GM2-GANGLIOSIDOSIS, TYPE I
HEXOSAMINIDASE A DEFICIENCY, ADULT TYPE, INCLUDED
GM2-GANGLIOSIDOSIS, VARIANT B1, INCLUDED
GM2-GANGLIOSIDOSIS, ADULT CHRONIC TYPE, INCLUDED
HEXA DEFICIENCY TAY-SACHS DISEASE, JUVENILE, INCLUDED
TAY-SACHS DISEASE, VARIANT B1, INCLUDED
B VARIANT GM2-GANGLIOSIDOSIS
TAY-SACHS DISEASE, PSEUDO-AB VARIANT, INCLUDED
TSD
hexosaminidase a deficiency
GM2-gangliosidosis, B, B1 variant
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.
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 ... 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.
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 ... 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).
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 ... 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 at 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.
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) ... 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. In Table 4 of their report, Lazarin et al. (2013) noted that among 21,985 ethnically diverse individuals screened for Tay-Sachs disease/HexA deficiency carrier status, they identified 151 carriers. These 151 carriers included 90 carriers of Ashkenazi Jewish ethnicity from a subset of 2,386 Ashkenazi Jewish individuals screened.
The common clinical findings in individuals with Tay-Sachs disease (TSD), the prototype hexosaminidase A deficiency, are:...
DiagnosisClinical DiagnosisThe common clinical findings in individuals with Tay-Sachs disease (TSD), the prototype hexosaminidase A deficiency, are:Progressive weakness and loss of motor skills beginning between ages three and six monthsDecreased attentivenessAn increased startle responseThe typical findings on physical examination are:A cherry-red spot of the fovea centralis of the macula of the retinaA normal-sized liver and spleenGeneralized muscular hypotonia with sustained ankle clonus and hyperreflexiaThe findings above are followed by signs of progressive neurodegeneration, seizures, blindness, and spasticity, usually leading to death before age four years.Individuals with the juvenile, chronic, and adult-onset forms have later onset, slower progression, and more variable neurologic findings.TestingBeta-hexosaminidase A (HEX A) enzymatic activityAffected individuals. The diagnosis of hexosaminidase A deficiency relies on the demonstration of absent to near-absent HEX A enzymatic activity in the serum, white blood cells, or other tissues from a symptomatic individual in the presence of normal or elevated activity of the beta-hexosaminidase B (HEX B) isoenzyme [Okada & O'Brien 1969].Individuals with the acute infantile form (TSD) have no or extremely low (0%-5%) HEX A enzymatic activity.Individuals with juvenile or chronic and adult-onset forms of hexosaminidase A deficiency have residual but low (<15%) HEX A enzymatic activity of HEX A activity.Note: HEX A is composed of one alpha subunit and one beta subunit; HEX B is a homodimer composed of two beta subunits.Carrier detection. In population screening, assay of HEX A enzymatic activity in serum or leukocytes using synthetic substrates provides a simple, inexpensive, and highly accurate method for heterozygote identification:Serum may be used to test all males and those women who are not pregnant and not using oral contraceptives.Leukocytes are used to test: (1) women who are pregnant; (2) women who are using oral contraceptives; and (3) any individual whose serum HEX A enzymatic activity is in an inconclusive range.Molecular Genetic TestingGene. HEXA, the gene encoding the alpha subunit of the HEX A enzyme, is the only gene in which mutations cause hexosaminidase A deficiency.Clinical testingTargeted mutation analysis. The panel of the six most common mutations comprises:Three null alleles, (p.Tyr427Ilefs*5, c.1421+1G>C, and c.1073+G>A), which in the homozygous state or in compound heterozygosity are associated with TSDThe p.Gly269Ser allele, which is associated with the adult-onset form of hexosaminidase A deficiency in the homozygous state or in compound heterozygosity with a null alleleTwo pseudodeficiency alleles (p.Arg247Trp and p.Arg249Trp), which are not associated with neurologic disease but are associated with reduced degradation of the synthetic substrate when HEX A enzymatic activity is determined Note: (1) The presence of one pseudodeficiency allele reduces HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a potential problem exists in distinguishing between a disease-causing allele, which reduces HEX A enzymatic activity to both artificial and natural substrates, and a pseudodeficiency allele, which reduces HEX A enzymatic activity to the artificial substrate only. The potential problem is avoided by using molecular genetic testing when the enzymatic activity is abnormal, to determine if the reduced HEX A enzymatic activity is caused by a disease-causing mutation or a pseudodeficiency mutation. