GM2 gangliosidoses …

Neurogenetic Disorders

Updated 03.15.2023
Released 02.17.1994
Expires For CME 03.15.2026

GM2 gangliosidoses

Authors: Margie A Ream MD PhD, Stephanie Rinne DO

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Editor: Erika Fullwood Augustine MD MS

GM2 gangliosidoses

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Introduction

Overview

The GM2 gangliosidoses are a group of lysosomal storage diseases characterized by a defect in ganglioside metabolism due to a deficiency of the catabolic enzyme beta-hexosaminidase. This leads to accumulation of GM2 ganglioside within the lysosome. Full catabolic activity of beta-hexosaminidase requires interaction of three molecules: the A and B subunits of gangliosides and the GM2 activator protein, which functions as a cofactor for the enzyme. Each of these molecules are encoded by a different gene, but defects in any of these three can cause GM2 gangliosidoses. Three diseases have been described, corresponding to mutations in one of these three genes: Tay-Sachs disease (caused by beta-hexosaminidase A deficiency, OMIM 272800), Sandhoff disease (caused by beta-hexosaminidase B deficiency, OMIM 268800), and the AB variant (deficiency of the GM2 activator protein, OMIM 272750). Although the precise pathophysiology in each disease state varies, the clinical presentation and course of progressive neurologic decline is nearly identical among the three types. Each subtype can be further characterized by age of onset (infantile, late infantile, juvenile, and adult-onset phenotypes), which corresponds to residual enzyme activity. New treatments for GM2 gangliosidosis are being explored through clinical trials and preclinical models.

Key points

	• Tay-Sachs disease and Sandhoff disease are lysosomal storage disorders.
	• Tay-Sachs disease is caused by a deficiency of beta-hexosaminidase A.
	• Sandhoff disease is caused by a deficiency of beta-hexosaminidase A and B.
	• Carrier detection in at risk populations is successful for prevention.
	• A gene therapy clinical trial is underway for infantile-onset GM2 gangliosidosis.

Historical note and terminology

The first clinical description of what is now known as GM2 gangliosidosis occurred in 1881, when British ophthalmologist Warren Tay described a peculiar bright-red macula in a child with developmental delay. Bernard Sachs later described the clinical findings and noted enlarged pyramidal neurons in this disorder, which he called "familial amaurotic idiocy." It was the ophthalmologist who also examined Sachs’s patient who termed the description, “cherry-red macula.”

In the 1930s, Ernst Klenk discovered gangliosides within the postmortem brain tissues of patients with “amaurotic idiocy” (52). It was not until 1969 that accumulation of ganglioside within the brain was found to be secondary to deficiency of the lysosomal enzyme beta-hexosaminidase A (42). Myerowitz and colleagues isolated the cDNA clone containing the coding sequence for beta-hexosaminidase A in 1985. The HEXA and HEXB genomic structures were characterized in 1987 (39; 48; 47).

Clinical manifestations

Presentation and course

	• There are three forms of GM2 gangliosidoses: Tay-Sachs (hexosaminidase A deficiency), Sandhoff (hexosaminidase B deficiency), and the AB variant (deficiency of the GM2 activator protein).
	• Within each form there can be infantile, late infantile, juvenile, and adult-onset phenotypes.
	• The clinical presentations of Tay-Sachs and Sandhoff are nearly indistinguishable from one another except for the presence of organomegaly in Sandhoff disease and its absence in Tay-Sachs disease (53).
	• Due to its higher prevalence, Tay-Sachs disease is more frequently addressed in the literature; therefore, it is the main focus of this discussion.

Infantile GM2 gangliosidoses. Within infantile-onset Tay-Sachs disease, symptoms most often begin within the first 6 months of life. However, despite early onset of progressive symptoms, a diagnosis is not made until 13 months of age, on average. Death occurs in early childhood, with a median life expectancy of 47 months. The most common presenting symptoms include developmental arrest (83%), abnormal startle response/acoustic hypersensitivity (65%), and low muscle tone (60%). Developmental regression rather than developmental delay is a prominent feature of GM2 gangliosidosis. Most infants meet early developmental milestones, such as reaching for objects and passing objects between their hands, within expected developmental norms but later lose these skills. On average, the ability to reach for objects is lost after approximately 12 ± 8.7 months. Half of infants achieve the ability to sit. If the ability to sit is not obtained by 10 months, it is usually never achieved.

