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Tay sachs

Devin Dersh, Yuichiro Iwamoto, Yair Argon
Loss of function of the enzyme β-hexosaminidase A (HexA) causes the lysosomal storage disorder Tay Sachs disease (TSD). It has been proposed that mutations in the α chain of HexA can impair folding, enzyme assembly, and/or trafficking, yet there is surprisingly little known about the mechanisms of these potential routes of pathogenesis. We therefore investigated the biosynthesis and trafficking of TSD-associated HexA α mutants, seeking to identify relevant cellular quality control mechanisms. α mutants E482K and G269S are defective in enzymatic activity, unprocessed by lysosomal proteases, and exhibit altered folding pathways compared to WT α...
September 28, 2016: Molecular Biology of the Cell
Rodolfo Gonzalez, Milton H Hamblin, Jean-Pyo Lee
In neurological disorders, pathological lesions in the central nervous system (CNS) may be globally dispersed throughout the brain or localized to specific regions. Although native neural stem cells (NSCs) are present in the adult mammalian brain, intrinsic self-repair of injured adult CNS tissue is inadequate or ineffective. The brain's poor regenerative ability may be due to the fact that NSCs are restricted to discrete locations, are few in number, or are surrounded by a microenvironment that does not support neuronal differentiation...
August 15, 2016: CNS & Neurological Disorders Drug Targets
Cheryl A Lawson, Douglas R Martin
GM2 gangliosidosis, a subset of lysosomal storage disorders, is caused by a deficiency of the glycohydrolase, β-N-acetylhexosaminidase, and includes the closely related Tay-Sachs and Sandhoff diseases. The enzyme deficiency prevents the normal, stepwise degradation of ganglioside, which accumulates unchecked within the cellular lysosome, particularly in neurons. As a result, individuals with GM2 gangliosidosis experience progressive neurological diseases including motor deficits, progressive weakness and hypotonia, decreased responsiveness, vision deterioration, and seizures...
2016: Application of Clinical Genetics
Gheona Altarescu
Abstract During the last two decades prenatal genetic screening and diagnosis has become the cornerstone of medical care for family planning to prevent genetic disease. Carrier screening programs for genetic disorders that are prevalent in various populations identify couples and pregnancies at risk of having an affected child. These couples can proceed with a choice of invasive prenatal diagnosis tests of the fetus (chorionic villous sampling and amniocentesis), or non-invasive prenatal testing of free fetal DNA circulation in the maternal blood which has emerged within the last few years and is currently available for fetal sexing for X Linked disorders...
June 2016: Pediatric Endocrinology Reviews: PER
Jayesh Sheth, Chaitanya Datar, Mehul Mistri, Riddhi Bhavsar, Frenny Sheth, Krati Shah
BACKGROUND: GM2 gangliosidosis-AB variants a rare autosomal recessive neurodegenerative disorder occurring due to deficiency of GM2 activator protein resulting from the mutation in GM2A gene. Only seven mutations in nine cases have been reported from different population except India. CASE PRESENTATION: Present case is a one year old male born to 3rd degree consanguineous Indian parents from Maharashtra. He was presented with global developmental delay, hypotonia and sensitive to hyperacusis...
2016: BMC Pediatrics
Nikita Mehta, Gabriel A Lazarin, Erica Spiegel, Kathleen Berentsen, Kelly Brennan, Jessica Giordano, Imran S Haque, Ronald Wapner
BACKGROUND AND AIMS: Carrier screening for Tay-Sachs disease is performed by sequence analysis of the HEXA gene and/or hexosaminidase A enzymatic activity testing. Enzymatic analysis (EA) has been suggested as the optimal carrier screening method, especially in non-Ashkenazi Jewish (non-AJ) individuals, but its utilization and efficacy have not been fully evaluated in the general population. This study assesses the reliability of EA in comparison with HEXA sequence analysis in non-AJ populations...
September 2016: Genetic Testing and Molecular Biomarkers
A E H Emery
In certain autosomal recessive disorders there is suggestive evidence that heterozygous carriers may have some selective advantage over normal homozygotes. These include, for example, cystic fibrosis, Tay-Sachs disease and phenylketonuria. The best example so far, however, is that of significant heterozygous advantage in sickle-cell anaemia with increased resistance to falciparum malaria.