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (Table 1).Other. Some laboratories offer extended panels or testing for selected mutations that are specific to certain populations. In Quebec, a 7.6-kb genomic deletion that involves the HEXA promoter and exon 1 is the most common allele associated with TSD [Myerowitz & Hogikyan 1987]. Note: When testing individuals from the French Canadian population or other populations with founder mutations, care should be taken to identify a laboratory performing analyses for the appropriate mutations.Sequence analysis/mutation scanning. More than 130 HEXA mutations have been detected to date by sequence analysis or mutation scanning [McGinniss et al 2002, Stenson et al 2009, www.hgmd.cf.ac.uk] Table 1. Summary of Molecular Genetic Testing Used in Hexosaminidase A DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityHEXASequence analysisSequence variants 299%ClinicalTargeted mutation analysisc.1274_1277dupTATC c.1421+1G>C c.1073+1G>A p.Gly269Ser p.Arg247Trp (pseudodeficiency) p.Arg249Trp (pseudodeficiency) 7.6-kb del including exon 1 3Depends on ethnicity; see Table 2Deletion / duplication analysis 4Exonic or whole-gene deletionsRare1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Mutation panels may vary by laboratory4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. Table 2. Molecular Genetic Testing Used in Carrier Detection for Hexosaminidase A DeficiencyView in own windowGene SymbolTest MethodMutations DetectedAllele StatusHeterozygote FrequencyTest AvailabilityObligate 1Screening 2JewishNon-JewishJewishNon-JewishHEXATargeted mutation analysis 3c.1274_1277dupTATCNull81%32%80%8%Clinical c.1421+1G>C Null15%09%0c.1073+1G>A Null014%010% 4p.Gly269Ser Adult onset2%03%5%p.Arg247Trp Pseudo-deficiency002%32%p.Arg249Trp Pseudo-deficiency0004%All of the aboveNot applicable98%46%94%59% 5From Kaback et al [1993], Scott et al [2010]1. Obligate heterozygotes (i.e., parents of a child with hexosaminidase A deficiency)2. Individuals identified in screening programs as having levels of HEX A enzymatic activity in the heterozygous range3. Mutation panels may vary by laboratory.4. Primarily persons of Celtic, French, Cajun, and Pennsylvania Dutch background5. Note: In non-Jewish individuals identified in screening programs as having levels of HEX A enzymatic activity in the heterozygous range: (1) the majority of identified alleles (36%/59%) are pseudodeficiency alleles; and (2) the minority of identified alleles (23%/59%) are disease-related.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo establish the diagnosis in a symptomatic infant proband Assay of HEX A enzymatic activity is the primary method of diagnosis for symptomatic individuals.Molecular genetic testing can be used to identify the two disease-causing mutations when assay of HEX A enzymatic activity is abnormal. The options are:Targeted mutation analysis for a panel of common HEXA mutations, followed by sequence analysis if only one or neither HEXA mutation was identified; OR Sequence analysis. If proband is of French Canadian descent, deletion/duplication analysis for the 7.6-kb genomic deletion that involves the HEX A promoter and exon 1 should be performed before sequence analysis. Carrier testing − population screening Assay of HEX A enzymatic activity is the primary method of population screening for carrier detection, as it has greater sensitivity than targeted mutation analysis. Note: When individuals are identified with apparent deficiency of HEX A enzymatic activity, targeted mutation analysis can then be used to distinguish pseudodeficiency alleles from disease-causing alleles.Targeted mutation analysis for a panel of common HEXA mutations can be used to screen Ashkenazi Jewish individuals for the three common disease-associated mutations that account for between 92% and 94% of heterozygotes in this population. Note: In the Ashkenazi Jewish population, the sensitivity of targeted mutation analysis is lower than assay of HEX A enzymatic activity; therefore, some carriers are not identified using targeted mutation analysis.Carrier testing of at-risk relatives requires prior identification of the disease-causing mutations in an affected family member either through use of targeted mutation analysis for a panel of common HEXA mutations or by sequence analysis of HEXA.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in HEXA. (See Differential Diagnosis for discussions of Sandhoff disease and GM2 activator disease)
The phenotypes of hexosaminidase A deficiency include the following:...
