Encyclopedia
GM2-gangliosidosis, AB variant is a rare inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord.
- genetic conditions
1. Introduction
Signs and symptoms of the AB variant become apparent in infancy. Infants with this disorder typically appear normal until the age of 3 to 6 months, when their development slows and muscles used for movement weaken. Affected infants lose motor skills such as turning over, sitting, and crawling. They also develop an exaggerated startle reaction to loud noises. As the disease progresses, children with the AB variant experience seizures, vision and hearing loss, intellectual disability, and paralysis. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Children with the AB variant usually live only into early childhood.
2. Frequency
The AB variant is extremely rare; only a few cases have been reported worldwide.
3. Causes
Mutations in the GM2A gene cause GM2-gangliosidosis, AB variant. The GM2A gene provides instructions for making a protein called the GM2 ganglioside activator. This protein is required for the normal function of an enzyme called beta-hexosaminidase A, which plays a critical role in the brain and spinal cord. Beta-hexosaminidase A and the GM2 ganglioside activator protein work together in lysosomes, which are structures in cells that break down toxic substances and act as recycling centers. Within lysosomes, the activator protein binds to a fatty substance called GM2 ganglioside and presents it to beta-hexosaminidase A to be broken down.
Mutations in the GM2A gene disrupt the activity of the GM2 ganglioside activator, which prevents beta-hexosaminidase A from breaking down GM2 ganglioside. As a result, this substance accumulates to toxic levels, particularly in neurons in the brain and spinal cord. Progressive damage caused by the buildup of GM2 ganglioside leads to the destruction of these neurons, which causes the signs and symptoms of the AB variant.
Because the AB variant impairs the function of a lysosomal enzyme and involves the buildup of GM2 ganglioside, this condition is sometimes referred to as a lysosomal storage disorder or a GM2-gangliosidosis.
4. Inheritance
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
5. Other Names for This Condition
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AB variant
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Activator Deficiency/GM2 Gangliosidosis
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Activator-deficient Tay-Sachs disease
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GM2 Activator Deficiency Disease
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GM2 gangliosidosis, type AB
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Hexosaminidase activator deficiency
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Tay-Sachs Disease, AB Variant
This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/gm2-gangliosidosis-ab-variant
References
- Chen B, Rigat B, Curry C, Mahuran DJ. Structure of the GM2A gene:identification of an exon 2 nonsense mutation and a naturally occurringtranscript with an in-frame deletion of exon 2. Am J Hum Genet. 1999Jul;65(1):77-87.
- Mahuran DJ. Biochemical consequences of mutations causing the GM2gangliosidoses. Biochim Biophys Acta. 1999 Oct 8;1455(2-3):105-38. Review.
- Sakuraba H, Itoh K, Shimmoto M, Utsumi K, Kase R, Hashimoto Y, Ozawa T, OhwadaY, Imataka G, Eguchi M, Furukawa T, Schepers U, Sandhoff K. GM2 gangliosidosis ABvariant: clinical and biochemical studies of a Japanese patient. Neurology. 1999 Jan 15;52(2):372-7.
- Schepers U, Glombitza G, Lemm T, Hoffmann A, Chabas A, Ozand P, Sandhoff K.Molecular analysis of a GM2-activator deficiency in two patients withGM2-gangliosidosis AB variant. Am J Hum Genet. 1996 Nov;59(5):1048-56.