The next symptoms to arise (in order from earliest onset to latest onset) often occur between the ages of 15 to 20 months and include loss of ability to sit, decreased vocalizations, spasticity, seizures, and decreased vision. Timing of specific symptom onset does not appear to correlate with rate of disease progression or life expectancy except, however, for the timing of seizure onset, which does correlate with rapidity of regression.

Seizures present at an average age of 17.4 months and affect 93% of patients. They are often complicated by apnea and are frequently intractable to two or more medications. Onset of seizures prior to 12 months of age can be used as a marker of disease severity. If onset of seizures occurs prior to 12 months, infants can be expected to lose the ability to sit within the next 14 months.

Over time, children with GM2 gangliosidosis lose the ability to manage secretions, require frequent suctioning, and lose the ability to feed by mouth (02).

On fundoscopic exam, a macular cherry-red spot can be observed in over 90% of infants with this disease (27). In the study performed by Bley and colleagues, 67% of infants with developmental concerns were initially found to have a cherry-red spot, prompting further genetic testing and ultimate diagnosis (02).

Late infantile onset. Onset of symptoms ranges between 13 and 20 months of age, with a median age of diagnosis of 22 months. In the late infantile-onset form of Tay-Sachs disease, children can meet 1-year developmental milestones, including crawling and ability to form some words. The primary presenting symptoms include regression of speech and difficulties with ambulation. The median age of loss of verbalizations is 28 months. Median survival is 5.6 years (26).

Juvenile-onset GM2 gangliosidosis. Presenting symptoms in juvenile-onset Tay-Sachs disease are similar to the late infantile-onset form, with regression of speech and ambulation. In juvenile-onset disease, symptom onset occurs between 36 and 60 months of age and decline in function is more gradual. On average, children with juvenile Tay-Sachs disease lose the ability to ambulate between the ages of 6 to 9 years and lose verbalization between 7 to 9 years. All children who were followed by King and colleagues developed seizures, with an age of onset between 46 months and 7 years. Like infantile Tay-Sachs disease, seizures are often refractory to medications. Median survival is 12.6 years (26).

Adult-onset GM2 gangliosidosis. The average age of presentation of adult-onset Tay-Sachs disease is 19 years, which is slightly younger than that seen in adult-onset Sandhoff disease, which is 21 years (range 10 to 54 years). The most common presenting symptom among these patients is lower extremity weakness secondary to lower motor neuron disease (81%). Cerebellar ataxia is present in 53% of patients and is likely to be present early in the disease course, if present. Upper extremity weakness is less common and is more commonly found late in the disease course. Problems with ambulation were identified in 93% of patients, of whom half required wheelchair assistance 20 years following onset of symptoms. Dysarthria is reported in 70% of patients; severe psychiatric disorders, including bipolar, and psychosis are seen in 30% of patients; and moderate cognitive impairment (rarely meeting criteria for dementia) is observed in 30% of patients (34). Although no patients described clinical visual symptoms, impaired pursuit and dysmetric saccades are commonly identified on exam (53).

Prognosis and complications

Children with Tay-Sachs disease or Sandhoff disease have a shortened lifespan, with complications of cachexia and aspiration pneumonia causing death by 4 to 5 years of age. The B1 variant often begins later in the first decade, and despite worsening mental and motor abilities, these children may survive until the end of the second decade. Those with late-onset GM2 gangliosidosis may have a normal lifespan despite the progressive proximal weakness, ataxia, and possible development of psychiatric symptoms.

