak,
  M.; Troxel, C.; Stirling, J. L.; Pitts, J. S.; Bapat, B.; Lamhonwah,
  A. M.; Mahuran, D. J.; Schuster, S. M.; Clarke, J. T. R.; Lowden,
  J. A.; Gravel, R. A.: Identification of an altered splice site in
  Ashkenazi Tay-Sachs disease. Nature 333: 85-86, 1988.
  
  11. Bach, G.; Tomczak, J.; Risch, N.; Ekstein, J.: Tay-Sachs screening
  in the Jewish Ashkenazi population: DNA testing is the preferred procedure. Am.
  J. Med. Genet. 99: 70-75, 2001.
  
  12. Balint, J. A.; Kyriakides, E. C.: Studies of red cell stromal
  proteins in Tay-Sachs disease. J. Clin. Invest. 47: 1858-1864, 1968.
  
  13. Balint, J. A.; Kyriakides, E. C.; Spitzer, H. L.: On the chemical
  changes in the red cell stroma in Tay-Sachs disease: their value as
  genetic tracers.In: Aronson, S. M.; Volk, B. W.: Inborn Disorders
  of Sphingolipid Metabolism.  Oxford: Pergamon Press (pub.)  1967.
  Pp. 423-430.
  
  14. Barnes, D.; Misra, V. P.; Young, E. P.; Thomas, P. K.; Harding,
  A. E.: An adult onset hexosaminidase A deficiency syndrome with sensory
  neuropathy and internuclear ophthalmoplegia. J. Neurol. Neurosurg.
  Psychiat. 54: 1112-1113, 1991.
  
  15. Bayleran, J.; Hechtman, P.; Kolodny, E.; Kaback, M.: Tay-Sachs
  disease with hexosaminidase A: characterization of the defective enzyme
  in two patients. Am. J. Hum. Genet. 41: 532-548, 1987.
  
  16. Ben-Yoseph, Y.; Reid, J. E.; Shapiro, B.; Nadler, H. L.: Diagnosis
  and carrier detection of Tay-Sachs disease: direct determination of
  hexosaminidase A using 4-methylumbelliferyl derivatives of beta-N-acetylglucosam  ine-6-sulfate
  and beta-N-acetylgalactosamine-6-sulfate. Am. J. Hum. Genet. 37:
  733-748, 1985.
  
  17. Beutler, E.; Kuhl, W.; Comings, D.: Hexosaminidase isozyme in
  type O Gm2 gangliosidosis (Sandhoff-Jatzkewitz disease). Am. J. Hum.
  Genet. 27: 628-638, 1975.
  
  18. Boustany, R.-M. N.; Tanaka, A.; Nishimoto, J.; Suzuki, K.: Genetic
  cause of a juvenile form of Tay-Sachs disease in a Lebanese child. Ann.
  Neurol. 29: 104-107, 1991.
  
  19. Brady, R. O.: Cerebral lipidoses. Ann. Rev. Med. 21: 317-334,
  1970.
  
  20. Brown, C. A.; Mahuran, D. J.: Beta-hexosaminidase isozymes from
  cells cotransfected with alpha and beta cDNA constructs: analysis
  of the alpha-subunit missense mutation associated with the adult form
  of Tay-Sachs disease. Am. J. Hum. Genet. 5: 497-508, 1993.
  
  21. Chamoles, N. A.; Blanco, M.; Gaggioli, D.; Casentini, C.: Tay-Sachs
  and Sandhoff diseases: enzymatic diagnosis in dried blood spots on
  filter paper: retrospective diagnoses in newborn-screening cards. Clin.
  Chim. Acta 318: 133-137, 2002.
  
  22. Charrow, J.; Inui, K.; Wenger, D. A.: Late onset GM(2) gangliosidosis:
  an alpha-locus genetic compound with near normal hexosaminidase activity. Clin.
  Genet. 27: 78-84, 1985.
  
  23. Chern, C. J.; Beutler, E.; Kuhl, W.; Gilbert, F.; Mellman, W.
  J.; Croce, C. M.: Characterization of heteropolymeric hexosaminidase
  A in human x mouse hybrid cells. Proc. Nat. Acad. Sci. 73: 3637-3640,
  1976.
  
  24. Chern, C. J.; Kennett, R.; Engel, E.; Mellman, W. J.; Croce, C.
  M.: Assignment of the structural genes for the alpha subunit of hexosaminidase
  A, mannosephosphate isomerase and pyruvate kinase to the region q22-qter
  of human chromosome 15. Somat. Cell Genet. 3: 553-560, 1977.
  
  25. Cohen-Tannoudji, M.; Marchand, P.; Akli, S.; Sheardown, S. A.;
  Puech, J.-P.; Kress, C.; Gressens, P.; Nassogne, M.-C.; Beccari, T.;
  Muggleton-Harris, A. L.; Evrard, P.; Stirling, J. L.; Poenaru, L.;
  Babinet, C.: Disruption of murine Hexa gene leads to enzymatic deficiency
  and to neuronal lysosomal storage, similar to that observed in Tay-Sachs
  disease. Mammalian Genome 6: 844-849, 1995.
  
  26. Conzelmann, E.; Kytzia, H.-J.; Navon, R.; Sandhoff, K.: Ganglioside
  GM2 N-acetyl-beta-D-galactosaminidase activity in cultured fibroblasts
  of late-infantile and adult GM2 gangliosidosis patients and of healthy
  probands with low hexosaminidase level. Am. J. Hum. Genet. 35: 900-913,
  1983.
  
  27. Conzelmann, E.; Nehrkorn, H.; Kytzia, H.-J.; Sandhoff, K.; Macek,
  M.; Lehovsky, M.; Elleder, M.; Jirasek, A.; Kobilkova, J.: Prenatal
  diagnosis of G(M)2 gangliosidosis with high residual hexosaminidase
  A activity (variant B-1; pseudo AB variant). Pediat. Res. 19: 1220-1224,
  1985.
  
  28. Coulter-Mackie, M. B.: Molecular characterization of both alleles
  in an unusual Tay-Sachs disease B1 variant. (Letter) Am. J. Hum.
  Genet. 54: 1126-1127, 1994.
  
