GM2 Activator Deficiency

Changrui Xiao; Camilo Toro; Cyndi Tifft

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

GeneReviews^® [Internet].

Show details

GeneReviews by Title

< Prev Next >

GM2 Activator Deficiency

Synonyms: GM2 Gangliosidosis, AB Variant; Hexosaminidase Activator Deficiency; Tay-Sachs Variant AB

Changrui Xiao, MD, Camilo Toro, MD, and Cyndi Tifft, MD, PhD.

Author Information and Affiliations

Initial Posting: August 25, 2022.

Estimated reading time: 18 minutes

Summary

Clinical characteristics.

Acute infantile GM2 activator deficiency is a neurodegenerative disorder in which infants, who are generally normal at birth, have progressive weakness and slowing of developmental progress between ages four and 12 months. An ensuing developmental plateau is followed by progressively rapid developmental regression. By the second year of life decerebrate posturing, difficulty in swallowing, and worsening seizures lead to an unresponsive vegetative state. Death usually occurs between ages two and three years.

Diagnosis/testing.

The diagnosis of GM2 activator deficiency is established in a proband with suggestive findings of GM2 gangliosidosis, normal beta-hexosaminidase A (HEX A) enzyme activity levels, and biallelic pathogenic (or likely pathogenic) variants in GM2A identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for GM2 activator deficiency. Supportive care to provide adequate nutrition and hydration, manage infectious disease, protect the airway, and control seizures involves multidisciplinary care by specialists in relevant fields.

Surveillance: Periodic multidisciplinary evaluations to monitor existing disease manifestations and identify new manifestations requiring modification of supportive care.

Agents/circumstances to avoid: Positioning that increases aspiration risk during feedings and seizure medication dosages that result in excessive sedation.

Genetic counseling.

GM2 activator deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GM2A pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the GM2A pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for GM2 activator deficiency have been published.

Suggestive Findings

GM2 activator deficiency should be suspected in children with the following clinical and imaging findings and family history.

Clinical findings

Neurologic
- Progressive weakness or loss of motor skills beginning between ages four to 12 months
- Decreased attentiveness
- Exaggerated startle response
- Hypotonia
- Hyperreflexia
- Seizures
Other. Cherry-red macula

Brain MRI findings

Delayed myelination and hyperintense T₂-weighted signal in the subcortical white matter, basal ganglia, and/or thalami [Chen et al 1999, Renaud & Brodsky 2016, Brackmann et al 2017]
Normal MRI has also been reported [Sakuraba et al 1999].

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of GM2 activator deficiency is established in a proband with suggestive findings, normal beta-hexosaminidase A (HEX A) enzyme activity levels, and biallelic pathogenic (or likely pathogenic) variants in GM2A 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 biallelic GM2A variants of uncertain significance (or identification of one known GM2A pathogenic variant and one GM2A variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) (see Option 1) and comprehensive genomic testing (exome sequencing, genome sequencing) (see Option 2).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GM2 activator deficiency overlaps with several biochemically related disorders (GM2 gangliosidoses), most infants with the findings described in Suggestive Findings are likely to be diagnosed using a multigene panel or genomic testing.

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of GM2 activator deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. In rare instances, single-gene testing can be considered for individuals with a high clinical suspicion of a GM2 gangliosidosis and normal HEX A and beta-hexosaminidase B (HEX B) activity. Sequence analysis of GM2A is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions.
Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
A multigene panel for GM2 gangliosidoses, lysosomal storage diseases, neurometabolic diseases, or neurodevelopmental diseases would be an appropriate initial test when seeking a molecular diagnosis in most individuals suspected clinically of having GM2 activator deficiency. Such panels include GM2A and other genes of interest (see Differential Diagnosis) and are most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by neurodegeneration, epilepsy, and/or hypotonia, comprehensive genomic testing, which does not require the clinician to determine which gene is likely involved, is appropriate. Exome sequencing is most commonly used; genome sequencing is also possible.

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 GM2 Activator Deficiency

Gene ¹	Method	Proportion of Pathogenic Variants ² Detectable by Method
GM2A	Sequence analysis ³	24/26 ⁴
GM2A	Gene-targeted deletion/duplication analysis ⁵	1 person reported ⁶

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 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.
6.: A homozygous 6-kb deletion of exon 2 (c.82-2668_243+3312del6142) was reported in one individual [Hall et al 2018].

