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GM2 gangliosidosis is a group of rare lysosomal storage disorders (LSDs) including Tay-Sachs disease (TSD) and Sandhoff disease (SD), caused by deficiency in activity of either β-hexosaminidase A (HexA) or both β-hexosaminidase A and β-hexosaminidase B (HexB). Methods for screening and diagnosis of TSD and SD include measurement and comparison of the activity of these two enzymes. Here we report a novel method for duplex screening of dried blood spots (DBS) for TSD and SD by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method requires incubation of a single 3 mm DBS punch with the assay cocktail followed by the injection into the LC-MS/MS. The performance of the method was evaluated by comparing the confirmed TSD and SD patient DBS to random healthy newborn DBS which showed easy discrimination between the three cohorts. The method is multiplexable with other LSD MS/MS enzyme assays which is critical to the continued expansion of the NBS panels., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

The late-onset GM2 gangliosidoses, comprising late-onset Tay-Sachs and Sandhoff diseases, are rare, slowly progressive, neurogenetic disorders primarily characterized by neurogenic weakness, ataxia, and dysarthria. The aim of this longitudinal study was to characterize the natural history of late-onset GM2 gangliosidoses using a number of clinical outcome assessments to measure different aspects of disease burden and progression over time, including neurological, functional, and quality of life, to inform the design of future clinical interventional trials. Patients attending the United States National Tay-Sachs & Allied Diseases Family Conference between 2015 and 2019 underwent annual clinical outcome assessments. Currently, there are no clinical outcome assessments validated to assess late-onset GM2 gangliosidoses; therefore, instruments used or designed for diseases with similar features, or to address various aspects of the clinical presentations, were used. Clinical outcome assessments included the Friedreich's Ataxia Rating Scale, the 9-Hole Peg Test, and the Assessment of Intelligibility of Dysarthric Speech. Twenty-three patients participated in at least one meeting visit (late-onset Tay-Sachs, n = 19; late-onset Sandhoff, n = 4). Patients had high disease burden at baseline, and scores for the different clinical outcome assessments were generally lower than would be expected for the general population. Longitudinal analyses showed slow, but statistically significant, neurological progression as evidenced by worsening scores on the 9-Hole Peg Test (2.68%/year, 95% CI: 0.13-5.29; p = 0.04) and the Friedreich's Ataxia Rating Scale neurological examination (1.31 points/year, 95% CI: 0.26-2.35; p = 0.02). Time since diagnosis to study entry correlated with worsening scores on the 9-Hole Peg Test (r = 0.728; p < 0.001), Friedreich's Ataxia Rating Scale neurological examination (r = 0.727; p < 0.001), and Assessment of Intelligibility of Dysarthric Speech intelligibility (r = -0.654; p = 0.001). In summary, patients with late-onset GM2 gangliosidoses had high disease burden and slow disease progression. Several clinical outcome assessments suitable for clinical trials showed only small changes and standardized effect sizes (change/standard deviation of change) over 4 years. These longitudinal natural history study results illustrate the challenge of identifying responsive endpoints for clinical trials in rare, slowly progressive, neurogenerative disorders where arguably the treatment goal is to halt or decrease the rate of decline rather than improve clinical status. Furthermore, powering such a study would require a large sample size and/or a long study duration, neither of which is an attractive option for an ultra-rare disease with no available treatment. These findings support the development of potentially more sensitive late-onset GM2 gangliosidoses-specific rating instruments and/or surrogate endpoints for use in future clinical trials., Competing Interests: Declaration of competing interest JK, CR, PM, and AH are employees of Sanofi and may hold shares and/or stock options in the company. GFC was a former employee of Sanofi through 2016, and since 2019, is the owner of Gerald Cox Rare Care Consulting, LLC and a member of the NTSAD Board of Directors. CDS and FE are neurologists volunteering at the NTSAD. CDS has provided scientific advisory for SwanBio Therapeutics and his institution has received research funding from Sanofi for a study of video oculography in late-onset GM2 gangliosidoses. CDS has received financial support from SwanBio Therapeutics, Encora Therapeutics, Sanofi, Biogen and Biohaven for the conduct of clinical trials. CDS has received honoraria from the International Parkinson's and Movement Disorders Society, the American Academy of Neurology/Continuum and Oakstone CME for the production of educational material. CDS has received grant support from the National Institutes of HealthK23 NS118045-03. FE is co-principal investigator of a gene therapy trial in GM2 sponsored by Sio Pharmaceuticals and site principal investigator of a trial on late onset GM2 sponsored by Sanofi. HL was a former employee of NYU Langone Hospital in New York City, and currently is employed by Ultragenyx and volunteers at NTSAD. JMJ and CT are employees of the Intramural Research Program (IRP) of the National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, Maryland. RK is an employee of IQVIA, which received funding from Sanofi to conduct qualitative research to develop the GM2 gangliosidoses conceptual framework, and to support selection of the COA instruments used in this study. GFC, FE, CDS, HL and CT assessed the patients and did not receive funding for their participation., (Copyright © 2024. Published by Elsevier Inc.)

