Hexa Disorders

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.

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).

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.

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.

Hereditary Disorders

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.

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.

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.

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.