Clinical Characteristics

Clinical Description

To date, 13 individuals have been reported with acute infantile GM2 activator deficiency [de Baecque et al 1975, Xie et al 1992, Schröder et al 1993, Schepers et al 1996, Chen et al 1999, Sakuraba et al 1999, Kolodny et al 2008, Renaud & Brodsky 2016, Sheth et al 2016, Brackmann et al 2017, Hall et al 2018, İnci et al 2021]. The following description of the phenotypic features associated with acute infantile GM2 activator deficiency is based on these reports.

Table 2.

Acute Infantile GM2 Activator Deficiency: Frequency of Select Features

Feature	# of Persons w/Feature	Comment
Developmental delay	13
Cherry-red macula	13
Hypotonia	12	Tone not specifically discussed in 13th case & is likely present in all affected persons. While axial tone is universally ↓, limb tone may be ↑ or ↓.
Seizures	9
Exaggerated startle response	8
Hyperreflexia	4	Hyperreflexia was present in all reports in which reflexes were specifically discussed.
Hepatomegaly	2

Acute Infantile GM2 Activator Deficiency

Affected infants are generally normal at birth. Progressive weakness, exaggerated startle, and slowing of developmental progress is typically noted between ages four to 12 months. Decreasing visual attentiveness and unusual eye movements including poor fix-and-follow, typically noted at age three to six months, may be the first signs prompting parents to seek medical attention; subsequent ophthalmologic evaluation reveals the characteristic cherry-red macula seen in virtually all affected children.

Affected infants reach a developmental plateau followed by developmental regression typically between ages six to ten months. After age eight to ten months, disease progression is rapid. Voluntary movements diminish and the infant becomes progressively less responsive. Vision deteriorates rapidly.

Seizures and myoclonic jerks are common by age 12 months. Partial complex seizures or absence seizures that are initially subtle typically become more severe and more frequent.

Progressive enlargement of the head resulting from reactive cerebral gliosis beginning by age 18 months followed by ventriculomegaly commonly seen in GM2 gangliosidosis has been inconsistently reported in GM2 activator deficiency [Nestrasil et al 2018].

Further deterioration in the second year of life results in decerebrate posturing, difficulty in swallowing, worsening seizures, and finally an unresponsive, vegetative state.

Prognosis. Death from respiratory complications usually occurs between ages two and three years.

Possible Subacute Juvenile GM2 Activator Deficiency

Three members of one family with childhood-onset progressive cognitive decline, hyperkinetic movement disorder, and global cerebral atrophy were homozygous for the GM2A missense variant c.164C>T [Salih et al 2015]; this variant, subsequently predicted to be deleterious in silico, segregates with the disease in this family.

Another unrelated individual with a childhood-onset progressive movement disorder, cognitive decline, and epilepsy was compound heterozygous for a GM2A nonsense variant and the c.164C>T GM2A missense variant [Martins et al 2017]. Further studies demonstrated decreased levels of GM2 activator protein and accumulation of GM2 gangliosides in cultured fibroblasts.

The phenotype in these two families likely represents a subacute juvenile form of GM2 activator deficiency similar to that seen in other GM2 gangliosidoses.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

GM2 activator deficiency was one of several disorders, including Tay-Sachs disease (see HEXA Disorders) and Sandhoff disease, formerly referred to collectively as "amaurotic idiocy." Once GM2 ganglioside was identified as the major accumulating substrate, the terms "infantile ganglioside lipidosis" and "GM2 gangliosidosis" were introduced. Likewise, when the relationship between the enzymatic activity of beta-hexosaminidase A (HEX A) and GM2 activator protein was identified, the terms "GM2 activator deficiency" and "hexosaminidase activator deficiency" were introduced.

To distinguish GM2 activator deficiency from Tay-Sachs disease and Sandhoff disease – both of which also involve GM2 ganglioside accumulation because of a shared biochemical pathway for the enzymes involved – GM2 activator deficiency is also referred to as "GM2 gangliosidosis, AB variant" or "Tay-Sachs disease variant AB."

Prevalence

To date, 13 individuals have been reported with infantile-onset GM2 activator deficiency [de Baecque et al 1975, Xie et al 1992, Schröder et al 1993, Schepers et al 1996, Chen et al 1999, Sakuraba et al 1999, Kolodny et al 2008, Renaud & Brodsky 2016, Sheth et al 2016, Brackmann et al 2017, Hall et al 2018, İnci et al 2021].

