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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Tay–Sachs disease may be caused by either: HEXA gene mutations which lead to a decrease activity of hexosaminidase A, orGM2 activator gene mutation (GM2A); this encodes for the hexosaminidase A cofactor.
Neurology and neurosurgery
Published in Jagdish M. Gupta, John Beveridge, MCQs in Paediatrics, 2020
Jagdish M. Gupta, John Beveridge
12.27. Which of the following statements is/are true of degenerative brain diseases?The infant is usually norma! at birth.Most of them are autosomal recessive.Tay Sachs disease carriers can be identified.Subacute sclerosing panencephalitis is caused by the mumps virus.Prenatal diagnosis of metachromatic leukodystrophy is possible.
Tay-Sachs disease/hexosaminidase A deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Tay-Sachs disease is transmitted as an autosomal recessive disease. The gene frequency in Ashkenazi Jews has been calculated to be approximately one in 30 [6]. This would predict an annual incidence of one in 4000 births with Tay-Sachs disease among parents from this population. These frequencies were so high that it became practical to undertake programs of prevention through heterozygote detection. Gene frequency in non-Jews has been calculated to be one in 300 [6]. The disease is also common in some isolates in Switzerland [34] and in French descendants in Eastern Quebec and Southern Louisiana [35].
From Community-Based Carrier Programs to Opportunistic Carrier Screening: How the Objective of Carrier Screening Was Lost in Translation
Published in The American Journal of Bioethics, 2023
The first carrier screening programs were built as public health interventions. Carrier screening started in the 1970s as structured population-based carrier screening programs (Kaback 2000). Their success was influenced by consideration of cultural and social issues, emphasizing the importance of education and community support (Laberge et al. 2010). The prototypical successful carrier screening program is Tay-Sachs disease (TSD) carrier screening in Ashkenazi Jewish (AJ) communities (Kaback 2000). TSD screening programs were developed in collaboration with Ashkenazi Jewish communities, included strong educational and counseling components, and adapted screening strategies to the needs of the target population. Although all AJ communities were considered at risk, different screening strategies were developed based on their different realities and needs. For example, in orthodox Jewish communities where arranged marriages were the norm, screening was done before marriage to enable matchmakers to avoid matching TSD carriers (Kaback 2000). In Montreal, screening was done in high schools to ensure maximal uptake of screening in the target population and identification of carriers before reproduction to help them make informed choices (Mitchell et al. 1996). Carrier screening for TSD was found to be so successful that a number of other diseases have been added to the Ashkenazi Jewish screening panel over the years. Similar success was seen for beta-thalassemia screening in Mediterranean communities, such as Cyprus, with strong involvement of the community (Cao et al. 2002).
UK guidelines for the medical and laboratory procurement and use of sperm, oocyte and embryo donors (2019)
Published in Human Fertility, 2021
Helen Clarke, Shona Harrison, Marta Jansa Perez, Jackson Kirkman-Brown
Furthermore, the potential donor should ordinarily not be heterozygous for an autosomal recessive gene known to be prevalent in the donor’s ethnic background. This includes: (i) cystic fibrosis in Caucasian populations; (ii) glucose-6-phosphate dehydrogenase deficiency or ∝0 or β-Thalassaemia in Mediterranean populations; (iii) sickle cell disease in African & Afro-Caribbean populations; and (iv) Tay-Sachs disease in Jews of Eastern European descent. However, in exceptional circumstances (e.g. in cases of known donation) the presence of a recessive gene disorder may not necessarily be a contraindication to donation provided that, when the donation is used, all parties are fully informed, the view of an appropriately qualified clinical geneticist is obtained and full records are kept. The decision whether or not to proceed should consider the type of treatment being offered as well as the genetic profile of the donor and recipient couple.
sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Manuel González-Cuesta, Irene Herrera-González, M. Isabel García-Moreno, Roger A. Ashmus, David J. Vocadlo, José M. García Fernández, Eiji Nanba, Katsumi Higaki, Carmen Ortiz Mellet
N-Acetyl-β-hexosaminidase (Hex; EC 3.2.1.52) is a member of the glycosyl hydrolase family 20 (GH20) that catalyses the removal of terminal, non-reducing N-acetyl-β-d-glucosamine (GlcNAc) or galactosamine (GalNAc) residues from gangliosides, glycoproteins or glycosaminoglycans1. In humans two Hex isoforms are readily detectable, namely HexA and HexB. The first one is a heterodimer formed by α and β subunits, encoded respectively by the evolutionary related HEXA and HEXB genes, whereas the second one is the ββ homodimer2. The thermodynamically less stable αα homodimer (HexS) is also formed, but only reaches measurable levels when the β subunit is deficient. Although the α and β subunits possess independent active sites, dimerisation is a prerequisite for their in vivo biological function. Exclusively the α-subunit of HexA can hydrolyse the GM2 ganglioside (GM2), an intermediate in the biosynthesis and degradation of higher brain gangliosides, in lysosomes by specifically interacting with the GM2 activator protein (GM2AP) co-factor3. Disabling mutations in HEXA, HEXB or the gene encoding for GM2AP results in Tay-Sachs disease (TSD; OMIM #272800), Sandhoff disease (SD; OMIM #268800) or the less common AB variant (OMIM #272750), respectively, a subset of lysosomal storage disorders (LSDs) collectively referred to as GM2 gangliosidosis4. All the three are autosomal recessive conditions associated with phenotypic neurodegeneration and devastating consequences. Currently, there are no effective treatment options for any of these diseases5.