Clinical vignette

Juvenile onset. A 2.75-year-old boy presented for neurologic evaluation due to the development of an uncoordinated gait. He had normal early motor development with sitting at the age of 6 months and standing by 9 to 10 months, but a mild delay in walking that occurred at 16.5 months. Between 24 and 28 months the child developed a problem with balance and gait ataxia. Also at this time, the child developed a startle response to loud noise and bright light. Expressive language was mildly delayed, with only 2-word phrases noted by 2.5 years of age. The examination of the eyes showed nystagmus on lateral gaze and evidence of a cherry-red macula on the funduscopic examination. The child had diffusely increased deep tendon reflexes with bilateral extensor plantar responses. After hearing a loud clap, the child developed a generalized startle response that did not attenuate to repeated stimuli. The gait was wide-based and ataxic, and past-pointing was noted on reaching for objects. MRI of brain was normal, and EEG was slow but without epileptiform discharges. A skin biopsy for electron microscopy demonstrated lysosomal inclusions compatible with a glycolipid storage disease. Beta-hexosaminidase A activity was markedly reduced to a sulfated artificial substrate. Molecular studies revealed the most common so-called B1 HEXA mutation, p.Arg178His, on one allele with another mutation also present.

Cherry-red spot in fundus photograph

Preservation of color in macula with lipid storage in surrounding retina. (Contributed by Dr. Edward Kaye.)
Lysosomal inclusions on electron micrograph of skin

Electron microscopic appearance of storage material. (Contributed by Dr. Edward Kaye.)

Biological basis

	• GM2 gangliosidoses are lysosomal disorders that result in the accumulation of gangliosides due to dysfunction of the enzyme beta-hexosaminidase A.
	• Beta-hexosaminidase A requires A and B subunits for normal function.
	• Tay-Sachs disease is due to a mutation in the HEXA gene, resulting in loss of function of the alpha subunit of hexosaminidase A.
	• Sandhoff disease is due to a mutation in the HEXB gene, resulting in loss of function of the beta subunit of hexosaminidase A.

Etiology and pathogenesis

Gangliosides are a typical component of neuronal plasma membranes. They are expressed in a cell-type and stage-specific manner based on their surface patterns, which are generated by a complex series of reactions involving biosynthetic and catabolic steps of intracellular trafficking. The gangliosidoses are caused by inherited defects in ganglioside catabolism. Lysosomes are intracellular organelles responsible for degrading macromolecules into their components, which can then be used for energy metabolism or in salvage pathways. Gangliosides are transported to the lysosome in vesicles, which are then prepared for digestion through lipid sorting within endosomes. Once in the lysosome, GM1 is hydrolyzed into GM2 by beta-galactosidase. Hydrolysis of GM2 is then performed by beta-hexosaminidase A, which is a heterodimer composed of alpha and beta subunits that are both required for its activity. When catabolism of GM2 is impaired, membranous cytoplasmic bodies (secondary storage lysosomes) fill with gangliosides, which causes neuronal distention and eventually cell death.

Tay-Sachs disease is caused by pathogenic variants of the HEXA gene, which maps to chromosome 15q23-24 and results in loss of function of the alpha subunit of hexosaminidase A. Sandhoff disease is secondary to a mutation in the HEXB gene on chromosome 5q11.2-13.3, which results in abnormal beta subunit production of hexosaminidase A. This results in accumulation of GM2 ganglioside, globoside, and oligosaccharides (responsible for mild ventriculomegaly seen in Sandhoff disease and not Tay-Sachs). Complete or near complete loss of GM2 catabolism results in the fatal infantile forms of these lysosomal storage disorders. However, there are some mutations that result in proteins with some maintained catabolic activity, which can result in the late infantile, juvenile, or chronic disease states of Tay-Sachs or Sandhoff (52).

The most common genetic mutations in Tay-Sachs disease are missense variants; however, nonsense variants, splice-site alterations, single codon deletions, large deletions, and frameshifts due to small deletions and insertions have all been described. The phenotype usually correlates with the less severe allele.