  29. d'Azzo, A.; Proia, R. L.; Kolodny, E. H.; Kaback, M. M.; Neufeld,
  E. F.: Faulty association of alpha- and beta-subunits in some forms
  of beta-hexosaminidase A deficiency. J. Biol. Chem. 259: 11070-11074,
  1984.
  
  30. De Braekeleer, M.; Hechtman, P.; Andermann, E.; Kaplan, F.: The
  French Canadian Tay-Sachs disease deletion mutation: identification
  of probable founders. Hum. Genet. 89: 83-87, 1992.
  
  31. De Gasperi, R.; Gama Sosa, M. A.; Battistini, S.; Yeretsian, J.;
  Raghavan, S.; Zelnik, N.; Leshinsky, E.; Kolodny, E. H.: Late-onset
  G(M2)-gangliosidosis: Ashkenazi Jewish family with an exon 5 mutation
  (tyr180-to-his) in the Hex A alpha-chain gene. Neurology 47: 547-552,
  1996.
  
  32. Diamond, J. M.: Tay-Sachs carriers and tuberculosis resistance.
  (Letter) Nature 331: 666, 1988.
  
  33. dos Santos, M. R.; Tanaka, A.; sa Miranda, M. C.; Ribeiro, M.
  G.; Maia, M.; Suzuki, K.: G(M2)-gangliosidosis B1 variant: analysis
  of beta-hexosaminidase alpha gene mutations in 11 patients from a
  defined region in Portugal. Am. J. Hum. Genet. 49: 886-890, 1991.
  
  34. Dreyfus, J.-C.; Poenaru, L.; Svennerholm, L.: Absence of hexosaminidase
  A and B in a normal adult. New Eng. J. Med. 292: 61-63, 1975.
  
  35. Drucker, L.; Navon, R.: Tay-Sachs disease in an Israeli Arab
  family: trp26-to-stop in the alpha-subunit of hexosaminidase A. Hum.
  Mutat. 2: 415-417, 1993.
  
  36. Drucker, L.; Proia, R. L.; Navon, R.: Identification and rapid
  detection of three Tay-Sachs mutations in the Moroccan Jewish population. Am.
  J. Hum. Genet. 51: 371-377, 1992.
  
  37. Fernandes, M.; Kaplan, F.; Natowicz, M.; Prence, E.; Kolodny,
  E.; Kaback, M.; Hechtman, P.: A new Tay-Sachs disease B1 allele in
  exon 7 in two compound heterozygotes each with a second novel mutation. Hum.
  Molec. Genet. 1: 759-761, 1992.
  
  38. Fernandes, M. J. G.; Hechtman, P.; Boulay, B.; Kaplan, F.: A
  chronic GM(2) gangliosidosis variant with a HEXA splicing defect:
  quantitation of HEXA mRNAs in normal and mutant fibroblasts. Europ.
  J. Hum. Genet. 5: 129-136, 1997.
  
  39. Fernandes Filho, J. A.; Shapiro, B. E.: Tay-Sachs disease. Arch.
  Neurol. 61: 1466-1468, 2004.
  
  40. Formiga, L. de F.; Poenaru, L.; Couronne, F.; Flori, E.; Eibel,
  J. L.; Deminatti, M. M.; Savary, J. B.; Lai, J. L.; Gilgenkrantz,
  S.; Pierson, M.: Interstitial deletion of chromosome 15: two cases. Hum.
  Genet. 80: 401-404, 1988.
  
  41. Galjaard, H.; Hoogeveen, A.; deWit-Verbeek, H. A.; Reuser, A.
  J. J.; Keijzer, W.; Westerveld, A.; Bootsma, D.: Tay-Sachs and Sandhoff's
  disease: intergenic complementation after somatic cell hybridization. Exp.
  Cell Res. 87: 444-448, 1974.
  
  42. Gilbert, F.; Kucherlapati, R. S.; Creagan, R. P.; Murnane, M.
  J.; Darlington, G. J.; Ruddle, F. H.: Tay-Sachs' and Sandhoff's diseases:
  the assignment of genes for hexosaminidase A and B to individual human
  chromosomes. Proc. Nat. Acad. Sci. 72: 263-267, 1975.
  
  43. Goebel, H. H.; Stolte, G.; Kustermann-Kuhn, B.; Harzer, K.: B(1)
  variant of G(M2) gangliosidosis in a 12-year-old patient. Pediat.
  Res. 25: 89-93, 1989.
  
  44. Gordon, B. A.; Gordon, K. E.; Hinton, G. G.; Cadera, W.; Feleki,
  V.; Bayleran, J.; Hechtman, P.: Tay Sachs disease: B1 variant. Pediat.
  Neurol. 4: 54-57, 1988.
  
  45. Grebner, E. E.; Mansfield, D. A.; Raghavan, S. S.; Kolodny, E.
  H.; d'Azzo, A.; Neufeld, E. F.; Jackson, L. G.: Two abnormalities
  of hexosaminidase A in clinically normal individuals. Am. J. Hum.
  Genet. 38: 505-515, 1986.
  
  46. Grebner, E. E.; Tomczak, J.: Distribution of three alpha-chain
  beta-hexosaminidase A mutations among Tay-Sachs carriers. Am. J.
  Hum. Genet. 48: 604-607, 1991.
  
  47. Greenberg, D. A.; Kaback, M. M.: Estimation of the frequency
  of hexosaminidase A variant alleles in the American Jewish population. Am.
  J. Hum. Genet. 34: 444-451, 1982.
  
  48. Griffin, J. W.: Personal Communication. Baltimore, Md.  5/16/1984.
  
  49. Guidotti, J. E.; Mignon, A.; Haase, G.; Caillaud, C.; McDonell,
  N.; Kahn, A.; Poenaru, L.: Adenoviral gene therapy of the Tay-Sachs
  disease in hexosaminidase A-deficient knock-out mice. Hum. Molec.
  Genet. 8: 831-838, 1999.
  
  50. Hanhart, E.: Ueber 27 Sippen mit infantiler amaurotischer Idiotie
  (Tay-Sachs). Acta Genet. Med. Gemellol. 3: 331-364, 1954.
  
  51. Hechtman, P.; Boulay, B.; De Braekeleer, M.; Andermann, E.; Melancon,
  S.; Larochelle, J.; Prevost, C.; Kaplan, F.: The intron 7 donor splice
  site transition: a second Tay-Sachs disease mutation in French Canada. Hum.
  Genet. 90: 402-406, 1992.
  
