GM2 gangliosidosis
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The GM2 gangliosidoses are a group of three related genetic disorders that result from a deficiency of the enzyme beta-hexosaminidase. This
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
catalyzes the
biodegradation Biodegradation is the breakdown of organic matter by microorganisms, such as bacteria and fungi. It is generally assumed to be a natural process, which differentiates it from composting. Composting is a human-driven process in which biodegrada ...
of fatty acid derivatives known as
gangliosides A ganglioside is a molecule composed of a glycosphingolipid (ceramide and oligosaccharide) with one or more sialic acids (e.g. ''N''-acetylneuraminic acid, NANA) linked on the sugar chain. NeuNAc, an acetylated derivative of the carbohydrate sial ...
. The diseases are better known by their individual names:
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 ...
, AB variant, and Sandhoff disease. Beta-hexosaminidase is a vital hydrolytic enzyme, found in the
lysosomes A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prote ...
, that breaks down lipids. When beta-hexosaminidase is no longer functioning properly, the lipids accumulate in the nervous tissue of the brain and cause problems. Gangliosides are made and biodegraded rapidly in early life as the brain develops. Except in some rare, late-onset forms, the GM2 gangliosidoses are fatal. All three disorders are rare in the general population. Tay–Sachs disease has become famous as a public health model because an
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 ...
test for TSD was discovered and developed in the late 1960s and early 1970s, providing one of the first "mass screening" tools in medical genetics. It became a research and public health model for understanding and preventing all autosomal genetic disorders. Tay–Sachs disease, AB variant, and Sandhoff disease might easily have been defined together as a single disease, because the three disorders are associated with failure of the same
metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
and have the same outcome. Classification and naming for many genetic disorders reflects history, because most diseases were first observed and classified based on
biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
and pathophysiology before genetic diagnosis was available. However, the three GM2 gangliosidoses were discovered and named separately. Each represents a distinct molecular point of failure in a subunit that is required for activation of the enzyme.


Tay–Sachs disease

Tay–Sachs disease is a rare autosomal recessive genetic disorder that causes a progressive deterioration of nerve cells and of mental and physical abilities that begins around six months of age and usually results in death by the age of four. It is the most common of the GM2 gangliosidoses. The disease occurs when harmful quantities of cell membrane gangliosides accumulate in the brain's nerve cells, eventually leading to the premature death of the cells.


Sandhoff disease

Sandhoff disease is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord. The disease results from mutations on chromosome 5 in the HEXB gene, critical for the lysosomal enzymes beta-N-acetylhexosaminidase A and B. Sandhoff disease is clinically indistinguishable from Tay–Sachs disease. The most common form, infantile Sandhoff disease, is usually fatal by early childhood.


AB variant

GM2-gangliosidosis, AB variant is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord. Mutations in the GM2A gene cause AB variant. The GM2A gene provides instructions for making a protein called the GM2 activator. This protein is a cofactor that is required for the normal function of beta-hexosaminidase A. The disease is usually fatal by early childhood.


Treatment

There are no authorized therapies for the treatment of the GM2 Gangliosidosis (Tay-Sachs and Sandhoff disease). The current standard of care for GM2 Gangliosidosis disease is limited to supportive care and aimed at providing adequate nutrition and hydration. This supportive care may substantially improve the quality of life of people affected by GM2. The therapeutic team may include specialists in
neurology Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal ...
, pulmonology,
gastroenterology Gastroenterology (from the Greek gastḗr- “belly”, -énteron “intestine”, and -logía "study of") is the branch of medicine focused on the digestive system and its disorders. The digestive system consists of the gastrointestinal tract ...
, psychiatrist,
orthopaedics Orthopedic surgery or orthopedics ( alternatively spelt orthopaedics), is the branch of surgery concerned with conditions involving the musculoskeletal system. Orthopedic surgeons use both surgical and nonsurgical means to treat musculoskeletal ...
,
nutrition Nutrition is the biochemical and physiological process by which an organism uses food to support its life. It provides organisms with nutrients, which can be metabolized to create energy and chemical structures. Failure to obtain sufficient ...
, physical therapy and occupational therapy.


N-Acetyl-Leucine

N-Acetyl-Leucine is an orally administered, modified amino acid that is being developed as a novel treatment for multiple rare and common neurological disorders by IntraBio Inc (Oxford, United Kingdom). N-Acetyl-Leucine has been granted multiple orphan drug designations from the U.S. Food & Drug Administration (FDA) and the European Medicines Agency (EMA) and the European Medicines Agency (EMA) for the treatment of a various genetic diseases, including GM2 Gangliosidosis (Tay-Sachs and Sandhoff). The US FDA has granted IntraBio a Rare Pediatric Disease Designation for N-Acetyl-Leucine for the treatment of GM2 Gangliosidosis. Compassionate use studies in both Tay-Sachs and Sandhoff patients have demonstrated the positive clinical effects of treatment with N-Acetyl-Leucine for GM2 Gangliosidosis  These studies further demonstrated that the treatment is well tolerated, with a good safety profile. A multinational clinical trial investigating N-Acetyl-L-Leucine for the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff) began in 2019 Recruitment is ongoing.  IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of Niemann-Pick disease type C and Ataxia-Telangiectasia. Future opportunities to develop N-Acetyl-Leucine include
Lewy body dementia Lewy body dementias are two similar and common subtypes of dementia—dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Both are characterized by changes in thinking, movement, behavior, and mood. The two conditions have si ...
, amyotrophic lateral sclerosis,
restless leg syndrome Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This ...
, multiple sclerosis, and migraine.


See also

* GM2 (ganglioside)


References


External links


GeneReview/NIH/UW entry on Hexosaminidase A Deficiency
{{DEFAULTSORT:Gm2 Gangliosidoses Autosomal recessive disorders Rare diseases Ashkenazi Jews topics Lipid storage disorders