Natural HistoryThe phenotypes of hexosaminidase A deficiency include the following:Acute infantile (Tay-Sachs disease) with rapid progression and death before age four years Juvenile (subacute) with later onset and survival into late childhood or adolescenceChronic and adult-onset with long-term survival. Affected individuals have several different phenotypes, including: progressive dystonia, spinocerebellar degeneration, motor neuron disease with muscle weakness and fasciculations, and/or psychosis.Acute infantile hexosaminidase A deficiency (Tay-Sachs disease, TSD). Affected infants generally appear to be completely normal at birth. Mild motor weakness begins between age three and six months, along with myoclonic jerks and an exaggerated startle reaction to sharp noise.By age six to ten months, the infant fails to achieve new motor skills or even loses previously demonstrated skills. Decreasing visual attentiveness and unusual eye movements are associated with pallor of the perifoveal macula of the retina with prominence of the fovea centralis, the so-called cherry-red spot, which is seen in virtually all affected children.After age eight to ten months, progression of the disease is rapid. Spontaneous or purposeful voluntary movements diminish, and the infant becomes progressively less responsive. Vision deteriorates rapidly. Seizures are common by age 12 months. Subtle partial complex seizures or absence attacks typically become more frequent and more severe.Progressive enlargement of the head typically begins by age 18 months; it results from reactive cerebral gliosis, not hydrocephalus.Further deterioration in the second year of life results in: decerebrate posturing, difficulties in swallowing, worsening seizures, and finally an unresponsive, vegetative state. Death from bronchopneumonia usually occurs between age two and four years.Juvenile (subacute) hexosaminidase A deficiency. Juvenile hexosaminidase A deficiency often begins with ataxia and incoordination between age two and ten years. Speech, life skills, and cognition decline. Spasticity and seizures are present by the end of the first decade of life. Loss of vision occurs much later than in the acute infantile form of the disease, and a cherry-red spot is not consistently observed. Instead, optic atrophy and retinitis pigmentosa may be seen late in the course. A vegetative state with decerebrate rigidity develops by age ten to 15 years, followed within a few years by death, usually from infection. In some cases, the disease pursues a particularly aggressive course, culminating in death in two to four years.Chronic and adult-onset hexosaminidase A deficiency. These conditions represent a spectrum of later-onset, more slowly progressive neurodegenerative disorders, associated with low levels of residual HEX A enzyme activity. Early symptoms may range from muscle weakness to extrapyramidal findings to altered cerebellar manifestations.In the chronic form, central nervous system involvement is widespread, although certain neurologic findings may predominate over others. Psychomotor regression may be less prominent. The age of onset ranges from early childhood to the end of the first decade. In some individuals, extrapyramidal signs of dystonia, choreoathetosis, and ataxia may be evident. In others, cerebellar signs of dysarthria, ataxia, incoordination, and abnormalities of posture develop between age two and ten years; mentation and verbal skills tend to be involved later in the course [Rapin et al 1976]. The clinical presentation of the chronic form of hexosaminidase A deficiency may suggest possible diagnosis of spinocerebellar degeneration, Friedreich ataxia, or amyotrophic lateral sclerosis (ALS).Individuals with adult-onset disease tend to show progressive muscle wasting, weakness, fasciculations, and dysarthria, indistinguishable from progressive adolescent-onset spinal muscular atrophy (Kugelberg-Welander disease) or early-onset ALS. Upper motor neuron signs, nonspecific cerebellar atrophy [Neudorfer et al 2005], and abnormalities of saccades [Rucker et al 2004] may be present.Cognitive dysfunction and dementia can be observed [Frey et al 2005]. As many as 40% of individuals have psychiatric manifestations (without dementia) including: recurrent psychotic depression, bipolar symptoms, and acute hebephrenic schizophrenia with disorganization of thought, agitation, delusions, hallucinations, and paranoia [Navon et al 1986]. Impairment of executive functioning and memory has also been observed [Zaroff et al 2004].Marked clinical variability is seen even within the same family; for example, psychosis may be severe by age 20 years in one individual, whereas another affected family member may function into the sixth or seventh decade with only neuromuscular findings.Neuropathology. Children with the acute infantile form (TSD) have excessive and ubiquitous neuronal glycolipid storage (≤12% of the brain dry weight) of which the enormous predominance is the specific glycolipid, GM2 ganglioside. Individuals with the chronic and adult-onset forms have less accumulation of glycolipid; it may even be restricted to specific brain regions. For example, in the adult-onset form, the cortex is almost unimpaired, whereas the hippocampus, the brain stem nuclei, and the spinal cord are markedly affected [Gravel et al 2001].