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with germline pathogenic variants in GM2A.

Differential Diagnosis

Table 3.

Genetic Disorders of Interest in the Differential Diagnosis of Acute Infantile GM2 Activator Deficiency

Gene	DiffDx Disorder ¹	Clinical Features of DiffDx Disorder
Gene	DiffDx Disorder ¹	Cherry-red macula (≤12 mos)	Onset of neurologic regression	Other features / Comments	Not observed in GM2 activator deficiency
ASPA	Canavan disease		≤6 mos	Macrocephaly, head lag, hypotonia, seizures	Leukoencephalopathy
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	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; ichthyosiform or collodion skin changes may be seen in persons w/severe involvement.
GFAP	Alexander disease, infantile form		≤6 mos	Macrocephaly, seizures	Leukodystrophy
GLB1	GM1 gangliosidosis type 1 (See GLB1 Disorders.)	+	≤12 mos	Seizures	Skeletal disease
GNPTAB	Mucolipidosis II (I-cell disease) (See GNPTAB Disorders.)		≤12 mos		Coarse facies, hyperplastic gums, skeletal disease; absence of seizures
HEXA	Tay-Sachs disease (See HEXA Disorders.)	+	≤6 mos	Clinical course nearly identical to GM2 activator deficiency
HEXB	Sandhoff disease	+	≤6 mos	Clinical course nearly identical to GM2 activator deficiency
NEU1	Sialidosis type II (OMIM 256550)	+	≤12 mos	Seizures	Coarse facies, skeletal abnormalities
SMPD1	Niemann-Pick disease type A (See Acid Sphingomyelinase Deficiency.)	+	≤12 mos		Poor growth, xanthomas, absence of seizures

: ERG = electroretinogram
1.: The disorders included in Table 3 are inherited in an autosomal recessive manner, with the exception of Alexander disease, which is inherited in an autosomal dominant manner.

Management

No clinical practice guidelines for acute infantile GM2 activator deficiency have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with acute infantile GM2 activator deficiency, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Acute Infantile GM2 Activator Deficiency

System/Concern	Evaluation	Comment
Neurologic	Neurology eval	To incl brain MRI Consider EEG if seizures are a concern.
Musculoskeletal system	Physical medicine & rehab / PT & OT eval	To incl assessment of: Gross motor & fine motor skills Need for adaptive devices Need for PT (to prevent deformities)
Gastrointestinal/ Feeding	Gastroenterology / nutrition / feeding team eval	To incl swallow study for eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Assess for constipation.
Eyes	Ophthalmologic exam	Eval for macular degeneration, cherry-red macula, visual loss
Respiratory	Evaluate for aspiration risk.	Assess need for airway hygiene.
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.
Ethics consultation	Clinical ethics services	Assess health care decisions in context of best interest of child & values & preferences of family. For difficult life-prolonging decisions or clarification of treatment options, consider further consultation w/independent clinical teams. ²

: EEG = electroencephalogram; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
1.: Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
2.: Linney et al [2019]

Treatment of Manifestations

There is no cure for GM2 activator deficiency.

Supportive treatment to provide adequate nutrition and hydration, manage infectious disease, protect the airway, and control seizures involves multidisciplinary care by specialists in relevant fields (see Table 5).

Table 5.

Supportive Treatment of Individuals with Acute Infantile GM2 Activator Deficiency

Manifestation/Concern	Treatment	Considerations/Other
Seizures	Standardized treatment w/ASM by experienced neurologist/epileptologist	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 ASMs. Education of parents/caregivers ¹
Abnormal tone / Impaired mobility	PT/OT	For prevention of contractures
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 preserve developmental function
Family support	In-home nursing & respite care	Support for health & quality of life of caregivers & sibs
Ethics consultation	Clinical ethics services	Assess health care decisions in context of best interest of child & values & preferences of family. For difficult life-prolonging decisions or clarification of treatment options, consider further consultation w/independent clinical teams. ²

: 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.
2.: Linney et al [2019]

Surveillance

There are no formal guidelines for surveillance for individuals with acute infantile GM2 activator deficiency. Table 6 provides suggestions for periodic evaluations to monitor existing disease manifestations and to identify new manifestations requiring modification of supportive care.