Among the Ashkenazi Jewish population, three pathogenic variants are predominant and detect 98% of cases within this population:

(1) A 4-nucleotide insertion (TATC) in exon 11 (c.1278ins4) accounting for approximately 81% of all HEXA mutations in the Jewish population.

(2) A mutation in intron 12 (c.1421+1G> C) accounting for approximately 15% of cases within the Jewish population.

(3) A missense mutation in exon 7, pGly269 Ser is found in juvenile and adult forms of Tay-Sachs (2% of the Jewish population).

In the non-Jewish population, about 32% of children have variant number one described above, and 14% have a splice site variant that results in a 17 base pair insertion (c. 1073+G > A). In Spain, 32.5% of patients have variant c.459+5G>A. Patients homozygous for c.459 + 5G>A had the infantile form of the disease. If one allele of p.R178H is present, a milder form of the disease can be expected.

There are over 20 pathogenic variants in HEXB described in a broad ethnic spectrum of the population that lead to Sandhoff disease (13). One of the most common mutations noted in approximately 50% of patients with Sandhoff disease, especially French and French-Canadian individuals, consists of a 16-kb deletion in one or both HEXB alleles. A CàT substitution in exon 11 is associated with a variant that causes a 3' splice site selection alteration.

Pathophysiology of the cherry-red spot. One of the characteristic ophthalmological findings in Tay-Sachs disease is the presence of a macular cherry-red spot. The storage of lipids within the retinal ganglion cells causes a whitish discoloration of most of the retina. The fovea, however, does not contain the bipolar ganglion cells and retains the normal red color, which appears accentuated by the contrasting white retina. The fovea gradually becomes a cherry-brown color, and the retina assumes a yellow-white appearance (27). Because the rod and cone cells in the retina are not affected by lipids, the loss of vision that frequently occurs by the end of the first year is due to cerebral pathology. On electron microscopic evaluation, lipids also appear to be stored within the corneal endothelium (11).

Prevention

• Prevention of GM2 gangliosidoses relies on carrier screening and prenatal testing.

Carrier screening is used to identify individuals or couples who are at risk of having a child with an autosomal recessive or X-linked genetic disorder. The purpose is to allow individuals to become educated about their risks and provide the opportunity to consider a range of reproductive options. GM2 gangliosidosis meets the criteria for prenatal screening established by the American College of Medical Genetics and Genomics (ACMG) due to risk for profoundly shortened lifespan, relatively high prevalence (> 1/100) among certain populations, presence of established screening methods, and a reliable genotype-phenotype correlation (14).

Screening for Tay-Sachs has been available since the 1970s among the Ashkenazi Jewish population, when it was found that the frequency of carriers among this population was significantly higher compared to the general population (1 of 33 compared to 1 of 260) (15). Since that time, implementation of screening analysis has decreased the prevalence of Tay-Sachs within the United States and Canada by more than 90% (23).

Traditionally, hexosaminidase A enzyme analysis or direct DNA analysis of HEXA have been used to test carrier status (OMIM *606869). This was followed by targeted variant panels, which have demonstrated high sensitivity among the Ashkenazi Jewish population. However, sensitivity is markedly reduced in panethnic populations (22; 44), which is problematic due to the majority of Tay-Sachs-affected births occurring among couples in which at least one partner is non-Ashkenazi Jewish (30). Therefore, recent focus has been placed on the development of a screening method that maximizes detection among all ethnicities. To try to accomplish this, next-generation sequencing of the HEXA gene has been utilized due to its ability to identify common, rare, and novel variants (17).

The ACMG currently recommends enzyme testing for all low-risk populations due to it being more reliable among all ethnicities (09), but it is important to note that results must be interpreted cautiously as there are not well-established detection rates and reference ranges (Mehta et at 2016). Next-generation sequencing can increase the sensitivity in panethnic populations (98.7%; 95% CI: 97.64%–99.37%) in comparison to enzyme analysis (95.55%; 95% CI: 93.87%–96.88%). However, one limitation is interpretation of variants of unknown significance, which are not reported to patients in the setting of carrier screening. Studies are currently underway to reclassify common variants of unknown significance as benign or pathogenic based on the ACMG criteria (06).