Background and Purpose: Tay-Sachs disease is a rare and often fatal, autosomal recessive, lysosomal storage disease. Deficiency in β-hexosaminidase leads to accumulation of GM2 ganglioside resulting in neuronal swelling and degeneration. Typical onset is in infancy with developmental regression and early death. Late-onset Tay-Sachs disease (LOTS) is extremely rare, especially in the non-Ashkenazi Jewish population, and is characterized by a more indolent presentation typically encompassing features of cerebellar and anterior horn cell dysfunction in addition to extrapyramidal and neuropsychiatric symptoms., Cases: A case series of four unrelated patients of non-Ashkenazi Jewish origin with a predominantly, and in some cases pure, neuromuscular phenotype with evidence of a motor neuronopathy on electromyography is presented. Cerebellar atrophy, reported to be a ubiquitous feature in LOTS, was absent in all patients., Conclusion: This case series provides evidence to support a pure neuromuscular phenotype in LOTS, which should be considered in the differential diagnosis of anterior horn cell disorders., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

GM2-Gangliosidosis are a group of inherited lysosomal storage pathologies characterized by a large accumulation of G M2 ganglioside in the lysosome. They are caused by mutation in HEXA or HEXB causing reduced or absent activity of a lysosomal β-hexosaminidase A, or mutation in GM2A causing defect in GM2 activator protein (GM2AP), an essential protein for the activity of the enzyme. Biochemical diagnosis relies on the measurement of β-hexosaminidases A and B activities, which is able to detect lysosomal enzyme deficiency but fails to identify defects in GM2AP. We developed a rapid, specific and sensitive liquid chromatography-mass spectrometry-based method to measure simultaneously G M1 , G M2 , G M3 and G D3 molecular species. Gangliosides were analysed in plasma from 19 patients with GM2-Gangliosidosis: Tay-Sachs (n = 9), Sandhoff (n = 9) and AB variant of GM2-Gangliosidosis (n = 1) and compared to 20 age-matched controls. Among patients, 12 have a late adult-juvenile-onset and 7 have an infantile early-onset of the disease. Plasma G M2 molecular species were increased in all GM2-Gangliosidosis patients (19/19), including the patient with GM2A mutation, compared to control individuals and compared to patients with different other lysosomal storage diseases. G M2 34:1 and G M2 34:1/G M3 34:1 ratio discriminated patients from controls with 100% sensitivity and specificity. G M2 34:1 and G M2 34:1/G M3 34:1 were higher in patients with early-onset compared to those with late-onset of the disease, suggesting a relationship with severity. Longitudinal analysis in one adult with Tay-Sachs disease over 9 years showed a positive correlation of G M2 34:1 and G M2 34:1/G M3 34:1 ratio with age at sampling. We propose that plasma G M2 34:1 and its ratio to G M3 34:1 could be sensitive and specific biochemical diagnostic biomarkers for GM2-Gangliosidosis including AB variant and could be useful as a first line diagnostic test and potential biomarkers for monitoring upcoming therapeutic efficacy., Competing Interests: Declaration of Competing Interest A competing interest statement: Authors have no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A boy, aged 5 years, attended the hospital due to progressive psychomotor regression for 2.5 years. Motor function regression was the main manifestation in the early stage, and brain MRI and whole-exome sequencing (WES) of the family showed no abnormalities. After the age of 4 years and 9 months, the boy developed cognitive function regression, and brain MRI showed cerebellar atrophy. The reanalysis of WES results revealed a compound heterozygous mutation, [NM&#95;000520, c.784C>T(p.His262Tyr]), c.1412C>T(p.Pro471Leu)], in the HEXA gene. The enzyme activity detection showed a significant reduction in the level of β-hexosaminidase encoded by this gene. The boy was diagnosed with juvenile Tay-Sachs disease (TSD). TSD has strong clinical heterogeneity, and cerebellar atrophy may be an important clue for the diagnosis of juvenile TSD. The reanalysis of genetic data when appropriate based on disease evolution may improve the positive rate of WES.