  52. Hechtman, P.; Kaplan, F.; Bayleran, J.; Boulay, B.; Andermann,
  E.; de Braekeleer, M.; Melancon, S.; Lambert, M.; Potier, M.; Gagne,
  R.; Kolodny, E.; Clow, C.; Capua, A.; Prevost, C.; Scriver, C.: More
  than one mutant allele causes infantile Tay-Sachs disease in French-Canadians. A  m.
  J. Hum. Genet. 47: 815-822, 1990.
  
  53. Hellkuhl, B.; Mayr, W. R.; Grzeschik, K.-H.: Localization of
  MPI, PK-M2, IDH-M, and the alpha subunit of hexosaminidase (HEX-A)
  to the q21-qter region of human chromosome 15. Cytogenet. Cell Genet. 22:
  503-505, 1978.
  
  54. Higami, S.; Nishizawa, K.; Omura, K.; Sugimoto, K.; Isshiki, G.;
  Tada, K.; Kamoshita, S.: Prenatal diagnosis and fetal pathology of
  Tay-Sachs disease. Tohoku J. Exp. Med. 118: 323-330, 1976.
  
  55. Hou, Y.; Vavougios, G.; Hinek, A.; Wu, K. K.; Hechtman, P.; Kaplan,
  F.; Mahuran, D. J.: The val192-to-leu mutation in the alpha-subunit
  of beta-hexosaminidase A is not associated with the B1-variant form
  of Tay-Sachs disease. Am. J. Hum. Genet. 59: 52-58, 1996.
  
  56. Hultberg, B.: N-acetylhexosaminidase activities in Tay-Sachs
  disease. (Letter) Lancet 294: 1195 only, 1969. Note: Originally
  Volume II.
  
  57. Inui, K.; Grebner, E. E.; Jackson, L. G.; Wenger, D. A.: Juvenile
  GM2 gangliosidosis (A(M)B variant): inability to activate hexosaminidase
  A by activator protein. Am. J. Hum. Genet. 35: 551-564, 1983.
  
  58. Johnson, W. G.; Cohen, C. S.; Miranda, A. F.; Waran, S. P.; Chutorian,
  A. M.: Alpha-locus hexosaminidase genetic compound with juvenile
  gangliosidosis phenotype: clinical, genetic, and biochemical studies. Am.
  J. Hum. Genet. 32: 508-518, 1980.
  
  59. Johnson, W. G.; Wigger, H. J.; Karp, H. R.; Glaubiger, L. M.;
  Rowland, L. P.: Juvenile spinal muscular atrophy: a new hexosaminidase
  deficiency phenotype. Ann. Neurol. 11: 11-16, 1982.
  
  60. Kaback, M.; Miles, J.; Yaffe, M.; Itabashi, H.; McIntyre, H.;
  Goldberg, M.; Mohandas, T.: Hexosaminidase-A (Hex A) deficiency in
  early adulthood: a new type of GM-2 gangliosidosis. (Abstract) Am.
  J. Hum. Genet. 30: 31A, 1978.
  
  61. Kaback, M. M.; Rimoin, D. L.; O'Brien, J. S.: Tay-Sachs Disease:
  Screening and Prevention.  New York: Alan R. Liss (pub.)  1977.
  
  62. Kappler, J.; Gieselmann, V.; Propping, P.: Hexosaminidase--pseudodeficiency?  
  (Letter) Am. J. Hum. Genet. 47: 880-881, 1990.
  
  63. Karni, A.; Navon, R.; Sadeh, M.: Hexosaminidase A deficiency
  manifesting as spinal muscular atrophy of late onset. Ann. Neurol. 24:
  451-453, 1988.
  
  64. Keats, B. J. B.; Elston, R. C.; Andermann, E.: Pedigree discriminant
  analysis of two French Canadian Tay-Sachs families. Genet. Epidemiol. 4:
  77-85, 1987.
  
  65. Kelly, T. E.; Chase, G. A.; Kaback, M. M.; Kumor, K.; McKusick,
  V. A.: Tay-Sachs disease: high gene frequency in a non-Jewish population. Am.
  J. Hum. Genet. 27: 287-291, 1975.
  
  66. Kelly, T. E.; Reynolds, L. W.; O'Brien, J. S.: Segregation within
  a family to two mutant alleles for hexosaminidase A. Clin. Genet. 9:
  540-543, 1976.
  
  67. Koeslag, J. H.; Schach, S. R.: Tay-Sachs disease and the role
  of reproductive compensation in the maintenance of ethnic variations
  in the incidence of autosomal recessive disease. Ann. Hum. Genet. 48:
  275-281, 1984.
  
  68. Kolodny, E. H.: Personal Communication. Boston, Mass.  1972.
  
  69. Korneluk, R. G.; Mahuran, D. J.; Neote, K.; Klavins, M. H.; O'Dowd,
  B. F.; Tropak, M.; Willard, H. F.; Anderson, M.-J.; Lowden, J. A.;
  Gravel, R. A.: Isolation of cDNA clones coding for the alpha-subunit
  of human beta-hexosaminidase: extensive homology between the alpha-
  and beta-subunits and studies on Tay-Sachs disease. J. Biol. Chem. 261:
  8407-8413, 1986.
  
  70. Kytzia, H. J.; Sandhoff, K.: Evidence for two different active
  sites on human beta-hexosaminidase A: interaction of G(M2) activator
  protein with beta-hexosaminidase A. J. Biol. Chem. 260: 7568-7572,
  1985.
  
  71. Lalley, P. A.; Rattazzi, M. C.; Shows, T. B.: Human beta-D-N-acetylhexosamin  idases
  A and B: expression and linkage relationships in somatic cell hybrids. Proc.
  Nat. Acad. Sci. 71: 1569-1573, 1975.
  
  72. Landels, E. C.; Green, P. M.; Ellis, I. H.; Fensom, A. H.; Bobrow,
  M.: Beta-hexosaminidase splice site mutation has a high frequency
  among non-Jewish Tay-Sachs disease carriers from the British Isles. J.
  Med. Genet. 29: 563-567, 1992.
  