The rare variants that cannot be detected by routine enzyme screening are the AB variant (normal functioning of beta-hexosaminidase A and beta-hexosaminidase B, but inability to form the necessary GM2 activator complex between the two enzymes) and the B1 variant (binding site affinity mutation) carriers, who usually have enzyme levels in the low to normal range (07).

Differential diagnosis

Confusing conditions

The differential for developmental regression and progressive encephalopathy is broad but can include infectious etiologies, disorders of amino acid or lysosomal metabolism, carbohydrate-deficient glycoprotein syndromes, hypothyroidism, mitochondrial disorders, neurocutaneous syndromes, disorders of gray matter, disorders of white matter (such as leukodystrophies), or progressive hydrocephalus (45).

GM1 gangliosidosis is characterized by accumulation of ganglioside substrate in lysosomes secondary to a deficiency of beta-galactosidase-1. There are three forms, including type I (infantile), type II (late infantile and juvenile), and type III (adult). Like GM2 gangliosidosis, progressive neurocognitive decline is a defining feature of this disease. The excessive startle response and cherry-red macula, which are seen early in the infantile variant of GM2 gangliosidosis, may also be present later in patients with GM1 gangliosidosis. However, the major differentiating factors between GM1 and GM2 are that hepatomegaly, coarsened features, kyphosis, scoliosis, and hip dysplasia are commonly seen in GM1 and are absent in GM2 (26).

The differential for a cherry-red macula includes central retinal artery occlusion and other metabolic storage diseases, such as Niemann-Pick disease, Fabry disease, Gaucher disease, and sialidosis (16). A major differentiating feature between GM2 gangliosidosis and Niemann-Pick disease is that in Nieman-Pick disease, a loss of auditory acuity is seen rather than a heightened auditory response. Sialidosis commonly presents with myoclonic seizures and gait disturbance in the second decade of life but is not associated with severe hypotonia and developmental deterioration.

The late-onset forms of GM2 gangliosidosis have presentations that may resemble progressive dystonia, milder forms of spinal muscular atrophy, amyotrophic lateral sclerosis, Friedreich ataxia, and other forms of spinocerebellar ataxia. The early childhood appearance of dysarthria and ataxia may differentiate a chronic form of GM2 gangliosidosis from other disorders.

Associated or underlying disorders

Intractable epilepsy
Organomegaly

Diagnostic workup

	• Diagnosis of GM2 gangliosidoses primarily relies on measurement of enzyme activity and molecular testing.
	• Neuroimaging and ophthalmologic evaluation can increase the index of suspicion.

The combination of progressive weakness; developmental regression; exaggerated startle response in association with clinical exam findings, including cherry-red spot; generalized hypotonia; sustained clonus; or hyperreflexia should prompt further investigation for gangliosidosis. Work-up can include the following.

Enzyme analysis. Enzyme analysis is the first step in the evaluation for GM2 gangliosidosis. Diagnosis can be made on a blood sample demonstrating low hexosaminidase activity, which can then be confirmed by genetic testing. Tay-Sachs disease is characterized by beta-hexosaminidase A deficiency secondary to biallelic HEXA pathogenic variants (OMIM 27800), and Sandhoff disease is characterized by deficiency in beta-hexosaminidase A and B secondary to biallelic pathogenic variants of HEXB (OMIM 26800).

Diagnosis of patients with the AB variant is complicated because they appear to have normal beta-hexosaminidase A and B activity when using an artificial substrate in the laboratory but lack the GM2 activator protein necessary for in vivo degradation of GM2 ganglioside. These patients with the AB variant can be diagnosed if the natural substrate is tested both with and without the GM2 activator protein, or if CSF is examined for the presence of GM2 ganglioside (49). Similarly, the B1 variant will not be detected using the usual artificial substrates within the lab but will show low activity when tested with sulfated artificial substrates.

