HEXA Disorders (original) (raw)

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

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HEXA Disorders: Included Phenotypes
Biochemical phenotype Clinical phenotypes
Beta-hexosaminidaseA deficiency 1 Acute infantile Tay-Sachs diseaseSubacute juvenile Tay-Sachs diseaseLate-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:

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

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

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 (or likely pathogenic) variants in HEXA identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of a heterozygous HEXA variant of uncertain significance does not establish or rule out the diagnosis.

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].

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, 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:

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 1.

Molecular Genetic Testing Used in HEXA Disorders

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Gene 1 Method Proportion of Pathogenic Variants 2 Detectable by Method
HEXA Sequence analysis 3 99% 4
Gene-targeted deletion/duplication analysis 5 Rare

1.

2.

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

3.

4.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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.

While case reports of individuals 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

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

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.

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].

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:

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 in virtually all population groups studied.

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:

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 2.

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

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Gene Disorder Cherry-Red Spot(≤12 mos) Onset of Neurologic Regression Other Features / Comment Features Distinguishing the Disorder from Acute Infantile TSD
ASPA Canavan disease – ≤6 mos Macrocephaly, head lag, hypotonia, seizures Leukoencephalopathy, ↑ N-acetyl aspartate in CSF
CLN5 CLN6 CLN8 CTSD MFSD8 PPT1 TPP1 Neuronal ceroid lipofuscinoses, infantile & late-infantile (OMIM PS256730) – ≤6 mos Visual deficits, seizures Abnormal ERG
CTSA Galactosialidosis (OMIM 256540) + <6 mos Seizures Hepatosplenomegaly w/coarse features & skeletal disease
GALC Krabbe disease – ≤6 mos Seizures Leukodystrophy, peripheral neuropathy, irritability
GBA1 (GBA) Gaucher disease type 2 – ≤6 mos Seizures in some persons Oculomotor abnormalities, hypertonia, opisthotonos
GFAP Alexander disease, infantile form – ≤6 mos Macrocephaly, seizures Leukodystrophy
GLB1 GM1 gangliosidosis type 1 (See GLB1 Disorders.) + ≤12 mos Seizures Hepatosplenomegaly w/coarse facies, skeletal disease
GM2A Activator-deficient TSD 1 (GM2 gangliosidosis, AB variant) (See GM2 Activator Deficiency.) + ≤6 mos Phenotype identical to classic TSD; 2 extremely rare disorder No distinguishing features
GNPTAB Mucolipidosis II (I-cell disease) (See GNPTAB Disorders.) – ≤12 mos Hepatosplenomegaly w/coarse facies, hyperplastic gums, skeletal disease; absence of seizures
HEXB Sandhoff disease 3 + ≤6 mos Seizures Hepatosplenomegaly, skeletal abnormalities, deficiency of both HEX A & HEX B enzyme activity
NEU1 Sialidosis type II (OMIM 256550) + ≤12 mos Seizures Hepatosplenomegaly w/coarse facies, skeletal abnormalities
SMPD1 Niemann-Pick disease type A (See Acid Sphingomyelinase Deficiency.) + ≤12 mos Hepatosplenomegaly, feeding difficulties, severe failure to thrive, xanthomas; absence of seizures

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 3.

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

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Gene Disorder Cherry-Red Spot (≤12 mos) Onset of Neurologic Regression Other Features / Comment Features Distinguishing the Disorder from Subacute Juvenile TSD
ASPA Canavan disease – ≤6 mos Macrocephaly, head lag, hypotonia, seizures Leukoencephalopathy & ↑ _N_-acetyl aspartate in CSF
CLN3 CLN3 disease (OMIM 204200) (Batten disease) – 9-18 yrs Seizures Progressive visual loss (onset age 4-5 yrs), retinitis pigmentosa, cataracts, myoclonus, parkinsonism, abnormal ERG, ultrastructural abnormalities in lymphocytes, skin & other tissues
CTSA Galactosialidosis (OMIM 256540) + >12 mos Seizures Hepatosplenomegaly w/coarse features, skeletal disease
GBA1 (GBA) Gaucher disease type 3 – ≥12 mos Seizures Characteristic looping of saccadic eye movements
GLB1 GM1 gangliosidosis type II (See GLB1 Disorders.) – 1-5 yrs Seizures Skeletal disease
HEXB Sandhoff disease + 3-5 yrs Clinical course nearly the same as subacute juvenile TSD Deficiency of both HEX A & HEX B enzyme activity

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 4.

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

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Gene Disorder MOI Overlapping Features Distinguishing Features
AR Spinal & bulbar muscular atrophy (SBMA) XL Neurogenic weakness/atrophy (proximal > distal), tremor, cramps & fasciculations, slow progression In SBMA: tongue atrophy, facial weakness, androgen insensitivity, gynecomastia, & glucose intolerance
C9orf72FUS SOD1TARDBP(>30 genes) 1 Amyotrophic lateral sclerosis (ALS) ADARXL Progressive neurogenic atrophy, cramps fasciculations, spasticity In 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) ARAD Ataxia In adult-onset CLN: seizures, myoclonus, early intellectual deterioration
FXN Friedreich ataxia (FRDA) AR Ataxia, abnormal eye movements, dysarthria, neurogenic weakness & long tract findings, slow progression In FRDA: cardiomyopathy, EKG conduction defects, diabetes, pes cavus, scoliosis, slow sensory nerve conduction velocity, optic atrophy, hearing loss, neurogenic bladder
HEXB Sandhoff disease AR Progressive motor weakness beginning in lower extremities In Sandhoff disease: sensory neuropathy, less dysarthria than in LOTS
SMN1 Later-onset spinal muscular atrophy (SMA types III & IV) AR Tremor, fasciculations, atrophy, cramps, proximal muscle involvement In 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) AD Neurogenic atrophy Large kindreds, no cerebellar deficits, ↑ CPK in some affected persons

