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HEXA Disorders

Synonyms: Beta-Hexosaminidase A Deficiency; GM2 Gangliosidosis, Type I; Tay-Sachs Disease

, MD, , BA, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: October 1, 2020.

Estimated reading time: 29 minutes

Summary

Clinical characteristics.

HEXA disorders are best considered as a disease continuum based on the amount of residual beta-hexosaminidase A (HEX A) enzyme activity. This, in turn, depends on the molecular characteristics and biological impact of the HEXA pathogenic variants. HEX A is necessary for degradation of GM2 ganglioside; without well-functioning enzymes, GM2 ganglioside builds up in the lysosomes of brain and nerve cells.

The classic clinical phenotype is known as Tay-Sachs disease (TSD), characterized by progressive weakness, loss of motor skills beginning between ages three and six months, decreased visual attentiveness, and increased or exaggerated startle response with a cherry-red spot observable on the retina followed by developmental plateau and loss of skills after eight to ten months. Seizures are common by 12 months with further deterioration in the second year of life and death occurring between ages two and three years with some survival to five to seven years.

Subacute juvenile TSD is associated with normal developmental milestones until age two years, when the emergence of abnormal gait or dysarthria is noted followed by loss of previously acquired skills and cognitive decline. Spasticity, dysphagia, and seizures are present by the end of the first decade of life, with death within the second decade of life, usually by aspiration.

Late-onset TSD presents in older teens or young adults with a slowly progressive spectrum of neurologic symptoms including lower-extremity weakness with muscle atrophy, dysarthria, incoordination, tremor, mild spasticity and/or dystonia, and psychiatric manifestations including acute psychosis. Clinical variability even among affected members of the same family is observed in both the subacute juvenile and the late-onset TSD phenotypes.

Diagnosis/testing.

The diagnosis of a HEXA disorder is established in a proband with abnormally low HEX A activity on enzyme testing and biallelic pathogenic variants in HEXA identified by molecular genetic testing. Targeted analysis for certain pathogenic variants can be performed first in individuals of specific ethnicity (e.g., French Canadian, Ashkenazi Jewish). Enzyme testing of affected individuals identifies absent to near-absent HEX A enzymatic activity in the serum, white blood cells, or other tissues in the presence of normal or elevated activity of the beta-hexosaminidase B enzyme. Pseudodeficiency refers to an in vitro phenomenon caused by specific HEXA variants that renders the enzyme unable to process the synthetic (but not the natural) GM2 substrates, and leads to false positive enzyme testing results.

Management.

Treatment of manifestations: Treatment is mostly supportive and directed to providing adequate nutrition and hydration, managing infectious disease, protecting the airway, and controlling seizures. The treatment for the subacute juvenile and late-onset Tay-Sachs phenotypes is directed to providing the services of a physiatrist and team of physical, occupational, and speech therapists for maximizing function and providing aids for activities of daily living.

Agents/circumstances to avoid: Positioning that increases aspiration risk during feedings and seizure medication dosages that result in excessive sedation for those with acute infantile TSD; situations that increase the likelihood of contractures or pressure sores, such as extended periods of immobility; circumstances that exacerbate the risk of falls (i.e., walking on uneven or unstable surfaces) in those with subacute juvenile TSD; psychiatric medications that have been associated with disease worsening, including haloperidol, risperidone, and chlorpromazine.

Genetic counseling.

Acute infantile Tay-Sachs disease (TSD), subacute juvenile TSD, and late-onset TSD (comprising the clinical spectrum of HEXA disorders) are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. Once both HEXA pathogenic variants have been identified in an affected family member, targeted analysis for the specific familial variants can be used for carrier testing in at-risk relatives. Molecular genetic testing and/or HEX A enzyme testing can be used for carrier detection in individuals who do not have a family history of TSD. If both members of a reproductive couple are known to be heterozygous for a HEXA pathogenic variant, molecular genetic prenatal testing and preimplantation genetic testing for the HEXA pathogenic variants identified in the parents are possible.

GeneReview Scope

Table 1.

HEXA Disorders: Included Phenotypes

Biochemical PhenotypeClinical Phenotypes
Beta-hexosaminidase
A deficiency 1
  • Acute infantile Tay-Sachs disease
  • Subacute juvenile Tay-Sachs disease
  • Late-onset Tay-Sachs disease

For synonyms and outdated names see Nomenclature.

1.

Beta-hexosaminidase A (HEX A; often referred to in the shortened form, "hexosaminidase A") is a heterodimer comprising a single alpha chain and a single beta chain. The alpha chain is encoded by HEXA; the beta chain is encoded by HEXB. Deficiency of HEX A can therefore be the result of pathogenic variants in HEXA or HEXB. (HEX A deficiency caused by pathogenic variants in HEXB is referred to as Sandhoff disease; see Differential Diagnosis.)

Diagnosis

HEXA disorders are best considered as a disease continuum based on the amount of residual beta-hexosaminidase A (HEX A) enzyme activity. This, in turn, depends on the molecular characteristics and biological impact of the HEXA pathogenic variants. HEX A is necessary for degradation of GM2 ganglioside; without well-functioning enzymes, GM2 ganglioside builds up in the lysosomes of brain and nerve cells. The classic clinical phenotype is known as Tay-Sachs disease (TSD), after ophthalmologist Warren Tay and neurologist Bernard Sachs, who originally described the disorder in the late 19th century. For convenience, the clinical phenotypes are often divided into acute infantile, subacute juvenile, and late-onset disorders, with unique phenotypes common to each subset.