Background: Tay-Sachs disease (TSD) is a lysosomal storage disease caused by mutations in the HEXA gene that encodes the HexosaminidaseA (HEXA) enzyme. As HEXA normally functions to degrade the protein GM2-ganglioside in lysosomes, decreased levels of HEXAcauses an accumulation of the protein and leads to neurological toxicity. Typical clinical manifestations of TSD include neurodevelopmental regression, muscle weakness, hypotonia, hyperreflexia, ataxia, seizures, and other neurological symptoms. It is quite rare in Asian populations, wherein only two cases have been reported in Korea to date., Methods: Clinical records, radiological assessments, and laboratory findings, such as plasma hexosaminidase assay and HEXA analysis, were extracted from the medical records of three (1 male and 2 female) independent Korean children with infantile form of Tay-Sachs disease., Results: All three children presented with neurodevelopmental regression and strabismus at around 8 months of age. Presence of cherry-red spots in the macula led to conduction of biochemical and genetic studies for TSD confirmation. The plasma hexosaminidase assay revealed decreased HEXA activity and low to normal total hexosaminidase activity. Similarly, genetic analysis revealed 4 variants from 6 alleles, including 2 previously reported and 2 novel variants, in the HEXA gene., Conclusion: We presented three Korean children, who were recently diagnosed with infantile-type TSDvia enzyme assay and genetic analysis. Furthermore, results showed that fundus examination can be helpful for early diagnosis of children with neurodevelopmental regression., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Tay-Sachs disease (TSD) is a hereditary neurodegenerative condition inherited through an autosomal recessive pattern. The incidence and carrier frequency of infantile TSD were found to be increased among French Canadians in specific areas of the province of Quebec or calculated from New England populations with French-Canadian heritage. No accurate infantile TSD carrier frequency for the whole French-Canadian population in Quebec has been published. In this study, we estimate the incidence and carrier frequency of infantile TSD in the Quebec French-Canadian population. The number of TSD cases was ascertained during the 1992-2015 period, as well as the number of births to mothers whose language of use is French. Seven cases of TSD have been diagnosed in Quebec during the period of ascertainment. This corresponds to an incidence of 1/218,144, which in turn corresponds to a carrier frequency of 1/234. In the same 24-year period, there are two French-Canadian couples who had a fetus prenatally diagnosed with TSD. If these cases are included, the incidence of TSD in the French-Canadian population of Quebec is 1/169,668 and the carrier frequency 1/206. These findings can be used for genetic counseling and policy decisions regarding carrier screening for TSD in populations of French-Canadian descent., (© 2020 National Society of Genetic Counselors.)

Tay-Sachs disease (TSD) is a type 1 gangliosidosis (GM2) and caused by hexosaminidase A deficiency resulting in abnormal sphingolipid metabolism and deposition of precursors in different organs. It is a progressive neurodegenerative disorder transmitted in an autosomal-recessive manner. There is an accumulation of GM2 in neurocytes and retinal ganglions which result in progressive loss of neurological function and formation of the cherry-red spot which is the hallmark of TSD. We report the first case of juvenile TSD from Pakistan in a child with death of an older sibling without the diagnosis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

JScreen is a national public health initiative based out of Emory University that provides reproductive carrier screening through an online portal and follow-up genetic counseling services. In 2014, JScreen began reporting to patients variants of uncertain significance (VUSs) in the gene that causes Tay-Sachs disease (HEXA). Genetic counseling was provided to discuss the VUS and patients were offered hexosaminidase A (HEXA) blood enzyme testing to assist with VUS reclassification. To identify patient reactions and factors influencing their follow-up testing decisions after receiving these results, we conducted a retrospective quantitative study by administering online surveys to 62 patients with HEXA VUSs. Participants who pursued enzyme testing and those who did not both experienced low levels of distress when receiving the VUS results. Perceptions of HEXA carrier status after genetic counseling, decisional conflict levels, plans to have children in the near future, time available to pursue enzyme testing, and eligibility for research were significant factors influencing decision-making to pursue or not pursue enzyme testing. Genetic counseling played an important role in helping patients understand the VUS and follow-up testing options. When discussing VUSs with patients, it would be beneficial for genetic counselors to focus on the patient's perception of the VUS, anxiety related to the uncertainty of their results, and follow-up options, when available., (© 2019 National Society of Genetic Counselors.)