  73. Landels, E. C.; Green, P. M.; Ellis, I. H.; Fensom, A. H.; Kaback,
  M. M.; Lim-Steele, J.; Zeiger, K.; Levy, N.; Bobrow, M.: Further
  investigation of the HEXA gene intron 9 donor splice site mutation
  frequently found in non-Jewish Tay-Sachs disease patients from the
  British Isles. J. Med. Genet. 30: 479-481, 1993.
  
  74. Lane, A. B.; Young, E.; Jenkins, T.: Segregation of Tay-Sachs
  and Sandhoff alleles in a non-Jewish family. Am. J. Hum. Genet. 32:
  920-926, 1980.
  
  75. Lau, M. M. H.; Neufeld, E. F.: A frameshift mutation in a patient
  with Tay-Sachs disease causes premature termination and defective
  intracellular transport of the alpha-subunit of beta-hexosaminidase. J.
  Biol. Chem. 264: 21376-21380, 1989.
  
  76. Li, S. C.; Hirabayashi, Y.; Li, Y. T.: A new variant of type-AB
  GM2-gangliosidosis. Biochem. Biophys. Res. Commun. 101: 479-485,
  1981.
  
  77. McDowell, G. A.; Mules, E. H.; Fabacher, P.; Shapira, E.; Blitzer,
  M. G.: The presence of two different infantile Tay-Sachs disease
  mutations in a Cajun population. Am. J. Hum. Genet. 51: 1071-1077,
  1992.
  
  78. McDowell, G. A.; Schultz, R. A.; Schwartz, S.; Blitzer, M. G.
  : Presence of both Ashkenazi Tay-Sachs mutations in a non-Jewish inbred
  population. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A9, 1989.
  
  79. Meek, D.; Wolfe, L. S.; Andermann, E.; Andermann, F.: Juvenile
  progressive dystonia: a new phenotype of G(M)-2 gangliosidosis. Ann.
  Neurol. 15: 348-352, 1984.
  
  80. Mitsumoto, H.; Sliman, R. J.; Schafer, I. A.; Sternick, C. S.;
  Kaufman, B.; Wilbourn, A.; Horwitz, S. J.: Motor neuron disease and
  adult hexosaminidase A deficiency in two families: evidence for multisystem
  degeneration. Ann. Neurol. 17: 378-385, 1985.
  
  81. Momoi, T.; Sudo, M.; Tanioka, K.; Nakao, Y.: Tay-Sachs disease
  with altered beta-hexosaminidase B: a new variant? Pediat. Res. 12:
  77-81, 1978.
  
  82. Mules, E. H.; Dowling, C. E.; Petersen, M. B.; Kazazian, H. H.,
  Jr.; Thomas, G. H.: A novel mutation in the invariant AG of the acceptor
  splice site of intron 4 of the beta-hexosaminidase alpha-subunit gene
  in two unrelated American black G(M2)-gangliosidosis (Tay-Sachs disease)
  patients. Am. J. Hum. Genet. 48: 1181-1185, 1991.
  
  83. Mules, E. H.; Hayflick, S.; Dowling, C. E.; Kelly, T. E.; Akerman,
  B. R.; Gravel, R. A.; Thomas, G. H.: Molecular basis of hexosaminidase
  A deficiency and pseudodeficiency in the Berks County Pennsylvania
  Dutch. Hum. Mutat. 1: 298-302, 1992.
  
  84. Mules, E. H.; Hayflick, S.; Miller, C. S.; Reynolds, L. W.; Thomas,
  G. H.: Six novel deleterious and three neutral mutations in the gene
  encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals. Am.
  J. Hum. Genet. 50: 834-841, 1992.
  
  85. Myerowitz, R.: Tay-Sachs disease-causing mutations and neutral
  polymorphisms in the Hex A gene. Hum. Mutat. 9: 195-208, 1997.
  
  86. Myerowitz, R.: Splice junction mutation in some Ashkenazi Jews
  with Tay-Sachs disease: evidence against a single defect within this
  ethnic group. Proc. Nat. Acad. Sci. 85: 3955-3959, 1988.
  
  87. Myerowitz, R.; Costigan, F. C.: The major defect in Ashkenazi
  Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain
  of beta-hexosaminidase. J. Biol. Chem. 263: 18587-18589, 1988.
  
  88. Myerowitz, R.; Hogikyan, N. D.: Different mutations in Ashkenazi
  Jewish and non-Jewish French Canadians with Tay-Sachs disease. Science 232:
  1646-1648, 1986.
  
  89. Myerowitz, R.; Hogikyan, N. D.: A deletion involving Alu sequences
  in the beta-hexosaminidase alpha-chain gene of French Canadians with
  Tay-Sachs disease. J. Biol. Chem. 262: 15396-15399, 1987.
  
  90. Myerowitz, R.; Lawson, D.; Mizukami, H.; Mi, Y.; Tifft, C. J.;
  Proia, R. L.: Molecular pathophysiology in Tay-Sachs and Sandhoff
  diseases as revealed by gene expression profiling. Hum. Molec. Genet. 11:
  1343-1350, 2002.
  
  91. Myerowitz, R.; Piekarz, R.; Neufeld, E. F.; Shows, T. B.; Suzuki,
  K.: Human beta-hexosaminidase alpha chain: coding sequence and homology
  with the beta chain. Proc. Nat. Acad. Sci. 82: 7830-7834, 1985.
  
  92. Myerowitz, R.; Proia, R. L.: cDNA clone for the alpha-chain of
  human beta-hexosaminidase: deficiency of alpha-chain mRNA in Ashkenazi
  Tay-Sachs fibroblasts. Proc. Nat. Acad. Sci. 81: 5394-5398, 1984.
  
  93. Nakai, H.; Byers, M. G.; Nowak, N. J.; Shows, T. B.: Assignment
  of beta-hexosaminidase A alpha-subunit to human chromosomal region
  15q23-q24. Cytogenet. Cell Genet. 56: 164, 1991.
  
  94. Nakano, T.; Muscillo, M.; Ohno, K.; Hoffman, A. J.; Suzuki, K.
  : A point mutation in the coding sequence of the beta-hexosaminidase
  alpha gene results in defective processing of the enzyme protein in
  an unusual GM2-gangliosidosis variant. J. Neurochem. 51: 984-987,
  1988.
  
  95. Nakano, T.; Nanba, E.; Tanaka, A.; Ohno, K.; Suzuki, Y.; Suzuki,
  K.: A new point mutation within exon 5 of beta-hexosaminidase alpha
  gene in a Japanese infant with Tay-Sachs disease. Ann. Neurol. 27:
  465-473, 1990.
  