Suggestive Findings

Acute infantile Tay-Sachs disease should be suspected in infants with the following clinical findings:

  • Progressive weakness and loss of motor skills beginning between ages three and six months
  • Decreased attentiveness
  • An increased or exaggerated startle response
  • A cherry-red spot of the fovea centralis of the macula of the retina
  • A normal-sized liver and spleen
  • Generalized muscular hypotonia with sustained ankle clonus and hyperreflexia
  • Onset of seizures beginning around age 12 months
  • Progressive macrocephaly with proportionate ventricular enlargement on neuroimaging beginning at age 18 months

Subacute juvenile Tay-Sachs disease should be suspected in individuals with the following clinical findings:

  • A period of normal development until ages two to five years followed by a plateauing of skills and then loss of previously acquired developmental skills
  • Progressive spasticity resulting in loss of independent ambulation
  • Progressive dysarthria, drooling, and eventually absent speech
  • Normal-sized liver and spleen
  • Onset of seizures
  • Progressive global brain atrophy on neuroimaging [Nestrasil et al 2018]

Late-onset Tay-Sachs disease should be suspected in individuals with the following clinical findings:

  • Onset of symptoms in teens or adulthood
  • Progressive neurogenic weakness of antigravity muscles in the lower extremities and frequent falls
  • Dysarthria, tremor, and incoordination
  • Acute psychiatric manifestations including psychosis (which can be the initial manifestation of disease)
  • Isolated cerebellar atrophy on neuroimaging

Establishing the Diagnosis

The diagnosis of a HEXA disorder is established in a proband with abnormally low HEX A activity on enzyme testing and biallelic pathogenic variants in HEXA identified by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous HEXA variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

HEX A enzymatic activity testing. Testing identifies absent to near-absent HEX A enzymatic activity in the serum, white blood cells, or other tissues in the presence of normal or elevated activity of the beta-hexosaminidase B (HEX B) enzyme [Hall et al 2014].

  • Individuals with acute infantile TSD have no or extremely low HEX A enzymatic activity.
  • Individuals with subacute juvenile or late-onset TSD have some minimal residual HEX A enzymatic activity.

Note: The enzyme HEX A is a heterodimer of one alpha subunit and one beta subunit (encoded by the genes HEXA and HEXB, respectively); the enzyme HEX B, on the other hand, is a homodimer composed of two beta subunits. Only HEX A is able to degrade GM2 ganglioside.

Note: Pseudodeficiency refers to an in vitro phenomenon caused by specific HEXA variants that renders the enzyme unable to process the synthetic (but not the natural) GM2 substrates, and leads to false positive enzyme testing results.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of HEXA disorders is broad, infants with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those (especially older individuals) with a phenotype indistinguishable from many other disorders presenting later in life with neurodegeneration or developmental regression are more likely to be diagnosed using comprehensive genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of a HEXA disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of HEXA is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
    Targeted analysis for pathogenic variants can be performed first in individuals of specific ethnicity:
    • French Canadian descent. A 7.6-kb genomic deletion of the HEXA promoter and exon 1
    • Ashkenazi Jewish populations. p.Tyr427IlefsTer5, c.1421+1G>C, c.1073+G>A, p.Gly269Ser, and two pseudodeficiency alleles: p.Arg247Trp and p.Arg249Trp (See Table 13.)
      Note: (1) The presence of one pseudodeficiency allele reduces the in vitro 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 problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (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 Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see Table 13).
  • A multigene panel that includes HEXA and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at a reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by a slowly progressive neurodegeneration, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by exome sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in HEXA Disorders

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
HEXASequence analysis 399% 4
Gene-targeted deletion/duplication analysis 5Rare
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

The clinical phenotype of HEXA disorders comprises a continuum including acute infantile, subacute juvenile, and late-onset Tay-Sachs disease. Although classification into subtypes is somewhat arbitrary, it is helpful in understanding the variation observed in the timing of disease onset, presenting symptoms, rate of progression, and longevity.

Although case reports of individuals from specific ethnic backgrounds abound, there is a paucity of prospective natural history studies for Tay-Sachs disease delineating the progression of disease subtypes over time.

Subtypes of HEXA disorders include the following phenotypes:

  • Acute infantile Tay-Sachs disease with onset before six months, rapid progression, and death generally before age five years
  • Subacute juvenile Tay-Sachs disease with later onset and survival into late childhood or adolescence
  • Late-onset Tay-Sachs disease with long-term survival. Affected individuals may present with various phenotypes including lower motor neuronopathy with progressive lower-extremity weakness, atrophy and fasciculations, progressive dystonia, spinocerebellar deficits, dysarthria, and/or psychosis.

Acute Infantile Tay-Sachs Disease

Presentation. Affected infants generally appear to be completely normal at birth.

  • Progressive weakness begins between ages three and six months, along with myoclonic jerks and an exaggerated startle reaction to sudden stimuli.
  • Decreasing visual attentiveness and unusual eye movements at age three to six months may be the first sign prompting parents to seek medical attention, where subsequent ophthalmologic evaluation reveals the characteristic cherry-red macula seen in virtually all children with infantile disease.

Progression. By age six to ten months, acquisition of developmental milestones plateaus and eventually ceases across multiple domains. Finally, children begin to lose previously demonstrated skills.