Table 6.

Recommended Surveillance for Individuals with Acute Infantile GM2 Activator Deficiency

System/Concern	Evaluation	Frequency
Neurologic decline	Eval by pediatric neurologist w/attention to seizure severity & response to ASM	Every 3-6 mos
Abnormal tone / Impaired mobility	OT/PT assessment of ADL & need for splinting for contractures/scoliosis Durable medical equipment for mobility	At each visit
Nutrition/feeding	By feeding team re aspiration risk / nutrition needs
Respiratory	Assess need for airway hygiene.
Family support & resources	Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).	As needed

: ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy

Agents/Circumstances to Avoid

Avoid the following:

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

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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

GM2 activator deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

The parents of an affected child are presumed to be heterozygous for a GM2A pathogenic variant.
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a GM2A pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
- A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
- Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

If both parents are known to be heterozygous for a GM2A pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with GM2 activator deficiency are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a GM2A pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the GM2A pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

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

Prenatal Testing and Preimplantation Genetic Testing

Once the GM2A pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing 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.

MedlinePlus
GM2-gangliosidosis, AB variant
Metabolic Support UK
United Kingdom
Phone: 0845 241 2173
www.metabolicsupportuk.org
National Tay-Sachs and Allied Diseases Association, Inc. (NTSAD)
Phone: 617-277-4463
Email: info@ntsad.org
www.ntsad.org

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.

GM2 Activator Deficiency: Genes and Databases

Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
GM2A	5q33.1	Ganglioside GM2 activator	GM2A database	GM2A	GM2A

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

Table B.

OMIM Entries for GM2 Activator Deficiency (View All in OMIM)

272750	GM2-GANGLIOSIDOSIS, AB VARIANT
613109	GM2 ACTIVATOR; GM2A

Molecular Pathogenesis

GM2 activator protein is a substrate-specific cofactor that, together with the enzyme beta-hexosaminidase A (HEX A), catalyzes the degradation of GM2 gangliosides. Gangliosides (normally present in neurons in very small quantities) are progressively stored in neurons, leading to neuronal impairment and loss and causing the characteristic central nervous system and peripheral nervous system neurodegeneration.

HEX A comprises an alpha subunit and a beta subunit encoded by the genes HEXA and HEXB, respectively. The combination of two beta subunits form the enzyme beta-hexosaminidase B (HEX B).

The forms of GM2 gangliosidosis are Tay-Sachs disease (resulting from biallelic pathogenic variants in HEXA), Sandhoff disease (resulting from biallelic pathogenic variants in HEXB), and GM2 activator deficiency (resulting from biallelic variants in GM2A). For hexosaminidase enzyme findings in these disorders, see Table 7.

A representative diagram of the interaction between these proteins can be found in Figure 1 of Cachon-Gonzalez et al [2018].

Table 7.

Hexosaminidase Enzyme Findings in GM2 Gangliosidoses

Disease	HEX A Activity	HEX B Activity	Total HEX Activity	HEX A % Contribution
Tay-Sachs disease	↓	nl	↓	↓
Sandhoff disease	↓	↓	↓	↑
GM2 activator deficiency	Normal	Normal	Normal	Normal

In Tay-Sachs disease total hexosaminidase activity (i.e., HEX A plus HEX B) is decreased, whereas HEX B activity is normal.

In Sandhoff disease both HEX A activity and HEX B activity, as well as total hexosaminidase activity, are decreased; however, the percent contribution from HEX A is increased, because the percent contribution from HEX B is disproportionately decreased by loss of the function of the beta subunit.

In GM2 activator deficiency HEX A and HEX B activity are both normal.

Disease severity in Tay-Sachs and Sandhoff disease is inversely correlated to the residual rate of GM2 ganglioside catabolism. Residual conversion rate of less than 0.5% is thought to correlate with infantile disease, while rates of 2%-4% correlate with juvenile or late-onset forms of Tay-Sachs and Sandhoff disease. Although the pathophysiology of subacute juvenile GM2 activator deficiency is likely also related to residual ganglioside catabolism rates, to date experiments to quantify GM2 conversion rate have not been reported.

Mechanism of disease causation. Loss-of-function GM2A variants cause decreased or absent activity of GM2 activator protein.

Table 8.

