Alternative titles; symbols
SNOMEDCT: 71253000; ORPHA: 309246; DO: 4795;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q33.1 | GM2-gangliosidosis, AB variant | 272750 | Autosomal recessive | 3 | GM2A | 613109 |
A number sign (#) is used with this entry because GM2-gangliosidosis AB variant is caused by homozygous mutation in the GM2A gene (613109) on chromosome 5q33.
The GM2-gangliosidoses are a group of disorders caused by excessive accumulation of ganglioside GM2 and related glycolipids in the lysosomes, mainly of neuronal cells. GM2-gangliosidosis AB variant is characterized by normal hexosaminidase A (HEXA; 606869) and hexosaminidase B (HEXB; 606873) but the inability to form a functional GM2 activator complex. The clinical and biochemical phenotype of the AB variant is very similar to that of classic Tay-Sachs disease (see 272800) (Gravel et al., 2001).
Sandhoff et al. (1971) referred to Sandhoff disease (268800) as variant 0 (since both hexosaminidases A and B are missing) and classic Tay-Sachs disease as variant B (since HEXA is absent but HEXB is present in increased amounts). They studied a single patient with a third form they called variant AB, because both Hex-A and Hex-B are increased in amounts. Sandhoff's patient with the AB variant was studied clinically by Hugo Moser, then of Boston. A brother and sister were affected. In the AB variant, Gm2-ganglioside accumulates as in the other 2 forms despite the presence of both HEXA and HEXB. The patients were French Canadian (Phillips, 1983).
De Baecque et al. (1975) reported a black female infant with the AB variant of GM2-gangliosidosis. She had normal early development, but showed loss of developmental skills beginning around 9 months of age. At age 12 months, she presented with a prolonged generalized seizure, and was found to have increased startle to sound, hypotonia, and cherry-red macular spots. By age 14 months, she could no longer sit or roll over. Brain biopsy showed neurons and astrocytes with cytoplasmic membranous inclusions of storage material, and HEXA and HEXB were normal.
Chen et al. (1999) reported a new patient with deficiency of the GM2 activator protein. No consanguinity was identified in the family, but the patient was derived from a geographically isolated, small Laotian hill tribe. The child was thought to be normal until the age of approximately 5 months when he was noted to have delayed motor milestones and increasing weakness. At age 9 months, magnetic resonance imaging showed increased signal density in the periventricular white matter and altered signal density in the basal ganglia. Ophthalmologic evaluation showed bilateral macular cherry red spots. At age 2.5 years, he was evaluated for his neurodegenerative course. The patient was experiencing approximately 3 major motor seizures and hundreds of myoclonic jerks per day. Hyperacusis was extreme, with an exaggerated startle response. Physical examination showed a nondysmorphic, profoundly hypotonic child, who was unresponsive to his environment. Despite normal Hex-A levels in lymphocytes, the clinical diagnosis strongly suggested Tay-Sachs disease.
Sakuraba et al. (1999) described complete absence of the GM2 activator protein by Western blot analysis and metabolic studies in a Japanese patient with a progressive neurologic disorder that began with muscular weakness and hypotonia at 1 month of age. The patient later developed a startle reaction, severe psychomotor retardation, and myoclonic seizures. Northern blot analysis demonstrated normal levels of mRNA of the appropriate size, and no mutations were detected in the protein coding region of the GM2 activator gene. The authors speculated that there may be other factors affecting the activity or stability of the GM2 activator.
Clinical Variability
Salih et al. (2015) reported 3 patients from a highly consanguineous Saudi family with childhood onset of a neurodegenerative disorder. The patients developed normally until 7 or 8 years of age, at which time they showed some abnormal behavior, including increased anxiety and phobias. Thereafter, all showed loss of developmental skills, including speech, cognition, and motor function. They developed spastic quadriparesis, limb dystonia, pyramidal signs, and generalized chorea. The hyperkinetic disorder gradually gave way to a rigid akinetic state, and all patients lost independent ambulation in the teenage years. Brain imaging showed cortical atrophy; biopsies were not reported. None of the patients had hyperacusis or cherry-red macular spots. Exome sequencing identified a homozygous mutation in the GM2A gene (P55L; 613109.0006). Functional studies of the variant and studies of patient cells were not performed. Salih et al. (2015) noted that the phenotype in this family was milder than that usually observed in patients with this disorder, thus expanding the phenotypic spectrum associated with GM2A mutations.