  • 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 seizures typically become more frequent and severe.
  • Progressive enlargement of the head typically begins by age 18 months resulting from reactive cerebral gliosis but eventually followed by ventriculomegaly [Nestrasil et al 2018].
  • 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 respiratory complications usually occurs between ages two and three years, although the use of a gastrostomy tube to minimize aspiration events and improved pulmonary hygiene with the use of vibrating vests has extended the life span of infantile patients to between five and seven years [Bley et al 2011, Regier et al 2016].

Subacute Juvenile Tay-Sachs Disease

Presentation. Children attain normal developmental milestones up until around age two years. Between ages two and five years, gains in motor and speech parameters slow down and eventually plateau. Abnormal gait or dysarthria begins to emerge, followed by loss of previously acquired skills and cognitive decline.

Progression. Spasticity, dysphagia, and seizures are present by the end of the first decade of life [Maegawa et al 2006].

  • A decrease in visual acuity occurs much later in subacute juvenile Tay-Sachs disease than in the acute infantile form of the disease and the cherry-red spot is rarely observed. Optic atrophy and retinal pigmentation may be seen late in the course of the disease.
  • A vegetative state with decerebrate posturing begins to appear in many individuals by age ten to 15 years, followed within a few years by death, usually from aspiration. Newer measures in supportive care that protect airways and improve pulmonary toilet may extend life span. In some individuals, the disease pursues a particularly aggressive course, culminating in death within two to four years of symptom onset.

Clinical variability is observed in the subacute juvenile form of TSD even among affected members of the same family.

Late-Onset Tay-Sachs Disease (LOTS)

Presentation. Affected individuals present with a slowly progressive spectrum of neurologic and psychiatric symptoms as older teenagers or young adults. In retrospect, many parents can describe nonspecific subtle clumsiness or developmental irregularities earlier in life. As most subjects achieve nearly normal milestones to adulthood and the disorder progresses slowly over decades, the presentation may resemble that of other "neurodegenerative" conditions of adults. The later development of symptoms compared to the acute infantile and subacute juvenile versions of Tay-Sachs disease is attributed to the presence of residual beta-hexosaminidase A (HEX A) enzyme activity, enough to forestall the onset of symptoms to adulthood. Early symptoms may range from neurogenic lower-extremity weakness with atrophy of the quadriceps muscles to dysarthria, incoordination, tremor, mild spasticity, and/or dystonia. Up to 40% of individuals with LOTS may experience psychiatric manifestations, including acute psychosis [Masingue et al 2020; Toro, personal observation].

Progression. Central nervous system involvement in LOTS is widespread, however, certain central nervous system structures appear to be more vulnerable to the disease than others, leading to particular clinical findings:

  • Most, if not all, individuals with LOTS develop progressive neurogenic muscle weakness and wasting.
    Early in the disease course, weakness involves the lower extremities, particularly the knee extensors and hip flexors. Atrophy, cramps, and fasciculations are common. Affected individuals relate progressive difficulty in climbing steps or bleachers, eventually requiring the aid of handrails. As knee extensor muscle weakness progresses, individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain knees locked results in collapse and injury.
    Upper-extremity strength may become affected years later with a predilection for elbow extension (triceps) weakness. Long tract findings including spasticity, upgoing toes, and brisk reflexes can be present but may be obscured by lower motor neuron weakness.
  • Dysarthria is common; the speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. The poor articulation emerges primarily from cerebellar dysfunction; however, patients may demonstrate associated features of focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Despite prominent dysarthria, dysphagia and aspiration events are not common early in LOTS.
  • Decreased balance requiring a wide base of support, decreased dexterity, and tremor are frequent findings in LOTS. These – along with the presence of saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination – are attributed at least in part to cerebellar dysfunction [Stephen et al 2020]. Cerebellar atrophy is evident even early in the disease, at times out of proportion to the extent of cerebellar deficits, and is almost universal in LOTS.
  • Psychiatric manifestations including comorbid anxiety and depression are common. Acute psychosis and mania can occur, representing the initial manifestation of disease in some individuals.
  • Deficits in executive function and memory are reported in some individuals and can be associated with progressive brain volume loss. Contrary to the acute infantile and subacute juvenile phenotypes, however, declines in higher cortical functioning develop slowly, often over decades after the onset of disease symptoms.

Clinical variability is significant for LOTS, even within a single family with more than one affected individual. Psychosis may be severe by age 20 years in one individual, whereas another older affected sib may function well into adulthood with mainly neuromuscular complaints [Author, personal observation].

Neuropathology

Children with the acute infantile form of 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 adult-onset forms have less accumulation of glycolipid; it may even be restricted to specific brain regions. For example, in LOTS the neocortex may be spared, while the hippocampus, brain stem nuclei, and the spinal cord are markedly affected [Gravel et al 2001].

Genotype-Phenotype Correlations

In general, individuals with two null (nonexpressing) alleles have the infantile form, individuals with one null allele and one missense allele have the subacute juvenile-onset phenotype, and individuals with two missense alleles have the milder late-onset phenotype. This reflects the inverse correlation of the level of the residual activity of the HEX A enzyme with the severity of the disease: the lower the level of the enzymatic activity, the more severe the phenotype is likely to be.

Nomenclature

Tay-Sachs disease was originally described as "infantile amaurotic idiocy" and "amaurotic familial infantile idiocy" by Tay and Sachs, respectively.