Genetic testing. Genetic testing is performed when enzymatic activity is absent or low and includes sequencing, targeted analysis for pathogenic variants, or deletion/duplication analysis. The use of panel testing is advised, which assesses for the most common variants, including but not limited to, null alleles p.Tyr427IlefsTer5, c.1421+1G>C, and c.1073+G>A, which is associated with Tay-Sachs disease in the homozygous or compound heterozygous state.

The most frequent pathogenic variant in patients with adult-onset Sandhoff disease was c.1514G>A (or p. Arg178His), and there are three common pathogenic variants identified in adult-onset Tay-Sachs disease: c.805G>A (or p.Gly269Ser), c. 533G>A (or p. Arg178 His), and c.1274_1277dup (or p.Tyr427Ilefs*5; 14% each) (34).

It is important to note two pseudo deficiency alleles (p.Arg247Trp and p.Arg249Trp) are not associated with neurologic disease but with reduced degradation of the synthetic substrate when hexosaminidase A activity is tested in vitro (54).

Imaging. Imaging features that can suggest infantile-onset Tay-Sachs disease include the presence of bilateral hyperdense thalami and hypodense cerebral white matter on CT. On MRI, this appears as bilateral hypointense thalami on T2-weighted imaging and hyperintense signal on T1-weighted imaging. Due to deposition of ganglioside within the brain, abnormal myelination is observed, presenting on MRI as hyperintense signal on T2-weighted imaging and hypointensity on T1-weighted imaging within the bilateral cerebral hemispheres. As the disease progresses, cerebellar and cerebral atrophy is seen. Prior to the age of 2 years, a progressive increase in ventricular and total brain volume is observed with a simultaneous, more gradual decrease in cerebellar white matter, caudate, putamen, and corpus callosum (40).

In a study of patients with juvenile-onset GM2 gangliosidosis by Maegawa and colleagues, 35.3% of patients were found to have subcortical white matter changes along with some degree of cerebellar or cerebral atrophy between the ages of 1.8 and 6.9 years of age. Approximately 25% of patients had a mild degree of atrophy, whereas 29.4% had more severe cerebellar atrophy. MR spectroscopy was performed in five patients and was significant for decreased N-acetylaspartic acid in four of the patients. Of note, 17.1% of patients had normal imaging at an average age of 7.5 years despite the presence of symptoms (32).

Adult-onset Tay-Sachs disease is characterized by severe cerebellar atrophy secondary to gray matter volume loss, most prominently affecting the vermis. Cerebellar atrophy is also seen in late-onset Sandhoff disease but to a lesser degree in comparison to Tay-Sachs. Less commonly, diffuse cerebral atrophy may be seen (34). MR spectroscopy (MRS) is significant for elevated myoinositol, decreased N-acetylaspartate, glutamine-glutamate and creatine within the cerebellum, and decreased N-acetylaspartate within the parietal cortex when patients are compared to healthy controls. There is no significant difference observed within the thalami on MRS. In late-onset Tay-Sachs disease, the degree of cerebellar volume loss and NAA levels are most strongly associated with clinical ataxia. Further supporting the slowly progressive nature of late-onset GM2 gangliosidosis, no significant changes are observed on MRI when performed 6 months apart (51).

EEG. Early EEG in Tay-Sachs disease will frequently show slowing. When seizures develop, multifocal spikes may appear.

EMG/nerve conduction. In late-onset GM gangliosidosis, nerve conduction studies are significant for lower motor neuron disease in the lower extremities. Less commonly, they can demonstrate sensory axonal neuropathy. When followed over time, EMG shows progressive deterioration in motor conduction in all nerves (34).

Other. The CSF in GM2 gangliosidosis does not reveal abnormalities of cell count, protein, or glucose. However, GM2 ganglioside is present in large quantities when the CSF is examined by thin-layer chromatography or high-performance liquid chromatography (25). Urinary oligosaccharides show an abnormal pattern in patients with Sandhoff disease, a finding that can be used to differentiate this variant from Tay-Sachs disease (57). Electron microscopic analysis of skin, conjunctiva, and rectal mucosa biopsies frequently show storage of membranous cytoplasmic bodies or other electron-dense storage material within nerve cells and myelinated and unmyelinated axons (56).