  96. Navon, R.: Personal Communication. Kfar Saba, Israel  6/13/1990.
  
  97. Navon, R.; Argov, Z.; Frisch, A.: Hexosaminidase A deficiency
  in adults. Am. J. Med. Genet. 24: 179-196, 1986.
  
  98. Navon, R.; Geiger, B.; Ben-Yoseph, Y.; Rattazzi, M. C.: Low levels
  of beta hexosaminidase A in healthy individuals with apparent deficiency
  of this enzyme. Am. J. Hum. Genet. 28: 339-349, 1976.
  
  99. Navon, R.; Kolodny, E. H.; Mitsumoto, H.; Thomas, G. H.; Proia,
  R. L.: Ashkenazi-Jewish and non-Jewish adult G(M2) gangliosidosis
  patients share a common genetic defect. Am. J. Hum. Genet. 46: 817-821,
  1990.
  
  100. Navon, R.; Proia, R. L.: Tay-Sachs disease in Moroccan Jews:
  deletion of a phenylalanine in the alpha-subunit of beta-hexosaminidase. Am.
  J. Hum. Genet. 48: 412-419, 1991.
  
  101. Navon, R.; Proia, R. L.: The mutations in Ashkenazi Jews with
  adult G(M2) gangliosidosis, the adult form of Tay-Sachs disease. Science 243:
  1471-1474, 1989.
  
  102. Neufeld, E. F.: Natural history and inherited disorders of a
  lysosomal enzyme, beta-hexosaminidase. J. Biol. Chem. 264: 10927-10930,
  1989.
  
  103. Nishimoto, J.; Tanaka, A.; Nanba, E.; Suzuki, K.: Expression
  of the beta-hexosaminidase alpha subunit gene with the four-base insertion
  of infantile Jewish Tay-Sachs disease. J. Biol. Chem. 266: 14306-14309,
  1991.
  
  104. O'Brien, J. S.: Ganglioside storage diseases.In: Harris, H.;
  Hirschhorn, K.: Advances in Human Genetics.  New York: Plenum Press
  (pub.)  3: 1972. Pp. 39-98.
  
  105. O'Brien, J. S.: Suggestions for a nomenclature for the GM2-gangliosidoses
  making certain (possibly unwarranted) assumptions. (Comments). Am.
  J. Hum. Genet. 30: 672-675, 1978.
  
  106. O'Brien, J. S.; Geiger, B.: Normal adult with absent HEX-A:
  immunoreactive HEX-A is present. Am. J. Hum. Genet. 31: 642-646,
  1979.
  
  107. O'Brien, J. S.; Okada, S.; Chen, A.; Fillerup, D. L.: Tay-Sachs
  disease: detection of heterozygotes and homozygotes by serum hexosaminidase
  assay. New Eng. J. Med. 283: 15-20, 1970.
  
  108. O'Brien, J. S.; Okada, S.; Fillerup, D. L.; Veath, M. L.; Adornato,
  B. T.; Brenner, P. H.; Leroy, J. G.: Tay-Sachs disease: prenatal
  diagnosis. Science 172: 61-64, 1971.
  
  109. O'Brien, J. S.; Tennant, L.; Veath, M. L.; Scott, C. R.; Bucknall,
  W. E.: Characterization of unusual hexosaminidase A (HEX A) deficient
  human mutants. Am. J. Hum. Genet. 30: 602-608, 1978.
  
  110. Oates, C. E.; Bosch, E. P.; Hart, M. N.: Movement disorders
  associated with chronic GM(2) gangliosidosis: case report and review
  of the literature. Europ. Neurol. 25: 154-159, 1986.
  
  111. Ohman, R.; Ekelund, H.; Svennerholm, L.: The diagnosis of Tay-Sachs
  disease. Acta Paediat. Scand. 60: 399-406, 1971.
  
  112. Ohno, K.; Suzuki, K.: A splicing defect due to an exon-intron
  junctional mutation results in abnormal beta-hexosaminidase alpha
  chain mRNAs in Ashkenazi Jewish patients with Tay-Sachs disease. Biochem.
  Biophys. Res. Commun. 153: 463-469, 1988.
  
  113. Ohno, K.; Suzuki, K.: Multiple abnormal beta-hexosaminidase
  alpha chain mRNAs in a compound-heterozygous Ashkenazi Jewish patient
  with Tay-Sachs disease. J. Biol. Chem. 263: 18563-18567, 1988.
  
  114. Ohno, K.; Suzuki, K.: Mutation in GM2-gangliosidosis B1 variant. J.
  Neurochem. 50: 316-318, 1988.
  
  115. Okada, S.; O'Brien, J. S.: Tay-Sachs disease: generalized absence
  of a beta-D-N-acetylhexosaminidase component. Science 165: 698-700,
  1969.
  
  116. Okada, S.; Veath, M. L.; Leroy, J. G.; O'Brien, J. S.: Ganglioside
  Gm(2) storage diseases: hexosaminidase deficiencies in cultured fibroblasts. Am.  
  J. Hum. Genet. 23: 55-61, 1971.
  
  117. Parnes, S.; Karpati, G.; Carpenter, S.; Ng Ying Kin, N. M. K.;
  Wolfe, L. S.; Suranyi, L.: Hexosaminidase--a deficiency presenting
  as atypical juvenile-onset spinal muscular atrophy. Arch. Neurol. 42:
  1176-1180, 1985.
  
  118. Paw, B. H.; Kaback, M. M.; Neufeld, E. F.: Molecular basis of
  adult-onset and chronic G(M2) gangliosidoses in patients of Ashkenazi
  Jewish origin: substitution of serine for glycine at position 269
  of the alpha-subunit of beta-hexosaminidase. Proc. Nat. Acad. Sci. 86:
  2413-2417, 1989.
  
  119. Paw, B. H.; Moskowitz, S. M.; Uhrhammer, N.; Wright, N.; Kaback,
  M. M.; Neufeld, E. F.: Juvenile G(M2) gangliosidosis caused by substitution
  of histidine for arginine at position 499 or 504 of the alpha-subunit
  of beta-hexosaminidase. J. Biol. Chem. 265: 9452-9457, 1990.
  