When GM2 ganglioside was identified as the major accumulating substrate, the nomenclature included the terms "infantile ganglioside lipidosis," "type 1 GM2 gangliosidosis," and "acute infantile GM2 gangliosidosis."

When deficient HEX A enzymatic activity was identified, the disease was then referred to as "hexosaminidase A deficiency," "HEX A deficiency," or "type 1 hexosaminidase A deficiency."

When the subacute juvenile and late-onset phenotypes were identified, they were referred to as the "B1 variant of GM2 gangliosidoses" or "juvenile (subacute) hexosaminidase deficiency" and "chronic or adult-onset hexosaminidase A deficiency," respectively.

Prevalence

Before the advent of population-based carrier screening, education, and counseling programs for the prevention of TSD in Jewish communities, the incidence of TSD was estimated at 1:3,600 Ashkenazi Jewish births. At that birth rate, the carrier rate for TSD is approximately 1:30 among Jewish Americans of Ashkenazi extraction (i.e., from Central and Eastern Europe).

Carrier screening studies have indicated that the frequency of the Ashkenazi Jewish founder variants in individuals whose parents and respective grandparents were of Ashkenazi Jewish descent is 1:27.4 [Scott et al 2010].

As the result of extensive genetic counseling of carriers identified through carrier screening programs and monitoring of at-risk pregnancies, the incidence of TSD in the Ashkenazi Jewish population of North America has been reduced by greater than 90% [Kaback et al 1993, Kaback 2000].

Among Sephardic Jews and all non-Jews, the disease incidence has been observed to be about 100 times lower, corresponding to a tenfold lower carrier frequency (between 1:250 and 1:300).

TSD has been reported in children of virtually all ethnic, racial, and religious groups.

Other genetically isolated populations have been found to carry founder HEXA pathogenic variants at frequencies comparable to or even greater than those observed in Ashkenazi Jews. These include:

  • French Canadians of the eastern St Lawrence River Valley area of Quebec;
  • Cajuns from Louisiana.

Differential Diagnosis

The neurologic symptoms that develop in the course of HEXA disorders are not unique and can be caused by a wide array of hereditary and acquired conditions, including toxic and infectious/post-infectious disorders.

Hereditary Disorders

Infantile Onset

Table 3.

Genetic Disorders of Interest in the Differential Diagnosis of Acute Infantile Tay-Sachs Disease

GeneDisorderCherry-Red Spot
(≤12 mos)
Onset of Neurologic RegressionOther Features / CommentFeatures Distinguishing the Disorder from Acute Infantile TSD
ASPACanavan disease≤6 mosMacrocephaly, head lag, hypotonia, seizuresLeukoencephalopathy, ↑ N-acetyl aspartate in CSF
CLN5
CLN6
CLN8
CTSD
MFSD8
PPT1
TPP1
Neuronal ceroid lipofuscinoses, infantile & late-infantile (OMIM PS256730)≤6 mosVisual deficits, seizuresAbnormal ERG
CTSAGalactosialidosis (OMIM 256540)+<6 mosSeizuresHepatosplenomegaly w/coarse features & skeletal disease
GALCKrabbe disease≤6 mosSeizuresLeukodystrophy, peripheral neuropathy, irritability
GBAGaucher disease type 2≤6 mosSeizures in some personsOculomotor abnormalities, hypertonia, opisthotonos
GFAPAlexander disease, infantile form≤6 mosMacrocephaly, seizuresLeukodystrophy
GLB1GM1 gangliosidosis type 1 (See GLB1 Disorders.)+≤12 mosSeizuresHepatosplenomegaly w/coarse facies, skeletal disease
GM2AActivator-deficient TSD 1 (GM2 gangliosidosis, AB variant) (OMIM 272750)+≤6 mosPhenotype identical to classic TSD; 2 extremely rare disorderNo distinguishing features
GNPTABMucolipidosis II (I-cell disease) (See GNPTAB Disorders.)≤12 mosHepatosplenomegaly w/coarse facies, hyperplastic gums, skeletal disease; absence of seizures
HEXBSandhoff disease 3 (OMIM 268800)+≤6 mosSeizuresHepatosplenomegaly, skeletal abnormalities, deficiency of both HEX A & HEX B enzyme activity
NEU1Sialidosis type II (OMIM 256550)+≤12 mosSeizuresHepatosplenomegaly w/coarse facies, skeletal abnormalities
SMPD1Niemann-Pick disease type A (See Acid Sphingomyelinase Deficiency.)+≤12 mosHepatosplenomegaly, feeding difficulties, severe failure to thrive, xanthomas; absence of seizures

The disorders included in Table 3 are inherited in an autosomal recessive manner, with the exception of Alexander disease, which is an autosomal dominant disorder.

CSF = cerebrospinal fluid; ERG = electroretinogram; HEX A = beta-hexosaminidase A; HEX B = hexosaminidase B; TSD = Tay-Sachs disease

1.

In activator-deficient TSD, 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.

2.

Progressive weakness and loss of motor skills between ages 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

3.

In Sandhoff disease, the activity of HEX A is deficient, as is the activity of HEX B, since both enzymes lack the common beta subunit.

Subacute Juvenile Onset

Table 4.