June 2016: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
Karlaina J L Osmon, Evan Woodley, Patrick Thompson, Katalina Ong, Subha Karumuthil-Melethil, John G Keimel, Brian L Mark, Don Mahuran, Steven J Gray, Jagdeep S Walia
GM2 gangliosidosis is a group of neurodegenerative diseases caused by β-hexosaminidase A (HexA) enzyme deficiency. There is currently no cure. HexA is composed of two similar, nonidentical subunits, α and β, which must interact with the GM2 activator protein (GM2AP), a substrate-specific cofactor, to hydrolyze GM2 ganglioside. Mutations in either subunit or the activator can result in the accumulation of GM2 ganglioside within neurons throughout the central nervous system. The resulting neuronal cell death induces the primary symptoms of the disease: motor impairment, seizures, and sensory impairments...
July 2016: Human Gene Therapy
Subha Karumuthil-Melethil, Sahana Nagabhushan Kalburgi, Patrick Thompson, Michael Tropak, Michael D Kaytor, John G Keimel, Brian L Mark, Don Mahuran, Jagdeep S Walia, Steven J Gray
GM2 gangliosidosis is a family of three genetic neurodegenerative disorders caused by the accumulation of GM2 ganglioside (GM2) in neuronal tissue. Two of these are due to the deficiency of the heterodimeric (α-β), "A" isoenzyme of lysosomal β-hexosaminidase (HexA). Mutations in the α-subunit (encoded by HEXA) lead to Tay-Sachs disease (TSD), whereas mutations in the β-subunit (encoded by HEXB) lead to Sandhoff disease (SD). The third form results from a deficiency of the GM2 activator protein (GM2AP), a substrate-specific cofactor for HexA...
July 2016: Human Gene Therapy
Aishwarya Arjunan, Karen Litwack, Nick Collins, Joel Charrow
PURPOSE: The Center for Jewish Genetics provides genetic education and carrier screening to individuals of Jewish descent. Carrier screening has traditionally been performed by targeted mutation analysis for founder mutations with an enzyme assay for Tay-Sachs carrier detection. The development of next-generation sequencing (NGS) allows for higher detection rates regardless of ethnicity. Here, we explore differences in carrier detection rates between genotyping and NGS in a primarily Jewish population...
April 7, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Katharina Marie Steiner, Johannes Brenck, Sophia Goericke, Dagmar Timmann
No abstract text is available yet for this article.
2016: BMJ Case Reports
Keisuke Kitakaze, Yasumichi Mizutani, Eiji Sugiyama, Chikako Tasaki, Daisuke Tsuji, Nobuo Maita, Takatsugu Hirokawa, Daisuke Asanuma, Mako Kamiya, Kohei Sato, Mitsutoshi Setou, Yasuteru Urano, Tadayasu Togawa, Akira Otaka, Hitoshi Sakuraba, Kohji Itoh
GM2 gangliosidoses, including Tay-Sachs and Sandhoff diseases, are neurodegenerative lysosomal storage diseases that are caused by deficiency of β-hexosaminidase A, which comprises an αβ heterodimer. There are no effective treatments for these diseases; however, various strategies aimed at restoring β-hexosaminidase A have been explored. Here, we produced a modified human hexosaminidase subunit β (HexB), which we have termed mod2B, composed of homodimeric β subunits that contain amino acid sequences from the α subunit that confer GM2 ganglioside-degrading activity and protease resistance...
May 2, 2016: Journal of Clinical Investigation
Jyotsna Verma, Divya C Thomas, David C Kasper, Sandeepika Sharma, Ratna D Puri, Sunita Bijarnia-Mahay, Pramod K Mistry, Ishwar C Verma
High consanguinity rates, poor access to accurate diagnostic tests, and costly therapies are the main causes of increased burden of lysosomal storage disorders (LSDs) in developing countries. Therefore, there is a major unmet need for accurate and economical diagnostic tests to facilitate diagnosis and consideration of therapies before irreversible complications occur. In cross-country study, we utilized dried blood spots (DBS) of 1,033 patients clinically suspected to harbor LSDs for enzymatic diagnosis using modified fluorometric assays from March 2013 through May 2015...