Notable GM2A Pathogenic Variants

Reference Sequences	DNA Nucleotide Change	Predicted Protein Change	Comment [Reference]
NM_000405.5 NP_000396.2	c.82-2668_243+3312del6142	p.Pro28_Lys81del	Homozygous exon 2 deletion reported in 1 person to date [Hall et al 2018]
NM_000405.5 NP_000396.2	c.164C>T	p.Pro55Leu	Present in 4 persons w/possible subacute-juvenile GM2 activator deficiency, in homozygous state in 1 family w/3 affected sibs [Salih et al 2015] & in compound heterozygous state in 1 affected person in unrelated family [Martins et al 2017]

: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author Notes

Dr Tifft and Dr Toro are actively involved in clinical research regarding individuals with GM2 activator deficiency. They would be happy to communicate with persons who have any questions regarding diagnosis of GM2 activator deficiency or other considerations.

Dr Tifft, Dr Toro, and Dr Xiao are also interested in hearing from clinicians treating families affected by a GM2 gangliosidosis in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

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 "Natural History of Glycosphingolipid and Glycoprotein Storage Disorders" study at the NIH (NCT00029965) and the long-standing contribution of the National Tay-Sachs and Allied Diseases Association to the support and education of patients and families with GM1 and GM2 gangliosidosis.

Revision History

25 August 2022 (bp) Review posted live
10 June 2022 (cx) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "GM2 Activator Deficiency" is in the public domain in the United States of America.

References

Literature Cited

Brackmann F, Kehrer C, Kustermann W, Böhringer J, Krägeloh-Mann I, Trollmann R. Rare variant of GM2 gangliosidosis through activator-protein deficiency. Neuropediatrics. 2017;48:127-30. [PubMed: 28192816]
Cachon-Gonzalez MB, Zaccariotto E, Cox TM. Genetics and therapies for GM2 gangliosidosis. Curr Gene Ther. 2018;18:68-89. [PMC free article: PMC6040173] [PubMed: 29618308]
Chen B, Rigat B, Curry C, Mahuran DJ. Structure of the GM2A gene: identification of an exon 2 nonsense mutation and a naturally occurring transcript with an in-frame deletion of exon 2. Am J Hum Genet. 1999;65:77-87. [PMC free article: PMC1378077] [PubMed: 10364519]
de Baecque CM, Suzuki K, Rapin I, Johnson AB, Whethers DL. GM2-gangliosidosis, AB variant: clinico-pathological study of a case. Acta Neuropathol. 1975;33:207-26. [PubMed: 174379]
Hall PL, Laine R, Alexander JJ, Ankala A, Teot LA, Lidov HGW, Anselm I. GM2 activator deficiency caused by a homozygous exon 2 deletion in GM2A. JIMD Rep. 2018;38:61-5. [PMC free article: PMC5874204] [PubMed: 28540636]
İnci A, Cengiz Ergin FB, Biberoğlu G, Okur İ, Ezgü FS, Tümer L. Two patients from Turkey with a novel variant in the GM2A gene and review of the literature. J Pediatr Endocrinol Metab. 2021;34:805-12. [PubMed: 33819415]
Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
Kolodny E, Sathe S, Zeng BJ, Torres P, Alroy J, Pastores G. A novel GM2-activator deficiency mutation as a cause of AB variant GM2-gangliosidosis. Mol Genet Metab. 2008;2:27-8.
Linney M, Hain RDW, Wilkinson D, Fortune PM, Barclay S, Larcher V, Fitzgerald J, Arkell E. Achieving consensus advice for paediatricians and other health professionals: on prevention, recognition and management of conflict in paediatric practice. Arch Dis Child. 2019;104:413-6. [PMC free article: PMC6557224] [PubMed: 31000533]
Martins C, Brunel-Guitton C, Lortie A, Gauvin F, Morales CR, Mitchell GA, Pshezhetsky AV. Atypical juvenile presentation of GM2 gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the GM2A gene. Mol Genet Metab Rep. 2017;11:24-9. [PMC free article: PMC5388932] [PubMed: 28417072]
Nestrasil I, Ahmed A, Utz JM, Rudser K, Whitley CB, Jarnes-Utz JR. Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study. Mol Genet Metab. 2018;123:97-104. [PMC free article: PMC5832355] [PubMed: 29352662]
Renaud D, Brodsky M. GM2-gangliosidosis, AB variant: clinical, ophthalmological, MRI, and molecular findings. JIMD Rep. 2016;25:83-6. [PMC free article: PMC5059184] [PubMed: 26082327]
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
Sakuraba H, Itoh K, Shimmoto M, Utsumi K, Kase R, Hashimoto Y, Ozawa T, Ohwada Y, Imataka G, Eguchi M, Furukawa T, Schepers U, Sandhoff K. GM2 gangliosidosis AB variant: clinical and biochemical studies of a Japanese patient. Neurology. 1999;52:372-7. [PubMed: 9932959]
Salih MA, Seidahmed MZ, El Khashab HY, Hamad MH, Bosley TM, Burn S, Myers A, Landsverk ML, Crotwell PL, Bilguvar K, Mane S, Kruer MC. Mutation in GM2A leads to a progressive chorea-dementia syndrome. Tremor Other Hyperkinet Mov (N Y). 2015;5:306. [PMC free article: PMC4502426] [PubMed: 26203402]
Schepers U, Glombitza G, Lemm T, Hoffmann A, Chabas A, Ozand P, Sandhoff K. Molecular analysis of a GM2-activator deficiency in two patients with GM2-gangliosidosis AB variant. Am J Hum Genet. 1996;59:1048-56. [PMC free article: PMC1914821] [PubMed: 8900233]
Schröder M, Schnabel D, Hurwitz R, Young E, Suzuki K, Sandhoff K. Molecular genetics of GM2-gangliosidosis AB variant: a novel mutation and expression in BHK cells. Hum Genet. 1993;92:437-40. [PubMed: 8244332]
Sheth J, Datar C, Mistri M, Bhavsar R, Sheth F, Shah K. GM2 gangliosidosis AB variant: novel mutation from India - a case report with a review. BMC Pediatr. 2016;16:88. [PMC free article: PMC4939586] [PubMed: 27402091]
Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
Xie B, Wang W, Mahuran DJ. A Cys138-to-Arg substitution in the GM2 activator protein is associated with the AB variant form of GM2 gangliosidosis. Am J Hum Genet. 1992;50:1046-52. [PMC free article: PMC1682593] [PubMed: 1570834]