Genetic Disorders of Interest in the Differential Diagnosis of Subacute Juvenile Tay-Sachs disease

GeneDisorderCherry-Red Spot (≤12 mos)Onset of Neurologic RegressionOther Features / CommentFeatures Distinguishing the Disorder from Subacute Juvenile TSD
ASPACanavan disease≤6 mosMacrocephaly, head lag, hypotonia, seizuresLeukoencephalopathy & ↑ N-acetyl aspartate in CSF
CLN3CLN3 disease (OMIM 204200) (Batten disease)9-18 yrsSeizuresProgressive visual loss (onset age 4-5 yrs), retinitis pigmentosa, cataracts, myoclonus, parkinsonism, abnormal ERG, ultrastructural abnormalities in lymphocytes, skin & other tissues
CTSAGalactosialidosis (OMIM 256540)+>12 mosSeizuresHepatosplenomegaly w/coarse features, skeletal disease
GBAGaucher disease type 3≥12 mosSeizuresCharacteristic looping of saccadic eye movements
GLB1GM1 gangliosidosis type II (See GLB1 Disorders.)1-5 yrsSeizuresSkeletal disease
HEXBSandhoff disease (OMIM 268800)+3-5 yrsClinical course nearly the same as subacute juvenile TSDDeficiency of both HEX A & HEX B enzyme activity

The disorders included in Table 4 are inherited in an autosomal recessive manner.

CSF = cerebrospinal fluid; ERG = electroretinogram; HEX A = beta-hexosaminidase A; HEX B = hexosaminidase B; TSD = Tay-Sachs disease

Spinocerebellar ataxia (SCA). Some spinocerebellar ataxia syndromes (e.g., ataxia caused by mutation of FGF14, MTCL1, or TXN2 or SCA7 with extreme anticipation) may be associated with early onset and can be considered in the differential diagnosis of subacute juvenile TSD (see Hereditary Ataxia Overview).

Late Onset

Table 5.

Genetic Disorders in the Differential Diagnosis of Late-Onset Tay-Sachs Disease

GeneDisorderMOIOverlapping FeaturesDistinguishing Features
ARSpinal & bulbar muscular atrophy (SBMA)XLNeurogenic weakness/atrophy (proximal > distal), tremor, cramps & fasciculations, slow progressionIn SBMA: tongue atrophy, facial weakness, androgen insensitivity, gynecomastia, & glucose intolerance
C9orf72
FUS
SOD1
TARDBP
(>30 genes) 1
Amyotrophic lateral sclerosis (ALS)AD
AR
XL
Progressive neurogenic atrophy, cramps fasciculations, spasticityIn ALS: neurogenic atrophy is often asymmetrical, bulbar onset (in some persons); absence of cerebellar deficits
CLN6
CTSF
DNAJC5
Adult-onset neuronal ceroid-lipofuscinosis (CLN) (OMIM 204300, 615362, 162350)AR
AD
AtaxiaIn adult-onset CLN: seizures, myoclonus, early intellectual deterioration
FXNFriedreich ataxia (FRDA)ARAtaxia, abnormal eye movements, dysarthria, neurogenic weakness & long tract findings, slow progressionIn FRDA: cardiomyopathy, EKG conduction defects, diabetes, pes cavus, scoliosis, slow sensory nerve conduction velocity, optic atrophy, hearing loss, neurogenic bladder
HEXBSandhoff disease (OMIM 268800)ARProgressive motor weakness beginning in lower extremitiesIn Sandhoff disease: sensory neuropathy, less dysarthria than in LOTS
SMN1Later-onset spinal muscular atrophy (SMA types III & IV)ARTremor, fasciculations, atrophy, cramps, proximal muscle involvementIn SMA: early scoliosis, tongue fasciculations, progressive ↓ in pulmonary function, absence of ataxia
CHCHD10
TFG
VAPB
Late onset SMA (See CHCHD10-Related Disorders.) & SMA-like disorder (OMIM 604484, 182980)ADNeurogenic atrophyLarge kindreds, no cerebellar deficits, ↑ CPK in some affected persons

AD = autosomal dominant; AR = autosomal recessive; CPK = creatine phosphokinase; EKG = electrocardiogram; LOTS = late-onset Tay-Sachs disease; MOI = mode of inheritance; XL = X-linked

1.

C9orf72, FUS, SOD1, and TARDBP are the most commonly involved genes; for other genes associated with amyotrophic lateral sclerosis see OMIM Phenotypic series: Amyotrophic lateral sclerosis.

Spinocerebellar ataxia (SCA). Similar to late-onset TSD, SCA is associated with tremor, cerebellar atrophy, and dysarthria and can be considered in the differential diagnosis (see Hereditary Ataxia Overview).

Acquired Disorders

Lead and other heavy metal poisoning, infectious and postinfectious meningoencephalitis, subacute sclerosing panencephalitis, hydrocephalus, and neurologic manifestations of other systemic diseases may mimic the neurologic findings associated with HEXA disorders.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a HEXA disorder, the evaluations summarized in Tables 6, 7, and 8 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 6.

Recommended Evaluations Following Initial Diagnosis in Individuals with Acute Infantile Tay-Sachs Disease

System/ConcernEvaluationComment
NeurologicNeurology eval
  • To incl brain MRI
  • Consider EEG if seizures are a concern.
Musculoskeletal
system
Physical medicine & rehab / PT/OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Need for adaptive devices
  • Need for PT (to prevent deformities)
Gastrointestinal/
Feeding
Gastroenterology / nutrition / feeding team eval
  • To incl swallow study for eval of aspiration risk & nutritional status
  • Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
  • Assess for constipation.
EyesOphthalmologic examEval for macular degeneration, cherry-red spot, visual loss
RespiratoryEvaluate aspiration risk.Assess need for airway toileting.
Genetic
counseling
By genetics professionals 1To inform paffected persons & families re nature, MOI, & implications of this disorder to facilitate medical & personal decision making
Family support/
resources
Assess:

EEG = electroencephalogram; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Table 7.