Background: Pathogenic variants in HEXA that impair β-hexosaminidase A (Hex A) enzyme activity cause Tay-Sachs Disease (TSD), a severe autosomal-recessive neurodegenerative disorder. Hex A enzyme analysis demonstrates near-zero activity in patients affected with TSD and can also identify carriers, whose single functional copy of HEXA results in reduced enzyme activity relative to noncarriers. Although enzyme testing has been optimized and widely used for carrier screening in Ashkenazi Jewish (AJ) individuals, it has unproven sensitivity and specificity in a pan-ethnic population. The ability to detect HEXA variants via DNA analysis has evolved from limited targeting of a few ethnicity-specific variants to next-generation sequencing (NGS) of the entire coding region coupled with interpretation of any discovered novel variants., Methods: We combined results of enzyme testing, retrospective computational analysis, and variant reclassification to estimate the respective clinical performance of TSD screening via enzyme analysis and NGS. We maximized NGS accuracy by reclassifying variants of uncertain significance and compared to the maximum performance of enzyme analysis estimated by calculating ethnicity-specific frequencies of variants known to yield false-positive or false-negative enzyme results (e.g., pseudodeficiency and B1 alleles)., Results: In both AJ and non-AJ populations, the estimated clinical sensitivity, specificity, and positive predictive value were higher by NGS than by enzyme testing. The differences were significant for all comparisons except for AJ clinical sensitivity, where NGS exceeded enzyme testing, but not significantly., Conclusions: Our results suggest that performance of an NGS-based TSD carrier screen that interrogates the entire coding region and employs novel variant interpretation exceeds that of Hex A enzyme testing, warranting a reconsideration of existing guidelines., (© 2019 Myriad Genetics. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Tay-Sachs disease (TSD) is an autosomal recessive lysosomal storage disorder caused by mutations of the HEXA gene resulting in the deficiency of hexosaminidase A (Hex A) and subsequent neuronal accumulation of G M2 gangliosides. Infantile TSD is a devastating and fetal neurodegenerative disease with death before the age of 3-5 years. A small proportion of TSD patients carry milder mutations and may present juvenile or adult onset milder disease. TSD is more prevalent among Ashkenazi Jewish (AJ) individuals and some other genetically isolated populations with carrier frequencies of approximately ~1:27 which is much higher than that of 1:300 in the general population. Carrier screening and prenatal testing for TSD are effective in preventing the birth of affected fetuses greatly diminishing the incidence of TSD. Testing of targeted HEXA mutations by genotyping or sequencing can detect 98% of carriers in AJ individuals; however, the detection rate is much lower for most other ethnic groups. When combined with enzyme analysis, above 98% of carriers can be reliably identified regardless of ethnic background. Multiplex PCR followed by allele-specific primer extension is one method to test for known and common mutations. Sanger sequencing or other sequencing methods are useful to identify private mutations. For prenatal testing, only predefined parental mutations need to be tested. In the event of unknown mutational status or the presence of variants of unknown significance (VUS), enzyme analysis must be performed in conjunction with DNA-based assays to enhance the diagnostic accuracy. Enzymatic assays involve the use of synthetic substrates 4-methylumbelliferyl-N-acetyl-β-glucosamine (4-MUG) and 4-methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-β-D-glucopyranoside (4-MUGS) to measure the percentage Hex A activity (Hex A%) and specific Hex A activity respectively. These biochemical and molecular tests can be performed in both direct specimens and cultured cells from chorionic villi sampling or amniocentesis.