Management

	• There are currently no effective or FDA-approved treatments specifically indicated for GM2 gangliosidosis.
	• Focus remains on supportive care for seizures, dysphagia, and infection management.

Supportive care

Dysphagia. Patients with the late infantile phenotype require G-tube placement at a median age of 3.2 years; for patients with juvenile Tay-Sachs disease, the median age for placement is 10.2 years.

Respiratory secretions. Respiratory secretions can be managed with chest wall oscillation therapy and frequent suctioning.

Seizures. Rarely, infantile spasms may be observed. Current recommendations are to treat with antiseizure medications following standard of care similar to idiopathic epilepsy.

The overarching goals when attempting to find curative treatments for GM2 gangliosidosis include decreasing substrate synthesis (GM2 ganglioside) and increasing beta-hexosaminidase A activity to prevent neuroinflammation and neurodegeneration. Multiple therapeutic approaches have been attempted, including enzyme replacement therapy, hematopoietic stem cell transplantation, pharmacological chaperones, substrate reduction therapy, and gene therapy, but the efficacy of these interventions has been limited (08). Although some of these therapies have reached clinical trials, there currently are no FDA approved treatments for Tay-Sachs or Sandhoff disease.

Investigational agents

Gene therapy. The GM2 gangliosidoses are monogenic diseases that make them good targets for gene therapy because, in theory, administration of a functional gene could correct the genetic defect (41). Along with this, it appears that neighboring cells can uptake the secreted enzyme, suggesting that not all cells need to be transfected (10). The first effective gene therapy was performed by Cachon-Gonzalez and colleagues in 2006, and again in 2012, when they were able to demonstrate that injecting AAV2 vectors containing HEXA and HEXB subunits of beta-hexosaminidase A intracranially increased the lifespan and function of the mice from 4 months to greater than 1 year (04; 05). This finding was later replicated by McCurdy and colleagues in 2021 using a feline model (37). McCurdy and colleagues also demonstrated improved survival in felines, even when gene therapy was performed following onset of symptoms. Due to the promising outcomes in animal models, a similar bicistronic AAV9 vector containing HEXA and HEXB was approved for a phase 1 clinical trial for patients with infantile GM2 gangliosidosis in March 2021 (NCT04798235); the estimated primary completion date is March 2023.

Other attempts at simplifying gene administration have included generation of a homodimer (HEXM) to alleviate the need to administer both HEXA and HEXB (20), which proved to successfully extend lifespan and improve behavior in mice (50).

Enzyme replacement therapy. One of the barriers to enzyme replacement therapy with administration of hexosaminidase A is the inability of this enzyme to cross the blood-brain barrier (21). One means of overcoming this is using molecular Trojan horses, which are recombinant chimeric enzymes fused to a monoclonal antibody that recognizes receptors on the blood-brain barrier to allow for passage through receptor-mediated endocytosis (03). Although this has not been evaluated in animal models of GM2 gangliosidosis, Boado and colleagues demonstrated that hexosaminidase A fused to HIRMAb has similar activity when compared to the nonfused enzyme. The other option includes altering the route of administration through intrathecal or intracerebroventricular injections. Multiple studies have demonstrated that when hexosaminidase A is injected intracerebroventricularly to mice, enzyme activity levels and lifespan increase while levels of GM2 decrease (29). This decrease in central neural storage is correlated to improvement of motor dysfunction and prolonged lifespan (55).

Hematopoietic stem cell transplantation. Allogenic bone marrow transplantation was performed in a child with Tay-Sachs disease who was 3 years 10 months of age (19). The child continued to show neurologic deterioration, and the natural course of the disease was not changed despite enzyme levels reaching heterozygote range. Hematopoietic stem cell therapy in five children with GM2 gangliosidosis showed no change in clinical course (02).