Recommended Evaluations Following Initial Diagnosis in Individuals with Subacute Juvenile Tay-Sachs Disease

System/ConcernEvaluationComment
NeurologicNeurology eval
  • To incl brain MRI
  • Consider EEG if seizures are a concern.
  • Evaluate for spasticity.
DevelopmentDevelopmental assessment
  • To incl motor, adaptive, cognitive, & speech/language eval
  • Eval for IEP
Musculoskeletal
system
Physical medicine & rehab / PT/OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Mobility, independence in ADL, & need for adaptive devices
  • Need for PT (to prevent fixed deformities)
Gastrointestinal/
Feeding
Gastroenterology / nutrition / feeding team eval
  • To incl swallow study for eval of aspiration risk & nutritional status
  • Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
  • Assess for constipation.
EyesOphthalmologic examAssess visual acuity.
RespiratoryEvaluate aspiration risk.Assess need for airway toileting & percussion vest.
Genetic
counseling
By genetics professionals 1To inform affected persons & families re nature, MOI, & implications of this disorder to facilitate medical & personal decision making
Family support/
resources
Assess:

ADL = activities of daily living; EEG = electroencephalogram; IEP = individualized education program; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Table 8.

Recommended Evaluations Following Initial Diagnosis in Individuals with Late-Onset Tay-Sachs Disease

System/ConcernEvaluationComment
NeurologicNeurology evalAssess for weakness & tremor.
DysarthriaSpeech eval
PsychiatricNeuropsychiatric evalAssess for psychosis, anxiety, & depression.
Musculoskeletal
system
Physical medicine & rehab / PT/OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Mobility, ADL, & need for adaptive devices
  • Need for PT (to prevent falls & pressure wounds) &/or OT to maximize independence in ADL
Genetic
counseling
By genetics professionals 1To inform affected persons & families re nature, MOI, & implications of this disorder to facilitate medical & personal decision making
Family support/
resources
Assess:
  • Use of community or online resources;
  • Need for social work involvement for support.

ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Treatment of Manifestations

For the most part, treatment for acute infantile Tay-Sachs disease (TSD) is supportive and directed to providing adequate nutrition and hydration, managing infectious disease, protecting the airway, and controlling seizures. The treatment for the subacute juvenile and late-onset TSD phenotypes is directed to providing the services of a physiatrist and team of physical, occupational, and speech therapists for maximizing function and providing aids for activities of daily living.

Table 9.

Treatment of Manifestations in Individuals with Acute Infantile Tay-Sachs Disease

Manifestation/ConcernTreatmentConsiderations/Other
SeizuresStandardized treatment w/AEDs by experienced neurologist
  • Seizures are often progressive & refractory.
  • Many AEDs may be effective; none has been demonstrated effective specifically for this disorder.
  • Complete seizure control is seldom achieved & requires balancing w/sedative side effects of AEDs.
  • Education of parents/caregivers 1
Abnormal tone /
Impaired mobility
PT/OTFor prevention of deformities
Feeding difficultiesGastrostomy tubeWill ↑ longevity but not preserve developmental function
Bowel dysfunctionMonitor for constipation.Stool softeners, prokinetics, osmotic agents, or laxatives as needed
Aspiration risks /
Excess secretion
Gastrostomy tube, vibrator vest, improved pulmonary toilet, suppression of saliva productionWill ↓ aspiration & improve longevity but not developmental function
Family supportIn-home nursing & respite careSupport for health & quality of life of caregivers & sibs

AED = antiepileptic drug; OT = occupational therapy; PT = physical therapy

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Table 10.

Treatment of Manifestations in Individuals with Subacute Juvenile Tay-Sachs Disease

Manifestation/ConcernTreatmentConsiderations/Other
SeizuresStandardized treatment w/AEDs by experienced neurologist
  • Seizures are often progressive & refractory.
  • Many AEDs may be effective; none has been demonstrated effective specifically for this disorder.
  • Complete seizure control is seldom achieved & requires balancing w/sedative side effects of AEDs.
  • Education of parents/caregivers 1
SpasticityStretching, splints, pharmacologic treatment
Developmental plateau /
Cognitive decline
IEP
Feeding difficultiesGastrostomy tubeWill ↑ longevity but not preserve developmental function
Bowel dysfunctionMonitor for constipation.Stool softeners, prokinetics, osmotic agents, or laxatives as needed
Saliva pooling /
Drooling
Botulinum toxin to salivary glands, topical (drops) anticholinergic agentsBotox may spread to adjacent bulbar muscles, worsening dysphagia.
Family supportIn-home nursing & respite care as needed w/progression of diseaseSupport for health & quality of life of caregivers & sibs

IEP = individualized education program

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Table 11.