We discuss the assessment and differential diagnoses of a young adult Hungarian man with a 1-year history of a progressive and symmetric amyotrophic lateral sclerosis-like syndrome, along with irregular action tremor and stimulus-sensitive myoclonus of the arms. MR scan of the brain showed isolated cerebellar atrophy and formal neuropsychometric testing identified significant subclinical deficits in attention, processing speed and memory. We suspected a form of GM 2 gangliosidosis, and white cell enzyme analysis showed markedly reduced enzymatic activity of β-hexosaminidase A. Genetic testing subsequently revealed two heterozygous pathogenic mutations in the HEXA gene (c.1499delT p.(Leu500fs) and c.805G>A p.(Gly269Ser)), confirming the very rare diagnosis of adult-onset Tay-Sachs disease., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Several genetic disorders are specific to Jewish heritage; one of the most devastating is Tay-Sachs disease.Tay-Sachs is a fatal hereditary disease, causing progressive neurological problems for which there is no cure. Ethical issues surrounding genetic testing for Tay-Sachs within the Jewish community continue to be complex and multifaceted. A perspective of Tay-Sachs, using rights-based ethics and virtue ethics as a theoretical framework, is explored.

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., Methods: Five hundred eight Hispanic and African American patients (516 samples) had EA of their leukocytes performed and 12 of these patients who tested positive by EA ("carriers") had subsequent HEXA gene sequencing performed., Results: Of the 508 patients, 25 (4.9%) were EA positive and 40 (7.9%) were inconclusive. Of the 12 patients who were sequenced, 11 did not carry a pathogenic variant and one carried a likely deleterious mutation (NM&#95;000520.4(HEXA):c.1510C>T)., Conclusions: High inconclusive rates and poor correlation between positive/inconclusive enzyme results and identification of pathogenic mutations suggest that ethnic-specific recalibration of reference ranges for EA may be necessary. Alternatively, HEXA gene sequencing could be performed.

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. Rosa believed U.S. doctors were wrong. Manuelo didn't have Tay-Sachs. Manuelo's difficulties were from mal de ojo-the evil eye. Rosa told me that they had stopped Manuelo's antiseizure medications a month before his death, and he had seemed better, almost rolling over again. This improvement was strong evidence that mal de ojo had caused his problems. But it had been discovered too late, so Manuelo had died. Caught between wanting to respect their beliefs and worrying about the baby, I probed for any doubt in Rosa's thinking. During their last clinic visit, I asked Rosa how she understood what had happened to Manuelo and Luz. She still believed mal de ojo was responsible. It has been 9 years since that farewell. Recently, I heard from Rosa's extended family in Minnesota that Rosa, Pedro, and their kids are well and plan to return to Minnesota this year. I am looking forward to seeing them. My existence as a physician is dependent on and continually shaped by the patients and families that come to me for care. There is a lot in that process that is not in my control. For me, caring for Rosa and her family was "one of those things that happens," and something that has sculpted me into the physician that I am. (PsycINFO Database Record, ((c) 2015 APA, all rights reserved).)

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. Several articles and letters from the popular media, concerning less favored twins, paternity issues surrounding superfecundation, twins with late-onset Tay-Sachs disease, and triplets admitted to MIT are informative and insightful.