HEX A enzymatic activity. The level of the residual activity of the HEX A enzyme correlates inversely with the severity of the disease; i.e., the lower the level of the enzymatic activity, the more severe the phenotype is likely to be:...
Genotype-Phenotype CorrelationsHEX A enzymatic activity. The level of the residual activity of the HEX A enzyme correlates inversely with the severity of the disease; i.e., the lower the level of the enzymatic activity, the more severe the phenotype is likely to be:Individuals with the acute infantile form (TSD) have two null (non-expressing) alleles with no HEX A enzymatic activity.Individuals with juvenile or chronic and adult-onset forms of hexosaminidase A deficiency are usually compound heterozygotes for a null allele and an allele that results in residual but low activity of the HEX A enzyme toward GM2 ganglioside, or two alleles that result in low residual HEX A activity.HEXA mutations associated with acute infantile hexosaminidase A deficiency (TSD). Of the more than 100 specific mutations in the alpha subunit of HEXA that have been described, the great majority (>90) are associated with the acute infantile form [Gravel et al 2001].B1 variant associated with juvenile and chronic hexosaminidase A deficiency. The B1 variant is a defective HEX A enzyme that has some activity toward GM2 ganglioside. The cause of the most common B1 variant is the mutation p.Arg178His, predominantly found in individuals of Portuguese background:An individual who is a compound heterozygote for a null allele and an allele causing a B1 variant has the juvenile phenotype.An individual who is homozygous for a mutation causing a B1 variant has twice the enzymatic activity of a compound heterozygote and has the milder chronic phenotype.HEXA mutations associated with adult-onset hexosaminidase A deficiency. While several private mutations have been identified with later-onset forms of hexosaminidase A deficiencies, two mutations are primarily associated with the adult-onset hexosaminidase A deficiency:The p.Gly269Ser mutation occurs with significant frequency in the Ashkenazi Jewish population and results in an unstable alpha subunit precursor, which fails to associate with the beta subunit.The p.Gly250Asp mutation occurs in exon 7 of the alpha subunit. Typically, either of these two mutations, when homozygous or combined with a null allele, results in the adult-onset phenotype.HEXA pseudodeficiency allelesIndividuals heterozygous for a pseudodeficiency allele have an apparent deficiency of HEX A enzymatic activity, as seen in heterozygotes for TSD.Individuals with two altered HEXA alleles, one a pseudodeficiency allele and the second a disease-related mutation, have extremely low or absent HEX A enzymatic activity with synthetic substrates but have no evidence of neurologic abnormality even into the seventh decade of life (the longest that any of these individuals has been followed). Such individuals have been called "pseudodeficient" or "HEX A minus, normal." Individuals with a pseudodeficiency allele are identified through carrier screening programs when a healthy individual appears to have HEX A enzymatic activity levels similar to those of a child with Tay-Sachs disease, or in carrier screening programs that specifically test for the pseudodeficiency mutations by DNA-based methods.
The neurologic symptoms observed in individuals with hexosaminidase A deficiency are not pathognomonic and could be caused by a wide array of other conditions including toxic or infectious agents....
Differential DiagnosisThe neurologic symptoms observed in individuals with hexosaminidase A deficiency are not pathognomonic and could be caused by a wide array of other conditions including toxic or infectious agents.Progressive weakness and loss of motor skills between age six and 12 months, associated with an increased startle response, a cherry-red spot of the macula of the retina, and normal-size liver and spleen, particularly in a child of Ashkenazi Jewish parents, strongly suggest a diagnosis of acute infantile hexosaminidase A deficiency (Tay-Sachs disease; TSD). Another extremely rare form of infantile GM2 ganglioside storage is called activator-deficient TSD. In this disorder, the enzymatic activity of both HEX A and HEX B is normal, but GM2 ganglioside accumulation occurs because of a deficit of the intralysosomal glycoprotein ("GM2 activator") that is required for the degradation of GM2 ganglioside. The phenotype of this condition is identical to classic TSD.The cherry-red spot of the fovea centralis of the macula of the retina, which is seen in virtually all individuals with TSD, can also be seen in the first 12 months of life in other disorders, including: infantile Gaucher disease, GM1 gangliosidosis, galactosialidosis, Niemann-Pick disease type A, and Sandhoff disease.Neurologic regression is seen in the first six months of life in many conditions, including: Krabbe disease, Canavan