  120. Paw, B. H.; Tieu, P. T.; Kaback, M. M.; Lim, J.; Neufeld, E.
  F.: Frequency of three Hex A mutant alleles among Jewish and non-Jewish
  carriers identified in a Tay-Sachs screening program. Am. J. Hum.
  Genet. 47: 698-705, 1990.
  
  121. Paw, B. H.; Wood, L. C.; Neufeld, E. F.: A third mutation at
  the CpG dinucleotide of codon 504 and a silent mutation at codon 506
  of the HEX A gene. Am. J. Hum. Genet. 48: 1139-1146, 1991.
  
  122. Perlman, S. L.: Late-onset Tay-Sachs disease as a Friedreich
  ataxia phenocopy. (Letter) Arch. Neurol. 59: 1832 only, 2002.
  
  123. Petersen, G. M.; Rotter, J. I.; Cantor, R. M.; Field, L. L.;
  Greenwald, S.; Lim, J. S. T.; Roy, C.; Schoenfeld, V.; Lowden, J.
  A.; Kaback, M. M.: The Tay-Sachs disease gene in North American Jewish
  populations: geographic variations and origin. Am. J. Hum. Genet. 35:
  1258-1269, 1983.
  
  124. Petroulakis, E.; Cao, Z.; Clarke, J. T. R.; Mahuran, D. J.; Lee,
  G.; Triggs-Raine, B.: W474C amino acid substitution affects early
  processing of the alpha-subunit of beta-hexosaminidase A and is associated
  with subacute G(M2) gangliosidosis. Hum. Mutat. 11: 432-442, 1998.
  
  125. Phaneuf, D.; Wakamatsu, N.; Huang, J.-Q.; Borowski, A.; Peterson,
  A. C.; Fortunato, S. R.; Ritter, G.; Igdoura, S. A.; Morales, C. R.;
  Benoit, G.; Akerman, B. R.; Leclerc, D.; Hanai, N.; Marth, J. D.;
  Trasler, J. M.; Gravel, R. A.: Dramatically different phenotypes
  in mouse models of human Tay-Sachs and Sandhoff disease. Hum. Molec.
  Genet. 5: 1-14, 1996.
  
  126. Platt, F. M.; Neises, G. R.; Reinkensmeier, G.; Townsend, M.
  J.; Perry, V. H.; Proia, R. L.; Winchester, B.; Dwek, R. A.; Butters,
  T. D.: Prevention of lysosomal storage in Tay-Sachs mice treated
  with N-butyldeoxynojirimycin. Science 276: 428-431, 1997.
  
  127. Proia, R. L.; Kolodny, E. H.; Navon, R.: Reply to Kappler et
  al. (Letter) Am. J. Hum. Genet. 47: 881-882, 1990.
  
  128. Proia, R. L.; Neufeld, E. F.: Synthesis of beta-hexosaminidase
  in cell-free translation and in intact fibroblasts: an insoluble precursor
  alpha chain in a rare form of Tay-Sachs disease. Proc. Nat. Acad.
  Sci. 79: 6360-6364, 1982.
  
  129. Proia, R. L.; Soravia, E.: Organization of the gene encoding
  the human beta-hexosaminidase alpha-chain. J. Biol. Chem. 262: 5677-5681,
  1987.
  
  130. Raghavan, S. S.; Krusell, A.; Krusell, J.; Lyerla, T. A.; Kolodny,
  E. H.: G(M2)-ganglioside metabolism in hexosaminidase A deficiency
  states: determination in situ using labeled G(M2) added to fibroblast
  cultures. Am. J. Hum. Genet. 37: 1071-1082, 1985.
  
  131. Rapin, I.; Suzuki, K.; Suzuki, K.; Valsamis, M. P.: Adult (chronic)
  Gm2 gangliosidosis. Arch. Neurol. 33: 120-130, 1976.
  
  132. Rattazzi, M. C.; Brown, J. A.; Davidson, R. G.; Shows, T. B.
  : Tay-Sachs and Sandhoff-Jatzkewitz diseases: complementation of hexosaminidase
  A deficiency by somatic cell hybridization. Birth Defects Orig. Art.
  Ser. XI(3): 232-235, 1975. Note: Alternate: Cytogenet. Cell Genet.
  14: 402-405, 1975.
  
  133. Rattazzi, M. C.; Brown, J. A.; Davidson, R. G.; Shows, T. B.
  : Studies on complementation of beta hexosaminidase deficiency in
  human Gm2 gangliosidosis. Am. J. Hum. Genet. 28: 143-154, 1976.
  
  134. Risch, N.; Tang, H.: Selection in the Ashkenazi Jewish population
  unlikely--reply to Zlotogora and Bach. (Letter) Am. J. Hum. Genet. 73:
  440-441, 2003.
  
  135. Risch, N.; Tang, H.; Katzenstein, H.; Ekstein, J.: Geographic
  distribution of disease mutations in the Ashkenazi Jewish population
  supports genetic drift over selection. Am. J. Hum. Genet. 72: 812-822,
  2003.
  
  136. Rucker, J. C.; Shapiro, B. E.; Han, Y. H.; Kumar, A. N.; Garbutt,
  S.; Keller, E. L.; Leigh, R. J.: Neuro-ophthalmology of late-onset
  Tay-Sachs disease (LOTS). Neurology 63: 1918-1926, 2004.
  
  137. Sango, K.; Yamanaka, S.; Hoffmann, A.; Okuda, Y.; Grinberg, A.;
  Westphal, H.; McDonald, M. P.; Crawley, J. N.; Sandhoff, K.; Suzuki,
  K.; Proia, R. L.: Mouse models of Tay-Sachs and Sandhoff diseases
  differ in neurologic phenotype and ganglioside metabolism. Nature
  Genet. 11: 170-176, 1995.
  
  138. Schneck, L.; Maisel, J.; Volk, B. W.: The startle response and
  serum enzyme profile in early detection of Tay-Sachs disease. J.
  Pediat. 65: 749-756, 1964.
  
  139. Seldin, M. F.; Saunders, A. M.; Rochelle, J. M.; Howard, T. A.
  : A proximal mouse chromosome 9 linkage map that further defines linkage
  groups homologous with segments of human chromosomes 11, 15, and 19. Genomics 9:  
  678-685, 1991.
  