Pharmacological chaperones. Pharmacological chaperones are small molecules that bind to proteins to stabilize their native conformation or promote correct folding. The molecule then dissociates from the protein in the lysosome due to the acidic pH. However, the greatest limitation includes their mutation-dependent activity, which decreases the number of patients who may benefit from treatment (29). The most promising chaperone to date for Tay-Sachs disease is pyrimethamine, which can increase activity of hexosaminidase A 3-fold (33; 01). Other studies demonstrated that a maximum dose of 30 + 24 mg significantly improved speech and mood (43).

Thus far, pyrrolidine 2,5-dideoxy-2,5-imino-D-mannitol (DMDP) amide is predicted to be the strongest inhibitor of hexosaminidase A and has the potential to increase hexosaminidase A activity up to 14.8-fold (up to 48% wild type levels) in Tay-Sachs disease–effected fibroblasts (24).

Substrate reduction therapy. Substrate reduction therapy involves the disruption of synthesis of the accumulating substrate (GM2 ganglioside). The most studied molecule in this category is N-butyldeoxynojirimycin (NB-DNJ, also termed miglustat or Zavesca), which inhibits glucosylceramide synthase (46). Miglustat is taken orally and has been shown to delay the progression of neurologic symptoms in murine models (Platt and Jeyakumar 2008). However, it does not appear to have any effect if used late in the course of juvenile-onset Tay-Sachs disease (31) or if used in adult-onset disease (35).

Outcomes

There are currently no disease-specific targeted therapies for GM2 gangliosidosis approved by the Food and Drug Administration (FDA). However, AXO-AAV-GM2 has received Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation from the FDA and is under ongoing study (NCT04798235).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Margie A Ream MD PhD

Dr. Ream of Ohio State University College of Medicine received consulting fees from Ionis Pharmaceuticals, INC.
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Stephanie Rinne DO

Dr. Rinne of Nationwide Children's Hospital has no relevant financial relationships to disclose.
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Editor

Erika Fullwood Augustine MD MS

Dr. Augustine of Kennedy Krieger Institute, Johns Hopkins University, and University of Rochester Medical Center received a clinical trial agreement as Central Rater from Neurogene Inc, and an honorarium as a member of the Data Safety and Monitory Board for PTC Therapeutics.
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Former Authors

Reuben Matalon MD PhD
Lisvania M Delgado-Pena MS2
Brianna M Young MS2
Dena Rae Matalon MD
Raphael Schiffmann MD
Edward M Kaye MD (original author), Gita Masand PhD, and Kimberlee Michals-Matalon PhD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity typical

heredity may be a factor

autosomal recessive
Population groups selectively affected: Ashkenazi Jews

French-Canadians

Portuguese
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: GM2 gangliosidosis: 330.1
ICD-10: GM2 gangliosidosis: E75.0
OMIM: B variant of GM2 gangliosidoses: #272800

B1 variant of GM2 gangliosidoses: #272800

O variant of GM2 gangliosidoses: #268800

AB variant of GM2 gangliosidoses: #272750

Late onset of GM2 gangliosidosis: #272800.0008

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GM2 gangliosidoses

Associated Disorders

intractable epilepsy
organomegaly

Differential Diagnosis

infectious etiologies
disorders of amino acid or lysosomal metabolism
carbohydrate-deficient glycoprotein syndromes
hypothyroidism
mitochondrial disorders
- neurocutaneous syndromes
- disorders of gray matter
- disorders of white matter (such as leukodystrophies)
- progressive hydrocephalus
- GM1 gangliosidosis
- central retinal artery occlusion
- Niemann-Pick disease
- Fabry disease
- Gaucher disease
- sialidosis

Also Relevant

Autosomal dominant hereditary ataxias
Gene therapy of neurogenetic disorders
GM1 gangliosidosis
Leukodystrophies
Nondominant hereditary ataxias

GM2 gangliosidoses

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Supportive care

Investigational agents

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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