The transmission pattern of the AB variant of GM2-gangliosidosis in the family reported by Salih et al. (2015) was consistent with autosomal recessive inheritance.
Conzelmann and Sandhoff (1978) showed that an activating factor necessary for the degradation of GM2-ganglioside by HEXA is defective in the AB variant. This activating factor is necessary for the interaction of lipid substrates and the water-soluble hydrolase. The factor is normal in Tay-Sachs and Sandhoff diseases.
In cultured fibroblasts derived from a black female infant, born of unrelated parents, with immunologically proven GM2 activator protein deficiency, Schroder et al. (1991) and Xie et al. (1992) identified a homozygous missense mutation in the GM2A gene (C138R; 613109.0001). The patient was originally reported by de Baecque et al. (1975).
By RT-PCR of the GM2A gene in a patient with deficiency of GM2-activator protein, Chen et al. (1999) detected some normal-sized cDNA and a smaller cDNA species, which was not seen in the RT-PCR products from normal controls. Sequencing revealed that although the patient's normal-sized cDNA contained a single nonsense mutation in exon 2, his smaller cDNA was the result of an in-frame deletion of exon 2. Long PCR was used to amplify introns 1 and 2 from the patient and normal genomic DNA, and no differences in size, in 5-prime and 3-prime end sequences, or in restriction-mapping patterns were observed. From these data, Chen et al. (1999) developed a set of 4 PCR primers that could be used to identify GM2A mutations. With this procedure, they demonstrated that the patient was probably homozygous for a nonsense mutation, glu54 to ter (613109.0005). Chen et al. (1999) pointed to the work of Dietz et al. (1993) and of others, indicating that shortened reading frames (i.e., early stop codons) can lead not only to mRNA instability, but also to the in-frame skipping of the constitutive exon in which the mutation is found. They also noted that Valentine and Heflich (1997), from a study of the association of nonsense mutations with exon skipping in hprt mRNA of Chinese hamster ovary cells, concluded that the association was the result of an RT-PCR artifact. Chen et al. (1999) interpreted their results as supporting the conclusion of Valentine and Heflich (1997).
Liu et al. (1997) generated mice with a disrupted Gm2a gene as a model; knockout mouse models for Tay-Sachs and Sandhoff disease had previously been studied. Mice with disruption of the Hexa gene (the Tay-Sachs disease model) were asymptomatic, whereas those with absence of Hexb (the Sandhoff disease model) were severely affected. The mice with disruption of Gm2a demonstrated neuronal storage, but only in restricted regions of the brain, reminiscent of the asymptomatic Tay-Sachs model mice. However, unlike the Tay-Sachs mice, the Gm2a -/- mice displayed significant storage in the cerebellum and defects in balance and coordination. The abnormal ganglioside storage in these mice consisted of GM2 with a low amount of GA2. Their results demonstrated that the activator protein is required for GM2 degradation and also may indicate a role for GM2 activator in GA2 degradation.
O'Neill et al. (1978) described a 22-year-old non-Jewish female who, although slow in school, had no recognized neurologic abnormality until age 18 when seizures began. They considered this an adult-onset form of the AB variant of GM2-gangliosidosis. However, Gravel et al. (2001) concluded that this was most likely not a case of the AB variant because the brain gangliosides showed only minor relative increases of monosialogangliosides, a highly nonspecific finding seen in many neurodegenerative disorders, and because no evidence of impaired GM2 ganglioside degradation was provided.
Chen, B., Rigat, B., Curry, C., Mahuran, D. J. 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. 65: 77-87, 1999. [PubMed: 10364519] [Full Text: https://doi.org/10.1086/302463]
Conzelmann, E., Sandhoff, K. AB variant of infantile Gm2-gangliosidosis: deficiency of a factor necessary for stimulation of hexosaminidase A-catalyzed degradation of ganglioside Gm2 and glycolipid Ga2. Proc. Nat. Acad. Sci. 75: 3979-3983, 1978. [PubMed: 99746] [Full Text: https://doi.org/10.1073/pnas.75.8.3979]
de Baecque, C. M., Suzuki, K., Rapin, I., Johnson, A. B., Whethers, D. L., Suzuki, K. GM2-gangliosidosis, AB variant: clinico-pathological study of a case. Acta Neuropath. (Berlin) 33: 207-226, 1975.