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK583219PMID: 36007105

GeneReviews by Title

< Prev Next >

PubReader
Print View
Cite this Page
Xiao C, Toro C, Tifft C. GM2 Activator Deficiency. 2022 Aug 25. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.
PDF version of this page (497K)
Disable Glossary Links

Bulk Download

Bulk download GeneReviews data from FTP

GeneReviews Links

Tests in GTR by Gene

GM2A

Related information

OMIM
Related OMIM records
PMC
PubMed Central citations
PubMed
Links to PubMed
Gene
Locus Links

Recent Activity

Clear Turn Off Turn On

GM2 Activator Deficiency - GeneReviews®
GM2 Activator Deficiency - GeneReviews®

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Bookshelf

GeneReviews® [Internet].

GM2 Activator Deficiency

Summary

Clinical characteristics.

Diagnosis/testing.

Management.

Genetic counseling.

Diagnosis

Suggestive Findings

Establishing the Diagnosis

Option 1

Option 2

Table 1.

Clinical Characteristics

Clinical Description

Table 2.

Acute Infantile GM2 Activator Deficiency

Possible Subacute Juvenile GM2 Activator Deficiency

Genotype-Phenotype Correlations

Nomenclature

Prevalence

Genetically Related (Allelic) Disorders

Differential Diagnosis

Table 3.

Management

Evaluations Following Initial Diagnosis

Table 4.

Treatment of Manifestations

Table 5.

Surveillance

Table 6.

Agents/Circumstances to Avoid

Evaluation of Relatives at Risk

Therapies Under Investigation

Genetic Counseling

Mode of Inheritance

Risk to Family Members

Carrier Detection

Related Genetic Counseling Issues

Prenatal Testing and Preimplantation Genetic Testing

Resources

Molecular Genetics

Table A.

Table B.

Molecular Pathogenesis

Table 7.

Table 8.

Chapter Notes

Author Notes

Acknowledgments

Revision History

References

Literature Cited

Views

In this GeneReview

Bulk Download

GeneReviews Links

Tests in GTR by Gene

Related information

Similar articles in PubMed

Recent Activity

GeneReviews^® [Internet].