  140. Shore, S.; Tomczak, J.; Grebner, E. E.; Myerowitz, R.: An unusual
  genotype in an Ashkenazi Jewish patient with Tay-Sachs disease. Hum.
  Mutat. 1: 486-490, 1992.
  
  141. Sloan, H. R.; Fredrickson, D. S.: Gm(2) gangliosidosis: Tay-Sachs
  disease.In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.
  : The Metabolic Basis of Inherited Disease.  New York: McGraw-Hill
  (pub.)  (3rd ed.): 1972. Pp. 615-638.
  
  142. Snabes, M. C.; Chong, S. S.; Subramanian, S. B.; Kristjansson,
  K.; DiSepio, D.; Hughes, M. R.: Preimplantation single-cell analysis
  of multiple genetic loci by whole-genome amplification. Proc. Nat.
  Acad. Sci. 91: 6181-6185, 1994.
  
  143. Sonderfeld, S.; Brendler, S.; Sandhoff, K.; Galjaard, H.; Hoogeveen,
  A. T.: Genetic complementation in somatic cell hybrids of four variants
  of infantile G(M2) gangliosidosis. Hum. Genet. 71: 196-200, 1985.
  
  144. Spyropoulos, B.; Moens, P. B.; Davidson, J.; Lowden, J. A.:
  Heterozygote advantage in Tay-Sachs carriers? Am. J. Hum. Genet. 33:
  375-380, 1981.
  
  145. Strasberg, P.; Warren, I.; Skomorowski, M.-A.; Feigenbaum, A.
  : Homozygosity for the common Ashkenazi Jewish Tay-Sachs +1 IVS-12
  splice-junction mutation: first report. Hum. Mutat. 10: 82-83, 1997.
  
  146. Suzuki, K.; Suzuki, K.; Rapin, I.; Suzuki, Y.; Ishii, N.: Juvenile
  Gm(2)-gangliosidosis: clinical variant of Tay-Sachs disease or a new
  disease. Neurology 20: 190-204, 1970.
  
  147. Suzuki, Y.; Suzuki, K.: Partial deficiency of hexosaminidase
  component A in juvenile Gm(2)-gangliosidosis. Neurology 20: 848-851,
  1970.
  
  148. Takeda, K.; Nakai, H.; Hagiwara, H.; Tada, K.; Shows, T. B.;
  Byers, M. G.; Myerowitz, R.: Fine assignment of beta-hexosaminidase
  A alpha-subunit on 15q23-q24 by high resolution in situ hybridization. Tohoku
  J. Exp. Med. 160: 203-211, 1990.
  
  149. Tanaka, A.; Ohno, K.; Sandhoff, K.; Maire, I.; Kolodny, E. H.;
  Brown, A.; Suzuki, K.: GM2-gangliosidosis B1 variant: analysis of
  beta-hexosaminidase alpha gene abnormalities in seven patients. Am.
  J. Hum. Genet. 46: 329-339, 1990.
  
  150. Tanaka, A.; Ohno, K.; Suzuki, K.: GM2-gangliosidosis B1 variant:
  a wide geographic and ethnic distribution of the specific beta-hexosaminidase
  alpha chain mutation originally identified in a Puerto Rican patient. Biochem.
  Biophys. Res. Commun. 156: 1015-1019, 1988.
  
  151. Tanaka, A.; Punnett, H. H.; Suzuki, K.: A new point mutation
  in the beta-hexosaminidase alpha subunit gene responsible for infantile
  Tay-Sachs disease in a non-Jewish Caucasian patient (a Kpn mutant). Am.
  J. Hum. Genet. 47: 567-574, 1990.
  
  152. Taniike, M.; Yamanaka, S.; Proia, R. L.; Langaman, C.; Bone-Turrentine,
  T.; Suzuki, K.: Neuropathology of mice with targeted disruption of
  Hexa gene, a model of Tay-Sachs disease. Acta Neuropath. 89: 296-304,
  1995.
  
  153. Thomas, G. H.; Raghavan, S.; Kolodny, E. H.; Frisch, A.; Neufeld,
  E. F.; O'Brien, J. S.; Reynolds, L. W.; Miller, C. S.; Shapiro, J.;
  Kazazian, H. H., Jr.; Heller, R. H.: Nonuniform deficiency of hexosaminidase
  A in tissues and fluids of two unrelated individuals. Pediat. Res. 16:
  232-237, 1982.
  
  154. Thomas, G. H.; Taylor, H. A.; Miller, C. S.; Axelman, J.; Migeon,
  B. R.: Genetic complementation after fusion of Tay-Sachs and Sandhoff
  cells. Nature 250: 580-582, 1974.
  
  155. Thurmon, T. F.: Tay-Sachs genes in Acadians. (Letter) Am. J.
  Hum. Genet. 53: 781-782, 1993.
  
  156. Tomczak, J.; Boogen, C.; Grebner, E. E.: Distribution of a pseudodeficiency  
  allele among Tay-Sachs carriers. (Letter) Am. J. Hum. Genet. 53:
  537-539, 1993.
  
  157. Triggs-Raine, B. L.; Akerman, B. R.; Clarke, J. T. R.; Gravel,
  R. A.: Sequence of DNA flanking the exons of the HEXA gene, and identification
  of mutations in Tay-Sachs disease. Am. J. Hum. Genet. 49: 1041-1054,
  1991.
  
  158. Triggs-Raine, B. L.; Feigenbaum, A. S. J.; Natowicz, M.; Skomorowski,
  M.-A.; Schuster, S. M.; Clarke, J. T. R.; Mahuran, D. J.; Kolodny,
  E. H.; Gravel, R. A.: Screening for carriers of Tay-Sachs disease
  among Ashkenazi Jews: a comparison of DNA-based and enzyme-based tests. New
  Eng. J. Med. 323: 6-12, 1990.
  
  159. Triggs-Raine, B. L.; Gravel, R. A.: Diagnostic heteroduplexes:
  simple detection of carriers of a 4-bp insertion mutation in Tay-Sachs
  disease. Am. J. Hum. Genet. 46: 183-184, 1990.
  
  160. Triggs-Raine, B. L.; Mules, E. H.; Kaback, M. M.; Lim-Steele,
  J. S. T.; Dowling, C. E.; Akerman, B. R.; Natowicz, M. R.; Grebner,
  E. E.; Navon, R.; Welch, J. P.; Greenberg, C. R.; Thomas, G. H.; Gravel,
  R. A.: A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers:
  implications for carrier screening. Am. J. Hum. Genet. 51: 793-801,
  1992.
  