Internationally, Tay-Sachs disease (TSD) preconception screening of Ashkenazi Jewish (AJ) individuals and couples has led to effective primary prevention of TSD. In Australia, adolescent preconception genetic screening programs operate mainly in Jewish community high schools. These existing programs offer an effective means of primary prevention of TSD, are cost effective and safe. However, in the broader Australian community TSD screening is not systematically performed and cases still occur in unscreened AJ individuals. In order to improve the effectiveness of Australian screening, there is a need for definitive guidelines for healthcare professionals to facilitate extension of the proven benefits of preconception TSD screening to all AJ individuals at risk. We performed a systematic review of the relevant literature relating to AJ pre-conception and antenatal screening for TSD. The evidence was assessed using an established National Health and Medical Research Council evidence grading system. Evaluations of efficacy of TSD screening programs design and execution, cost-benefit and cost-utility health economic evaluation, and population outcomes were undertaken. The results have been used to propose a model for universal AJ TSD preconception and antenatal screening for the primary care setting., (© 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Background: The gangliosidoses (Tay-Sachs disease, Sandhoff disease, and GM1-gangliosidosis) are progressive neurodegenerative diseases caused by lysosomal enzyme activity deficiencies and consequent accumulation of gangliosides in the central nervous system (CNS). The infantile forms are distinguished from the juvenile forms by age of onset, rate of disease progression, and age of death. There are no approved treatments for the gangliosidoses. In search of potential biomarkers of disease, we quantified 188 analytes in CSF and serum from living human patients with longitudinal (serial) measurements. Notably, several associated with inflammation were elevated in the CSF of infantile gangliosidosis patients, and less so in more slowly progressing forms of juvenile gangliosidosis, but not in MPS disease. Thirteen CSF and two serum biomarker candidates were identified. Five candidate biomarkers were distinguished by persistent elevation in the CSF of patients with the severe infantile phenotype: ENA-78, MCP-1, MIP-1α, MIP-1β, and TNFR2. Correspondence of abnormal elevation with other variables of disease-i.e., severity of clinical phenotype, differentiation from changes in serum, and lack of abnormality in other neurodegenerative lysosomal diseases-identifies these analytes as biomarkers of neuropathology specific to the gangliosidosis diseases., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to determine analytic performance of laboratories offering molecular testing for conditions such as Tay-Sachs disease, Canavan disease, and familial dysautonomia, which are prevalent in the Ashkenazi Jewish population., Methods: The College of American Pathologists and the American College of Medical Genetics and Genomics cosponsor molecular proficiency testing for these disorders. Responses from 2006 to 2013 were analyzed for accuracy (genotyping and interpretations)., Results: Between 11 and 36 laboratories participated in each Tay-Sachs disease distribution. Samples tested per month were constant (2,900) from 2006 to 2011 but recently increased. Participants reporting <10 samples tested per month had longer turnaround times (42 vs. 7%, longer than 14 days; P = 0.03). Analytic sensitivity and specificity for US participants were 97.2% (95% confidence interval: 94.7-98.7%) and 99.8% (95% confidence interval: 99.1-99.9%), respectively. Of 11 genotyping errors, 2 were due to sample mix-up. Analytic interpretations were correct in 99.3% of challenges (956/963; 95% confidence interval: 98.5-99.7%). Better performance was found for Canavan disease and familial dysautonomia. International laboratories performed equally well., Conclusion: These results demonstrated high analytic sensitivity and specificity along with excellent analytic interpretation performance, confirming the genetics community impression that laboratories provide accurate test results in both diagnostic and screening settings. Proficiency testing can identify potential laboratory issues and helps document overall laboratory performance.

Introduction: Late-onset Tay-Sachs disease (LOTS) is a lysosomal storage disease caused by deficient Beta-hexosaminidase A activity., Methods: We describe a 53-year-old woman who presented with adult-onset leg weakness, and whose initial diagnosis was progressive muscular atrophy without identifiable etiology. Development of cerebellar ataxia in mid-life prompted reassessment., Results: Beta-hexosaminidase A quantification assay demonstrated absence of the isozyme. Genetic testing identified compound heterozygous mutations in the HEXA gene, confirming the diagnosis of LOTS., Conclusions: The phenotypic spectrum of LOTS includes motor neuronopathy, ataxia, choreoathetosis, neuropathy, and psychiatric symptoms in various combinations. This patient highlights the emergence of different clinical features over many years and emphasizes the need to consider LOTS in the differential diagnosis of progressive muscular atrophy., (Copyright © 2013 Wiley Periodicals, Inc.)

Traditional carrier screening assays are designed to look for only the most common mutations within a gene owing to cost considerations. Although this can yield high detection rates in specific populations for specific genes (such as cystic fibrosis in Caucasians), they are suboptimal for other ethnicities or for patients of mixed or unknown ethnic background. Next-generation DNA sequencing provides an opportunity to provide carrier screening using more comprehensive mutation panels that are limited primarily by information about the clinical impact of detected sequence changes. We describe a next-generation DNA sequencing-based assay capable of reliably screening patient samples in a timely and comprehensive manner. The analytic accuracy in a research setting has been documented. Here, we describe the additional studies performed to ensure the accuracy (analytic validity) and robustness of our assay for use in clinical practice and provide data from our experience offering this testing. Our clinical experience using this approach to screen 11,691 in vitro fertilization patients has identified 449 mutant alleles: 447 in carriers and 2 in an affected individual. In total, we found 87 distinct mutations in 14 different genes. Approximately one quarter of the mutations found are not included in traditional, limited, mutation panels, including 16 known mutations unique to our panel, and novel truncating mutations in several genes., (Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Tay-Sachs disease (TSD), or GM2 gangliosidosis, is a lethal autosomal recessive neurodegenerative disorder, which is caused by a deficiency of beta-hexosaminidase A (HEXA), resulting in lysosomal accumulation of GM2 ganglioside. The aim of this study was to identify the TSD-causing mutations in an Iranian population., Methods: In this study, we examined 31 patients for TSD-causing mutations using PCR, followed by restriction enzyme digestion., Results: Molecular genetics analysis of DNA from 23 patients of TSD revealed mutations that has been previously reported, including four-base duplications c.1274&#95;1277dupTATC in exon 11 and IVS2+1G>A, deletion TTAGGCAAGGGC in exon 10 as well as a few novel mutations, including C331G, which altered Gln>Glu in HEXB, A>G, T>C, and p.R510X in exon 14, which predicted a termination codon or nonsense mutation., Conclusion: In conclusion, with the discovery of these novel mutations, the genotypic spectrum of Iranian patients with TSD disease has been extended and could facilitate definition of disease-related mutations.