Treatment of Manifestations in Individuals with Late-Onset Tay-Sachs Disease

Manifestation/ConcernTreatmentConsiderations/Other
Weakness /
Impaired mobility
PT/OTAdaptive equipment & mobility assists
Spasticity/TremorSymptom-targeted pharmacotherapy by experienced neurologist
Communication needsVoice therapyFocus on strategies to slow speech rate.
Occupational
counseling
Vocational rehab
Psychiatric issues
  • Antidepressant or antipsychotic medications may be used, but clinical response is variable & can be poor.
  • Cognitive behavioral therapy ↑ coping skills.
  • Electroconvulsive therapy reported beneficial in some cases
Treatment needs to be individualized.
Family supportIn-home nursing & respite careCould be indicated for patients w/advanced disease

OT = occupational therapy; PT = physical therapy

Surveillance

There are no formal guidelines for surveillance for those affected with HEXA disorders.

Neurology evaluations should commence at the time of diagnosis for all subtypes of TSD if not previously established, and follow up should be dictated by emergent clinical concerns.

Agents/Circumstances to Avoid

For individuals with acute infantile TSD, avoid:

  • Positioning that increases aspiration risk during feedings;
  • Seizure medication dosages that result in excessive sedation.

For individuals with subacute juvenile TSD, avoid:

  • Situations that increase the likelihood of contractures or pressure sores, such as extended periods of immobility;
  • Circumstances that exacerbate the risk of falls.

For individuals with late-onset TSD, avoid:

  • Situations that exacerbate fall risk (i.e., walking on uneven or unstable surfaces);
  • Psychiatric medications that have been associated with disease worsening (e.g., haloperidol, risperidone, and chlorpromazine) [Shapiro et al 2006].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Current studies include:

  • A Phase II study to assess the safety and efficacy of N-acetyl-L-leucine for the treatment of GM2 gangliosidosis (Tay-Sachs disease and Sandhoff disease);
  • A multicenter study to assess the efficacy and pharmacodynamics of daily oral dosing of venglustat when administered over a 104-week period in late-onset and subacute juvenile GM2 gangliosidosis (Tay-Sachs disease and Sandhoff disease);
  • A combination therapy using miglustat and the ketogenic diet for infantile and juvenile patients with gangliosidoses;
  • A survey of miglustat therapeutic effects on neurologic and systemic symptoms of infantile type of Tay-Sachs and Sandhoff Disease.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on other clinical studies.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Acute infantile Tay-Sachs disease (TSD), subacute juvenile TSD, and late-onset TSD (comprising the clinical spectrum of HEXA disorders) are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • If both parents are known to be heterozygous for a HEXA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Sibs who inherit biallelic HEXA pathogenic variants will have the same HEXA disorder phenotype (i.e., acute infantile, subacute juvenile, or late-onset TSD) as the proband (see Genotype-Phenotype Correlations). However, the subacute juvenile and late-onset phenotypes are associated with significant intrafamilial clinical variability (see Clinical Description).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an individual with late-onset TSD has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in HEXA; it is appropriate to offer carrier detection to the reproductive partners of such individuals (see Related Genetic Counseling Issues, Population screening).

Other family members. Each sib of a proband's parents is at a 50% risk of being a carrier of a HEXA pathogenic variant.

Carrier Detection

Molecular genetic testing. Once both HEXA pathogenic variants have been identified in an affected family member, targeted analysis for the specific familial variants can be used for carrier testing in at-risk relatives.

Biochemical testing. Assay of beta-hexosaminidase A activity is a highly sensitive method for the identification of carriers; however, follow-up molecular testing is required if a carrier couple wishes to pursue prenatal/preimplantation genetic testing. Note: Leukocyte testing (rather than serum testing) should be ordered for TSD carrier detection in women who are pregnant or using oral contraceptive medication. Additional limitations of enzyme testing are addressed in Related Genetic Counseling Issues, Population screening.

Carrier testing recommendations for the reproductive partners of known carriers (or the reproductive partners of individuals with late-onset TSD) who do not have a family history of TSD are addressed in Population screening.

Related Genetic Counseling Issues

Population screening. Recent studies suggest that full-exon HEXA next-generation sequencing (NGS) is equally or more sensitive for the detection of carriers than targeted testing for specific variants and HEX A enzyme testing [Hoffman et al 2013, Cecchi et al 2019]. These findings are reflected in the 2019 position statement of the National Tay-Sachs and Allied Disorders Association (NTSAD Position Statement); see Table 12 for a summary of the NTSAD recommendations.

Table 12.

Population Screening for HEXA Disorders Based on Recommendations from the 2019 Update of the NTSAD Position Statement on Standards for Tay-Sachs Carrier Screening

MethodAdvantagesDisadvantages/LimitationsComment
Full-exon HEXA NGS (detects coding sequence changes throughout HEXA)Highly sensitive in all ethnic groups
  • Does not detect some noncoding pathogenic variants.
  • Detection of VUS
There is an evolving trend toward routine use of full-exon HEXA NGS for carrier screening in persons of all ethnic backgrounds.
Ethnicity-based (e.g., Ashkenazi Jewish1 or comprehensive 2 targeted analysis for specific HEXA pathogenic variantsVUS are not detected.
  • Limited sensitivity
  • As intermarriage between ethnic groups becomes more common, ethnicity-based targeted screening loses predictive value.
Generally not recommended for population screening
HEX A enzyme activity testingHighly sensitive in all ethnic groups
  • Serum enzyme assay results may be w/in "inconclusive" range. 3
  • False positives resulting from pseudodeficiency alleles 4
  • False negatives resulting from B1 variant allele 5
  • Follow-up molecular testing required if a carrier couple wants to pursue prenatal testing / PGT
  • Leukocyte testing (rather than serum testing) should be ordered in women who are pregnant or using oral contraceptive medication.