disease, Alexander disease, infantile Gaucher disease, and the infantile form (Santavuori-Haltia disease) and late-infantile form (Bielschowsky-Jansky) of neuronal ceroid-lipofuscinosis.Neurologic regression in the first year of life and hepatosplenomegaly with coarse facies may suggest GM1 gangliosidosis, mucolipidosis II (I-cell disease), sialidosis, and Niemann-Pick disease type A.Sandhoff disease and its variants are associated with deficiencies of both HEX A and HEX B enzymatic activity. Sandhoff disease presents with the same neurologic findings as TSD; however, Sandhoff disease is rarely seen in Jewish infants. In Sandhoff disease, involvement outside of the nervous system is evidenced by organomegaly, skeletal abnormalities, oligosacchariduria, and storage cells, as seen on histologic examination of a bone marrow aspirate. The enzymatic activity of HEX A is deficient, as is that of HEX B, since both enzymes lack the common beta subunit.In the child presenting with symptoms of juvenile hexosaminidase A deficiency, the two TSD variants, combined HEX A and HEX B deficiency (Sandhoff disease variants), juvenile neuronal ceroid-lipofuscinosis (Batten disease), and other neurodegenerative disorders need to be considered.Hexosaminidase A deficiency of late onset may mimic other conditions. Adolescent-onset spinal muscular atrophy (SMA3) as well as Friedreich ataxia (FRDA), amyotrophic lateral sclerosis (ALS), adult-onset neuronal ceroid-lipofuscinosis (Kuf's disease), and other lysosomal storage diseases need to be considered in individuals with the chronic or adult-onset forms of hexosaminidase A deficiency. As noted, these individuals often present with muscle wasting and weakness, fasciculations, and diverse other neurologic findings.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Acute infantile hexosaminidase deficiency (Tay-Sachs disease)Juvenile hexosaminidase deficiencyChronic hexosaminidase deficiencyAdult-onset hexosaminidase deficiency
To establish the extent of disease in an individual diagnosed with hexosaminidase A deficiency, the following are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with hexosaminidase A deficiency, the following are recommended:Complete history and physical examination, including ophthalmologic examinationFamily history, including ethnicityReferral to a pediatric neurologist and/or ophthalmologistTreatment of ManifestationsFor the most part, treatment for Tay-Sachs disease is supportive and directed to providing adequate nutrition and hydration, managing infectious disease, protecting the airway, and controlling seizures.Seizure control can usually be achieved using conventional antiepileptic drugs (AEDs) such as benzodiazepines, phenytoins, and/or barbiturates. However, seizures are progressive and change in type and severity; thus, over time changes in the dose or type of AEDs may be necessary for optimal seizure control.For older individuals with adult-onset hexosaminidase A deficiency who have psychiatric manifestations, conventional antipsychotic or antidepressant therapy may be used; but the clinical response is unpredictable and generally poor.Treatment with lithium salts and electroconvulsive therapy has been reported to be beneficial, at least in ameliorating for a period the episodes of psychotic depression.Prevention of Secondary ComplicationsAs the child with the acute infantile form (Tay-Sachs disease) becomes more debilitated and disabled, good bowel management becomes essential. Good hydration, food additives, stool softeners, laxatives, and other measures should be employed to avoid severe constipation.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationEarly experimental intravenous enzyme replacement trials were unsuccessful, as the large molecular weight enzyme did not cross the blood-brain barrier [reviewed in Desnick & Kaback 2001]. Central nervous system enzyme replacement or neuronal-corrective gene therapy are experimental considerations [Matsuoka et al 2011, Tsuji et al 2011]. A clinical trial used HEX A inhibitors to reduce the biosynthesis of glycosphingolipid precursors to GM2 ganglioside. Although one such agent, N-deoxynojirimycin, showed some efficacy with the non-CNS neuronal storage disorder, type I Gaucher disease [Pastores et al 2005], no improvement was observed in a trial of substrate reduction therapy for individuals with adult-onset GM2 gangliosidosis [Shapiro et al 2009]. Preclinical studies for individuals with later-onset Tay-Sachs disease are underway to evaluate pharmacologic chaperone therapy using an immuno sugar that is an active site inhibitor of HEX A activity [Clarke et al 2011]. Since residual enzyme activity is very low (but detectable), chaperone therapy is designed to rescue newly synthesized mutant enzymes in the endoplasmic reticulum before they are removed for degradation and to deliver them to the lysosome where they may function [Rountree et al 2009].For studies of pathogenesis and preclinical