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 5, 6, and 7 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

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

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System/Concern Evaluation Comment
Neurologic Neurology eval To incl brain MRIConsider EEG if seizures are a concern.
Musculoskeletal system Physical medicine & rehab / PT & OT eval To incl assessment of:Gross motor & fine motor skillsNeed for adaptive devicesNeed for PT (to prevent deformities)
Gastrointestinal/ Feeding Gastroenterology / nutrition / feeding team eval To incl swallow study for eval of aspiration risk & nutritional statusConsider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.Assess for constipation.
Eyes Ophthalmologic exam Eval for macular degeneration, cherry-red spot, visual loss
Respiratory Evaluate aspiration risk. Assess need for airway toileting.
Genetic counseling By genetics professionals 1 To inform affected persons & families re nature, MOI, & implications of this disorder to facilitate medical & personal decision making
Family support & resources Assess need for:Community or online resources such as Parent to Parent;Social work involvement for parental support;Home nursing referral.

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

1.

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

Table 6.

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

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System/Concern Evaluation Comment
Neurologic Neurology eval To incl brain MRIConsider EEG if seizures are a concern.Evaluate for spasticity.
Development Developmental assessment To incl motor, adaptive, cognitive, & speech-language evalEval for IEP
Musculoskeletal system Physical medicine & rehab / PT & OT eval To incl assessment of:Gross motor & fine motor skillsMobility, independence in ADL, & need for adaptive devicesNeed for PT (to prevent fixed deformities)
Gastrointestinal/ Feeding Gastroenterology / nutrition / feeding team eval To incl swallow study for eval of aspiration risk & nutritional statusConsider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.Assess for constipation.
Eyes Ophthalmologic exam Assess visual acuity.
Respiratory Evaluate aspiration risk. Assess need for airway toileting & percussion vest.
Genetic counseling By genetics professionals 1 To inform affected persons & families re nature, MOI, & implications of this disorder to facilitate medical & personal decision making
Family support & resources Assess need for:Community or online resources such as Parent to Parent;Social work involvement for parental support.

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 7.

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

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System/Concern Evaluation Comment
Neurologic Neurology eval Assess for weakness & tremor.
Dysarthria Speech eval
Psychiatric Neuropsychiatric eval Assess for psychosis, anxiety, & depression.
Musculoskeletal system Physical medicine & rehab / PT & OT eval To incl assessment of:Gross motor & fine motor skillsMobility, ADL, & need for adaptive devicesNeed for PT (to prevent falls & pressure wounds) &/or OT to maximize independence in ADL
Genetic counseling By genetics professionals 1 To inform affected persons & families re nature, MOI, & implications of this disorder to facilitate medical & personal decision making
Family support & resources Assess need for:Community or online resources;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 8.

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

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Manifestation/Concern Treatment Considerations/Other
Seizures Standardized treatment w/ASM by experienced neurologist Seizures are often progressive & refractory.Many ASMs 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 ASM.Education of parents/caregivers 1
Abnormal tone / Impaired mobility PT/OT For prevention of deformities
Feeding difficulties Gastrostomy tube Will ↑ longevity but not preserve developmental function
Bowel dysfunction Monitor 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 production Will ↓ aspiration & improve longevity but not developmental function
Family support In-home nursing & respite care Support for health & quality of life of caregivers & sibs

ASM = anti-seizure medication; 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 Foundation Toolbox.

Table 9.

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

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Manifestation/Concern Treatment Considerations/Other
Seizures Standardized treatment w/ASM by experienced neurologist Seizures are often progressive & refractory.Many ASMs 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 ASM.Education of parents/caregivers 1
Spasticity Stretching, splints, pharmacologic treatment
Developmental plateau / Cognitive decline IEP
Feeding difficulties Gastrostomy tube Will ↑ longevity but not preserve developmental function
Bowel dysfunction Monitor for constipation. Stool softeners, prokinetics, osmotic agents, or laxatives as needed
Saliva pooling / Drooling Botulinum toxin to salivary glands, topical (drops) anticholinergic agents Botox may spread to adjacent bulbar muscles, worsening dysphagia.
Family support In-home nursing & respite care as needed w/progression of disease Support for health & quality of life of caregivers & sibs

ASM = anti-seizure medication; 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 Foundation Toolbox.

Table 10.

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

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Manifestation/Concern Treatment Considerations/Other
Weakness / Impaired mobility PT/OT Adaptive equipment & mobility assists
Spasticity/Tremor Symptom-targeted pharmacotherapy by experienced neurologist
Communication needs Voice therapy Focus 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 support In-home nursing & respite care Could be indicated for individuals 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:

For individuals with subacute juvenile TSD, avoid:

For individuals with late-onset TSD, avoid:

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:

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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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

Offspring of a proband. Unless an individual with late-onset TSD has children with an affected individual or a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in HEXA; it is appropriate to offer carrier testing to the reproductive partners of individuals with late-onset TSD (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.

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

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

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 12) 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 12.

Notable HEXA Variants

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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

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

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

Literature Cited