  161. Trop, I.; Kaplan, F.; Brown, C.; Mahuran, D.; Hechtman, P.:
  A gly250-to-asp substitution in the alpha-subunit of hexosaminidase
  A causes juvenile-onset Tay-Sachs disease in a Lebanese-Canadian family. Hum.
  Mutat. 1: 35-39, 1992.
  
  162. Trop, I.; Kaplan, F.; Hechtman, P.: Juvenile-onset Tay-Sachs
  disease in a Lebanese proband is caused by gly(250)-to-asp substitution
  in the alpha subunit of hexosaminidase A. (Abstract) Am. J. Hum.
  Genet. 47 (suppl.): A168, 1990.
  
  163. Vallance, H.; Morris, T. J.; Coulter-Mackie, M.; Lim-Steele,
  J.; Kaback, M.: Common HEXB polymorphisms reduce serum HexA and HexB
  enzymatic activities, potentially masking Tay-Sachs disease carrier
  identification. Molec. Genet. Metab. 87: 122-127, 2006.
  
  164. Van Cong, N.; Weil, D.; Rebourcet, R.; Frezal, J.: A study of
  hexosaminidases in interspecific hybrids and in Gm2 gangliosidosis
  with a discussion on their genetic control. Ann. Hum. Genet. 39:
  111-123, 1975.
  
  165. Van Heyningen, V.; Bobrow, M.; Bodmer, W. F.; Gardiner, S. E.;
  Povey, S.; Hopkinson, D. A.: Chromosome assignment of some human
  enzyme loci: mitochondrial malate dehydrogenase to 7, mannosephosphate
  isomerase and pyruvate kinase to 15 and probably, esterase D to 13. Ann.
  Hum. Genet. 38: 295-303, 1975.
  
  166. Volk, B. W.: Tay-Sachs Disease.  New York: Grune and Stratton
  (pub.)  1964.
  
  167. Whitley, C. B.; Anderson, R. A.; McIvor, R. S.: Heterozygosity
  for the 'DN allele' (G533-to-A) of the beta-hexosaminidase alpha subunit
  gene identified by direct DNA sequencing in a family with the B1 variant
  of G(M2)-gangliosidosis. Neuropediatrics 23: 96-101, 1992.
  
  168. Wicklow, B. A.; Ivanovich, J. L.; Plews, M. M.; Salo, T. J.;
  Noetzel, M. J.; Lueder, G. T.; Cartegni, L.; Kaback, M. M.; Sandhoff,
  K.; Steiner, R. D.; Triggs-Raine, B. L.: Severe subacute GM2 gangliosidosis
  caused by an apparently silent HEXA mutation (V324V) that results
  in aberrant splicing and reduced HEXA mRNA. Am. J. Med. Genet. 127A:
  158-166, 2004.
  
  169. Willner, J. P.; Grabowski, G. A.; Gordon, R. E.; Bender, A. N.;
  Desnick, R. J.: Chronic GM(2) gangliosidosis masquerading as atypical
  Friedreich ataxia: clinical morphologic and biochemical studies of
  nine cases. Neurology 31: 787-798, 1981.
  
  170. Yaffe, M. G.; Kaback, M.; Goldberg, M.; Miles, J.; Itabashi,
  H.; McIntyre, H.; Mohandas, T.: An amyotrophic lateral sclerosis-like
  syndrome with hexosaminidase-A deficiency: a new type of GM(2) gangliosidosis.
  (Abstract) Neurology 29: 611, 1979.
  
  171. Yokoyama, S.: Role of genetic drift in the high frequency of
  Tay-Sachs disease among Ashkenazic Jews. Ann. Hum. Genet. 43: 133-136,
  1979.
  
  172. Zlotogora, J.: Is the presence of two different Tay-Sachs disease
  mutations in a Cajun population an unexpected observation? (Letter) Am.
  J. Hum. Genet. 52: 1014-1015, 1993.
  
  173. Zlotogora, J.; Bach, G.: The possibility of a selection process
  in the Ashkenazi Jewish population. (Letter) Am. J. Hum. Genet. 73:
  438-440, 2003.
  
  174. Zokaeem, G.; Bayleran, J.; Kaplan, P.; Hechtman, P.; Neufeld,
  E. F.: A shortened beta-hexosaminidase alpha-chain in an Italian
  patient with infantile Tay-Sachs disease. Am. J. Hum. Genet. 40:
  537-547, 1987.
  
Clinical Synopsis:
  INHERITANCE:
     Autosomal recessive
  
  HEAD AND NECK:
     [Eyes];
     Macular pallor with prominence of fovea centralis (cherry red spot);
     Blindness
  
  RESPIRATORY:
     [Airways];
     Aspiration
  
  NEUROLOGIC:
     [Central nervous system];
     Increased startle response;
     Hypotonia;
     Late hypertonia;
     Poor head control;
     Psychomotor degeneration;
     Seizures;
     Dementia;
     [Behavioral/psychiatric manifestations];
     Apathy
  
  LABORATORY ABNORMALITIES:
     Gm2-ganglioside accumulation;
     Ballooned neurons;
     Hexosaminidase A deficiency
  
  MISCELLANEOUS:
     Infantile onset;
     Usually fatal by age 5 years;
     Incidence of 1 in 3,900 births among Jewish persons;
     Incidence of 1 in 320,000 births among non-Jewish persons
  
  MOLECULAR BASIS:
     Caused by mutations in the hexosaminidase A, alpha polypeptide gene
     (HEXA, 272800.0001)
  
Contributors: 
  Cassandra L. Kniffin - updated: 05/27/2009
  Michael J. Wright  - revised: 6/23/1999
  Ada Hamosh - revised: 6/23/1999
  
Creation Date: 
  John F. Jackson: 6/15/1995
  
Edit Dates: 
  ckniffin: 05/27/2009
  joanna: 5/6/2002
  kayiaros: 6/23/1999
  
Contributors: 
  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 Dates: 
  wwang: 02/16/2010
  ckniffin: 1/4/2010
  carol: 11/4/2009
  carol: 11/2/2009
  terry: 3/25/2009
  carol: 11/20/2008
  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
  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
  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
  
OMIM
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