GM2-gangliosidosis, AB variant is a rare,

autosomal recessive In genetics, dominance is the phenomenon of one variant ( allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...

metabolic disorder A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter t ...

that causes progressive destruction of nerve cells in the brain and spinal cord. It has a similar pathology to

Sandhoff disease Sandhoff disease is a lysosomal genetic, lipid storage disorder caused by the inherited deficiency to create functional beta-hexosaminidases A and B. These catabolic enzymes are needed to degrade the neuronal membrane components, ganglioside GM2, ...

and

Tay–Sachs disease Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent around three to six months of age, with the baby ...

. The three diseases are classified together as the GM2 gangliosidoses, because each disease represents a distinct molecular point of failure in the activation of the same enzyme, beta-hexosaminidase. AB variant is caused by a failure in the gene that makes an enzyme cofactor for beta-hexosaminidase, called the GM2 activator.

Symptoms and signs

Signs and symptoms of GM2-gangliosidosis, AB variant are identical with those of infantile

, except that enzyme assay testing shows normal levels of hexosaminidase A. Infantile

has similar symptoms and prognosis, except that there is deficiency of both hexosaminidase A and hexosaminidase B. Infants with this disorder typically appear normal until the age of 3 to 6 months, when development slows and muscles used for movement weaken. Affected infants lose motor skills such as turning over, sitting, and crawling. As the disease progresses, infants develop seizures, vision and hearing loss, mental retardation, and

paralysis Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 5 ...

. An

ophthalmological Ophthalmology ( ) is a surgical subspecialty within medicine that deals with the diagnosis and treatment of eye disorders. An ophthalmologist is a physician who undergoes subspecialty training in medical and surgical eye care. Following a medic ...

abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. This cherry-red spot is the same finding that Warren Tay first reported in 1881, when he identified a case of Tay–Sachs disease, and it has the same etiology. The prognosis for AB variant is the same as for infantile Tay–Sachs disease. Children with AB variant die in infancy or early childhood.

Cause

Mutations in the GM2A gene cause GM2-gangliosidosis, AB variant. This condition is inherited in an

pattern. The GM2A gene provides instructions for making a protein called the GM2 activator. This protein is required for the normal function of beta-hexosaminidase A, a critical enzyme in the nervous system that breaks down a lipid called GM2 ganglioside. If mutations in both

alleles An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chrom ...

at this locus disrupt the activity of the GM2 activator, beta-hexosaminidase A cannot perform its normal function. As a result, gangliosides accumulate in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

until they interfere with normal biological processes. Progressive damage caused by buildup of gangliosides leads to the destruction of nerve cells. GM2-gangliosidosis, AB variant is extremely rare. In contrast with both Tay–Sachs disease and Sandhoff disease, in which many mutant polymorphic

have been discovered, including pseudodeficiency alleles, very few GM2A mutations have been reported. When AB variant is reported, in often occurs with

consanguineous Consanguinity ("blood relation", from Latin '' consanguinitas'') is the characteristic of having a kinship with another person (being descended from a common ancestor). Many jurisdictions have laws prohibiting people who are related by blood fro ...

parents or in genetically isolated populations. GM2A is expressed in many tissues, and the GM2 activator protein has been reported to have other cellular functions. Because AB variant is so rarely diagnosed, it is likely that most mutations of GM2A are fatal at the

embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

nic or fetal stage of development in homozygotes and genetic compounds, and thus are never observed clinically.

Diagnosis

Treatment

History

AB variant was first observed clinically shortly after the biochemical characterization of Tay–Sachs disease in 1969. The disease was initially thought to be caused by variant alleles of the HEXA gene, and Konrad Sandhoff designated it as AB variant in 1971.

Enzyme assay Enzyme assays are laboratory methods for measuring enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibition. Enzyme units The quantity or concentration of an enzyme can be expressed in molar amounts, as with a ...

tests of TSD patients revealed a few unusual

false negative A false positive is an error in binary classification in which a test result incorrectly indicates the presence of a condition (such as a disease when the disease is not present), while a false negative is the opposite error, where the test resul ...

cases, patients who developed the disease, yet had normal enzyme activity. In other cases, parents who had not tested as carriers for TSD had children who nevertheless became ill with the symptoms of classic infantile TSD. It was eventually determined that GM2 gangliosidosis could be caused by mutations on three distinct genes, one of which was an activator protein. Disease caused by a mutation that disables this protein was termed AB variant. In 1992, the GM2A gene itself was localized to

chromosome 5 Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. Ch ...

, and the precise locus was determined the following year.

References

External links

{{Lipid storage disorders Lipid storage disorders Autosomal recessive disorders Rare diseases