March 24, 2016: JIMD Reports
Michael B Tropak, Sayuri Yonekawa, Subha Karumuthil-Melethil, Patrick Thompson, Warren Wakarchuk, Steven J Gray, Jagdeep S Walia, Brian L Mark, Don Mahuran
Tay-Sachs or Sandhoff disease result from mutations in either the evolutionarily related HEXA or HEXB genes encoding respectively, the α- or β-subunits of β-hexosaminidase A (HexA). Of the three Hex isozymes, only HexA can interact with its cofactor, the GM2 activator protein (GM2AP), and hydrolyze GM2 ganglioside. A major impediment to establishing gene or enzyme replacement therapy based on HexA is the need to synthesize both subunits. Thus, we combined the critical features of both α- and β-subunits into a single hybrid µ-subunit that contains the α-subunit active site, the stable β-subunit interface and unique areas in each subunit needed to interact with GM2AP...
2016: Molecular Therapy. Methods & Clinical Development
Z K Timur, S Akyildiz Demir, C Marsching, R Sandhoff, V Seyrantepe
No abstract text is available yet for this article.
September 2015: Molecular Genetics and Metabolism Reports
Nancy K Newman
I thought this prenatal visit would be like any other. But then I read the patient's name-Rosa. Six months earlier, Rosa had left Minnesota with her husband and kids to visit their home and family in Mexico. Their 18-month-old, Manuelo, had been dying. He was diagnosed with the neurodegenerative condition Tay-Sachs disease. She had a second pregnancy that developed normally and I worried. Two days later, her baby, Luz was in my clinic and a blood test showed she had Tay-Sachs disease. Luz died on the way home after two days after Rosa' delivered her next baby...
December 2015: Families, Systems & Health: the Journal of Collaborative Family Healthcare
E Rose, N Schreiber-Agus, K Bajaj, S Klugman, T Goldwaser
The Jewish community has traditionally taken ownership of its health, and has taken great strides to raise awareness about genetic issues that affect the community, such as Tay-Sachs disease and Hereditary Breast and Ovarian Cancer syndrome. Thanks in part to these heightened awareness efforts, many Orthodox Jewish individuals are now using genetics services as they begin to plan their families. Due to unique cultural and religious beliefs and perceptions, the Orthodox Jewish patients who seek genetic counseling face many barriers to a successful counseling session, and often seek the guidance of programs such as the Program for Jewish Genetic Health (PJGH)...
February 2016: Journal of Genetic Counseling
Olcay Güngör, Gülay Güngör, Nursel Yurttutan, Cengiz Dilber
No abstract text is available yet for this article.
June 2016: Acta Neurologica Belgica
Nancy L Segal
Physicians and other medical professionals do not always provide new parents with an accurate diagnosis of their twins' zygosity. An overview of this problem is presented, supplemented by an interview with a mother who recently learned that her 2-year-old 'dizygotic (DZ)' twin girls are actually 'monozygotic (MZ)'. Reviews of two case studies, one of twins with sex-discordance and chimerism and the other of twins with congenital amegakaryotic thrombocytopenia, follow. Two additional studies, one a twin analysis of attractiveness to mosquitoes and the other a study of twins coping with crisis, are also described...
October 2015: Twin Research and Human Genetics: the Official Journal of the International Society for Twin Studies
Rita Barone, Luisella Sturiale, Agata Fiumara, Angelo Palmigiano, Rosaria O Bua, Renata Rizzo, Mario Zappia, Domenico Garozzo
Protein N-glycosylation consists in the synthesis and processing of the oligosaccharide moiety (N-glycan) linked to a protein and it serves several functions for the proper central nervous system (CNS) development and function. Previous experimental and clinical studies have shown the importance of proper glycoprotein sialylation for the synaptic function and the occurrence of autism spectrum disorders (ASD) in the presence of sialylation deficiency in the CNS. Late-onset Tay Sachs disease (LOTSD) is a lysosomal disorder caused by mutations in the HEXA gene resulting in GM2-ganglioside storage in the CNS...
April 2016: Autism Research: Official Journal of the International Society for Autism Research
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