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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 the age of three to six months of age, with the baby losing the ability to turn over, sit, or crawl. This is then followed by seizures, hearing loss, and inability to move, with death usually occurring by the age of three to five. Less commonly, the disease may occur later in childhood, adolescence, or adulthood. These forms tend to be less severe, but the juvenile form typically results in death by age 15.
Gaucher's disease or Gaucher disease (GD) is a genetic disorder in which glucocerebroside accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase, which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages. Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.
Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.
Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or due to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic disorders. To this concept it's possible to include the new term of Enzymopathy. This term was created following the study of Biodynamic Enzymology, a science based on the study of the enzymes and their derivated products. Finally, inborn errors of metabolism were studied for the first time by British physician Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism, was published in 1923.
Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys.
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, its derivative GA2, the glycolipid globoside in visceral tissues, and some oligosaccharides. Accumulation of these metabolites leads to a progressive destruction of the central nervous system and eventually to death. The rare autosomal recessive neurodegenerative disorder is clinically almost indistinguishable from Tay–Sachs disease, another genetic disorder that disrupts beta-hexosaminidases A and S. There are three subsets of Sandhoff disease based on when first symptoms appear: classic infantile, juvenile and adult late onset.
GM2-gangliosidosis, AB variant is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord. It has a similar pathology to Sandhoff disease and Tay–Sachs disease. 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.
A lipid storage disorder is any one of a group of inherited metabolic disorders in which harmful amounts of fats or lipids accumulate in some body cells and tissues. People with these disorders either do not produce enough of one of the enzymes needed to metabolize and break down lipids or, they produce enzymes that do not work properly. Over time, the buildup of fats may cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system, liver, spleen, and bone marrow.
Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.
Roscoe Owen Brady was an American biochemist.
Sphingolipidoses are a class of lipid storage disorders or degenerative storage disorders caused by deficiency of an enzyme that is required for the catabolism of lipids that contain ceramide, also relating to sphingolipid metabolism. The main members of this group are Niemann–Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay–Sachs disease and metachromatic leukodystrophy. They are generally inherited in an autosomal recessive fashion, but notably Fabry disease is X-linked recessive. Taken together, sphingolipidoses have an incidence of approximately 1 in 10,000, but substantially more in certain populations such as Ashkenazi Jews. Enzyme replacement therapy is available to treat mainly Fabry disease and Gaucher disease, and people with these types of sphingolipidoses may live well into adulthood. The other types are generally fatal by age 1 to 5 years for infantile forms, but progression may be mild for juvenile- or adult-onset forms.
The GM2 gangliosidoses are a group of three related genetic disorders that result from a deficiency of the enzyme beta-hexosaminidase. This enzyme catalyzes the biodegradation of fatty acid derivatives known as gangliosides. The diseases are better known by their individual names: Tay–Sachs disease, AB variant, and Sandhoff disease.
Hexosaminidase is an enzyme involved in the hydrolysis of terminal N-acetyl-D-hexosamine residues in N-acetyl-β-D-hexosaminides.
Beta-hexosaminidase subunit beta is an enzyme that in humans is encoded by the HEXB gene.
Miglustat, sold under the brand name Zavesca among others, is a medication used to treat type I Gaucher disease and Pompe disease.
GM2 ganglioside activator also known as GM2A is a protein which in humans is encoded by the GM2A gene.
Hexosaminidase A (alpha polypeptide), also known as HEXA, is an enzyme that in humans is encoded by the HEXA gene, located on the 15th chromosome.
The history of Tay–Sachs disease started with the development and acceptance of the evolution theory of disease in the 1860s and 1870s, the possibility that science could explain and even prevent or cure illness prompted medical doctors to undertake more precise description and diagnosis of disease. Waren Tay and Bernard Sachs, two physicians of the late 19th century described the progression of the disease precisely and provided differential diagnostic criteria to distinguish it from other neurological disorders with similar symptoms.
Frances Mary Platt is a British biochemist and pharmacologist who is a professor at the University of Oxford. Her research investigates rare genetic disorders known as lysosomal storage diseases, progressive conditions that lead to neurodegeneration. She was elected Fellow of the Royal Society in 2021.
James Alan Shayman is an American physician scientist, nephrologist, and pharmacologist. He is Professor of Internal Medicine and Pharmacology and the Agnes C. And Frank D. McKay Professor at the Medical School of the University of Michigan. He also serves as a staff nephrologist at the Ann Arbor Veterans Administration Medical Center.
References
- ↑ Platt FM, Neises GR, Reinkensmeier G, et al. (1997). "Prevention of lysosomal storage in Tay–Sachs mice treated with N-butyldeoxynojirimycin". Science. American Academy for the Advancement of Sciences. 276 (5311): 428–431. doi:10.1126/science.276.5311.428. PMID 9103204.
- ↑ Lachmann RH, Platt FM (2001). "Substrate reduction therapy for glycosphingolipid storage disorders". Expert Opinion on Investigational Drugs. Expert Opinion Investigational Drugs. 10 (3): 455–66. doi:10.1517/13543784.10.3.455. PMID 11227045. S2CID 5625586.
- ↑ Igdoura SA, Mertineit C, Trasler JM, Gravel RA (1999). "Sialidase-mediated depletion of GM2 ganglioside in Tay–Sachs neuroglia cells". Human Molecular Genetics. Oxford University Press. 8 (6): 1111–1116. doi: 10.1093/hmg/8.6.1111 . PMID 10332044.
- ↑ Kolodny EH, Neudorfer O, Gianutsos J, et al. (2004). "Late-onset Tay–Sachs disease: natural history and treatment with OGT 918 (Zavesca[TM])". Journal of Neurochemistry. 90 (S1): 54. doi: 10.1111/j.1471-4159.2004.02650_.x . ISSN 0022-3042.
- ↑ Rossum AV, Holsopple M (1999). "Enzyme Replacement or Substrate Reduction? A Review of Gaucher Disease Treatment Options". Hospital Pharmacy. Oxford University Press. 51 (7): 553–563. doi: 10.1310/hpj5107-553 . PMC 4981103 . PMID 27559188.