Dietz, H. C., Valle, D., Francomano, C. A., Kendzior, R. J., Jr., Pyeritz, R. E., Cutting, G. R. The skipping of constitutive exons in vivo induced by nonsense mutations. Science 259: 680-683, 1993. [PubMed: 8430317] [Full Text: https://doi.org/10.1126/science.8430317]
Gravel, R. A., Kaback, M. M., Proia, R. L., Sandhoff, K., Suzuki, K., Suzuki, K. The GM2 gangliosidoses. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. III (8th ed.) New York: McGraw-Hill (pub.) 2001.
Hechtman, P., Gordon, B. A., Ng Ying Kin, N. M. K. Deficiency of the hexosaminidase A activator protein in a case of GM2 gangliosidosis; variant AB. Pediat. Res. 16: 217-222, 1982. [PubMed: 6801612] [Full Text: https://doi.org/10.1203/00006450-198203000-00011]
Liu, Y., Hoffmann, A., Grinberg, A., Westphal, H., McDonald, M. P., Miller, K. M., Crawley, J. N., Sandhoff, K., Suzuki, K., Proia, R. L. Mouse model of GM2 activator deficiency manifests cerebellar pathology and motor impairment. Proc. Nat. Acad. Sci. 94: 8138-8143, 1997. [PubMed: 9223328] [Full Text: https://doi.org/10.1073/pnas.94.15.8138]
O'Neill, B., Butler, A. B., Young, E., Falk, P. M., Bass, N. H. Adult-onset Gm2-gangliosidosis: seizures, dementia, and normal pressure hydrocephalus associated with glycolipid storage in the brain and arachnoid granulation. Neurology 28: 1117-1123, 1978. [PubMed: 568730] [Full Text: https://doi.org/10.1212/wnl.28.11.1117]
Phillips, J. A., III. Personal Communication. Baltimore, Md. 8/11/1983.
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 52: 372-377, 1999. [PubMed: 9932959] [Full Text: https://doi.org/10.1212/wnl.52.2.372]
Salih, M. A., Seidahmed, M. Z., El Khashab, H. Y., Hamad, M. H. A., Bosley, T. M., Burn, S., Myers, A., Landsverk, M. L., Crotwell, P. L., Bilguvar, K., Mane, S., Kruer, M. C. Mutation in GM2A leads to a progressive chorea-dementia syndrome. Tremor Other Hyperkinet. Mov. (N.Y.) 5: 306, 2015. Note: Electronic Article. [PubMed: 26203402] [Full Text: https://doi.org/10.7916/D8D21WQ0]
Sandhoff, K., Harzer, K., Wassle, W., Jatzkewitz, H. Enzyme alterations and lipid storage in three variants of Tay-Sachs disease. J. Neurochem. 18: 2469-2489, 1971. [PubMed: 5135907] [Full Text: https://doi.org/10.1111/j.1471-4159.1971.tb00204.x]
Schroder, M., Schnabel, D., Suzuki, K., Sandhoff, K. A mutation in the gene of a glycolipid-binding protein (GM2 activator) that causes GM2-gangliosidosis variant AB. FEBS Lett. 290: 1-3, 1991. [PubMed: 1915858] [Full Text: https://doi.org/10.1016/0014-5793(91)81211-p]
Valentine, C. R., Heflich, R. H. The association of nonsense mutations with exon-skipping in hprt mRNA of Chinese hamster ovary cells results from an artifact of RT-PCR. RNA 3: 660-676, 1997. [PubMed: 9174100]
Xie, B., Wang, W., Mahuran, D. J. A cys138-to-arg substitution in the G-M2 activator protein is associated with the AB variant form of G-M2 gangliosidosis. Am. J. Hum. Genet. 50: 1046-1052, 1992. [PubMed: 1570834]