evaluation of various therapeutic strategies, animal models are available. A genetically engineered mouse model of infantile hexosaminidase A deficiency (TSD) has been constructed and can be used to evaluate innovative treatment modalities. Recently, a sheep model of TSD with HEX A deficiency was identified in which affected animals progressively accumulate GM2 ganglioside, have neurologic pathology, and experience a neurodegenerative clinical course [Torres et al 2010]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherThe poor response to tricyclic antidepressants and phenothiazines has been attributed to the observation that these drugs inhibit HEX A enzymatic activity in vitro and induce lysosomal lipidosis in fibroblasts and accumulation of lipids in experimental animals in vivo.Several attempts have been made at purified enzyme replacement therapy for children with acute infantile hexosaminidase A deficiency; none has been successful. Cellular infusions and even bone marrow transplantation have been attempted, with no evidence of benefit.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hexosaminidase A Deficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDHEXA15q23Beta-hexosaminidase subunit alphaHexosaminidase A; Tay-Sachs Disease alsod/HEXA genetic mutations HEXA homepage - Mendelian genesHEXAData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hexosaminidase A Deficiency (View All in OMIM) View in own window 272800TAY-SACHS DISEASE; TSD 606869HEXOSAMINIDASE A; HEXANormal allelic variants. HEXA spans approximately 35,000 base pairs and comprises 14 exons. Pathologic allelic variants. Of the more than 100 HEXA mutations identified to date, the vast majority (>90) are associated with the acute infantile phenotype (Tay-Sachs disease) [Gravel et al 2001]. All the small insertions or deletions producing frameshifts and the nucleotide substitutions causing premature stop codons result in this clinical phenotype. In general, these mutations are immunologically negative for cross-reactive material. Most splice mutations fall into this category, but important exceptions exist. Among Ashkenazi Jews in North America and Israel, the two mutations associated with the acute infantile form account for 90%-95% of all alleles; the mutation p.Gly269Ser associated with the chronic form accounts for 3%, and the two pseudodeficiency alleles p.Arg247Trp and p.Arg249Trp account for 2%. In the non-Jewish general population, about 35% of alleles are accounted for by two mutations associated with the acute infantile phenotype; and about 5% are accounted for by mutations associated with the juvenile, chronic, and adult-onset types. Of particular importance, approximately 35% of enzymatically defined, non-Jewish heterozygotes are carriers for one of the two pseudodeficiency alleles (p.Arg247Trp or p.Arg249Trp). The mutations that account for most of the TSD occurring in Ashkenazi Jews are null alleles because they result in no protein product, although the gene is transcriptionally active in both cases. The most frequent allele is a 4-bp insertion in exon 11 (p.Tyr427Ilefs*5), c.1274_1277dupTATC, which creates a frameshift and downstream stop codon in the coding sequence. Although HEXA is transcribed normally, the mRNA is undetectable by Northern blotting. The second major allele is a donor splice-junction mutation in intron 12 (c.1421+1G>C), which results in the production of several aberrantly spliced mRNAs. The most common mutation in the French Canadian population is a 7.6-kb genomic deletion involving the HEXA promoter and exon 1; no mRNA is produced by this allele.Several mutations that affect subunit assembly or processing of the newly synthesized alpha precursor polypeptide have been described. Most have been detected at the 3' end of the protein, although there is no direct evidence for a sequence or structure near the C terminus specifically involved in subcellular transport.Table 3. Selected HEXA Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequence Pseudodeficiencyc.739C>Tp.Arg247TrpNM_000520.4 NP_000511.2c.745C>Tp.Arg249TrpPathologicc.533G>Ap.Arg178Hisc.749G>Ap.Gly250Aspc.805G>Ap.Gly269Serc.1073+1G>A (+1IVS9)--c.1274_1277dupTATC (+TATC1278) (1278dupTATC)p.Tyr427Ilefs*5c.1421+1G>C (+1IVS12) --(7.6-kb del) 2--See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. See Molecular Genetic Testing, Clinical Testing and Molecular Genetics, Pathologic allelic variants.Normal gene product. HEXA encodes the alpha chain of the heterodimeric protein, beta-hexosaminidase A (HEX A), also called GM2 gangliosidase. The HEX A protein comprises a single alpha chain and a single beta chain, which is encoded by HEXB. This isoenzyme cleaves the terminal beta-linked N-acetylgalactosamine from GM2 ganglioside.Abnormal gene product. The mutations result in a variety of effects, ranging from defective processing or subunit assembly to defective catalytic activity (see Genotype-Phenotype Correlations).