HEX A = beta-hexosaminidase A; NGS = next-generation sequencing; PGT = preimplantation genetic testing; VUS = variants of uncertain significance

1.

See Prevalence for other genetically isolated populations known to carry founder HEXA pathogenic variants.

2.

More than 150 HEXA variants have been reported (see Clinvar).

3.

In individuals with an inconclusive result on serum enzyme assay (as well as pregnant women and women taking oral contraceptives), white blood cells rather than serum must be assayed.

4.

Alleles that code for an enzyme that does not metabolize the synthetic substrate for GM2 ganglioside in vitro, but does metabolize GM2 ganglioside in vivo

5.

The protein encoded by the B1 allele metabolizes the synthetic substrate for GM2 ganglioside in vitro but does not metabolize GM2 ganglioside in vivo.

Assisted reproductive technologies. Individuals who are pursuing reproductive technologies that involve gamete (egg or sperm) donation and who are at increased risk of being heterozygous for a HEXA pathogenic variant because of family history (see Carrier Detection) or ethnic background (see Related Genetic Counseling Issues, Population screening; Prevalence) should be offered testing. If the gamete recipient is a known carrier, any potential gamete donor must undergo molecular testing to determine if s/he is also a carrier.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Positive family history. Once the HEXA pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Population screening. If both members of a reproductive couple are known to be heterozygous for a HEXA pathogenic variant, prenatal and preimplantation genetic testing for the HEXA pathogenic variants identified in the parents are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

HEXA Disorders: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
HEXA15q23Beta-hexosaminidase subunit alphaHEXA databaseHEXAHEXA

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for HEXA Disorders (View All in OMIM)

272800TAY-SACHS DISEASE; TSD
606869HEXOSAMINIDASE A; HEXA

Molecular Pathogenesis

Biallelic pathogenic variants in HEXA lead to absent or reduced activity in β-hexosaminidase A, a lysosomal hydrolytic enzyme required for the breakdown of ganglioside GM2 in neurons, where synthesis of complex gangliosides is the highest. The buildup of GM2 ganglioside, normally present in neurons in very small quantities, leads to impairment and subsequent progressive loss of neurons and resultant neurodegeneration.

Mechanism of disease causation. Loss-of-function variants cause decreased to absent β-hexosaminidase activity.

HEXA-specific laboratory technical considerations. Pseudodeficiency refers to an in vitro phenomenon caused by specific HEXA alleles (see Table 13) that renders the β-hexosaminidase A enzyme unable to process the synthetic (but not the natural) GM2 substrates, and leads to false positive enzyme testing results.

In contrast, the so-called B1 variant allele results in a β-hexosaminidase A enzyme that is able to degrade the artificial substrate, but not the natural GM2 ganglioside, which leads to false negative enzyme testing results.

Table 13.

Notable HEXA Variants

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_000520​.5
NP_000511​.2
c.1274_1277dupTATCp.Tyr427IlefsTer5Most common Ashkenazi Jewish pathogenic variant [Kaback et al 1993]
c.1421+1G>C--Second-most frequent Ashkenazi Jewish pathogenic variant [Kaback et al 1993]
c.-207-2357_253+5128delinsG
(7.6-kb del)
--Most common French Canadian pathogenic variant [Myerowitz & Hogikyan 1987]
c.805G>Ap.Gly269SerMost common in LOTS [Paw et al 1989]
c.533G>Ap.Arg178HisB1 variant allele [Tanaka et al 1988]
c.739C>Tp.Arg247TrpPseudodeficiency allele [Cao et al 1993]
c.745C>Tp.Arg249TrpPseudodeficiency allele [Cao et al 1993]

LOTS = late-onset Tay Sachs

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author Notes

Authors' websites:

Cynthia Tifft, MD, PhD

Camilo Toro, MD

Acknowledgments

This work was supported by funds from the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

The authors wish to acknowledge all participants in the Neurodegeneration in Glycosphingolipid Storage Disorders' Natural History Study at the NIH (ClinicalTrials.gov Identifier: NCT00029965) and the longstanding contribution of the National Tay-Sachs and Allied Diseases Association (www.ntsad.org) to the support and education of patients and families with GM1 and GM2 gangliosidosis.

Author History

Robert J Desnick, PhD, MD, FACMG; Icahn School of Medicine at Mount Sinai (1999-2020)
Michael M Kaback, MD, FACMG; University of California, San Diego (1999-2020)
Leila Shirvan, BA (2020-present)
Cynthia Tifft, MD, PhD (2020-present)
Camilo Toro, MD (2020-present)

Revision History

  • 1 October 2020 (ha) Comprehensive update posted live
  • 11 August 2011 (me) Comprehensive update posted live
  • 19 May 2006 (me) Comprehensive update posted live
  • 9 January 2004 (me) Comprehensive update posted live
  • 30 October 2001 (me) Comprehensive update posted live
  • 11 March 1999 (me) Review posted live
  • April 1998 (mk) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "HEXA Disorders" is in the public domain in the United States of America.

References

Published Guidelines / Consensus Statements

  • NTSAD. Position Statement 2019 Update – "Standards for Tay-Sachs Carrier Screening." Available online. 2019. Accessed 9-23-20.

Literature Cited

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