Objectives: To evaluate the outcomes of preconception screening of Jewish Australians for Tay Sachs disease (TSD) carrier status on Jewish TSD-affected births., Design, Participants and Setting: Epidemiological observational study involving a complete retrospective audit of infantile and intermediate TSD cases diagnosed in Sydney and Melbourne between 1 January 1995 and 31 December 2011 (Royal Children's Hospital Melbourne; Pacific Laboratory Medicine Services, Pathology North, NSW Health Pathology, Sydney; Victorian Clinical Genetics Services, Melbourne; and SA Pathology, Adelaide), and carrier frequency among Jewish high school students attending schools participating in TSD screening programs over the same period., Main Outcome Measures: Jewish TSD carrier frequency; and expected versus observed Jewish TSD-affected births., Results: The 2006 Census indicated that most of the total 88,826 Jewish Australians live in Melbourne (46%) and Sydney (40%). The 7,756 Jewish high school students screened for TSD in Sydney and Melbourne during the study period had a carrier frequency of one in 31 (3.26%; 95% CI, 2.89%-3.68%).The estimated expected number of TSD-affected births in Melbourne and Sydney in 1995-2011 was 4.1 for Jewish births and 7.4 for other births (a ratio of Jewish to non-Jewish births of 1:2). The actual number was 12 (four in Sydney and eight in Melbourne), of which two were Jewish (a ratio of Jewish to non-Jewish births of 1:5). This finding of fewer than expected Jewish TSD cases coincided with a period during which screening programs were operating. There have been no Jewish TSD-affected children born to parents who were screened previously., Conclusion: Community education, appreciation of autosomal recessive inheritance and genetic carrier screening before pregnancy are the likely factors in our finding of fewer than expected Jewish babies with TSD. Ongoing outcome monitoring must continue.

Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277&#95;1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.

Tay-Sachs disease, also known as GM2 gangliosidosis or Hexosaminidase A deficiency is an autosomal recessive genetic fatal disorder. The disease is known to appear in East European Ashkenazi Jews, North African Jews, and Quebec French Canadians exclusively, but, with different frequency and type of mutation. Its most common variant is the infantile type Tay-Sachs disease. Juvenile and late-onset forms of the disease are infrequent and slowly progressive. At nearly 3 to 6 months old, a baby with Tay-Sachs progressively loses his motor skills and attentiveness. Startle responses and hyperreflexia become prominent, especially on eliciting deep patellar and Achilles reflexes, as a consequence of neurodegeneration of the upper motor neuron. Other systemic damage ensues gradually; seizures, blindness, spasticity of limbs, inability to swallow and breathe, and eventually the baby dies at 1-4 years of age. All Tay-Sachs patients have a "cherry red spot", easily seen in the macula area of the retina, using an ophthalmoscope. The "cherry red spot" is the only normal part of the retina in these sick babies. The case presented here emphasizes that Tay-Sachs disease is sometimes misdiagnosed at first visits even by an experienced clinician, because of his lack of awareness that this disease is not exclusively a Jewish disease.

Tay-Sachs disease (TSD), a pan-ethnic, autosomal recessive, neurodegenerative, lysosomal disease, results from deficient β-hexosaminidase A activity due to β-hexosaminidase α-subunit (HEXA) mutations. Prenatal/premarital carrier screening programs in the Ashkenazi Jewish community have markedly reduced disease occurrence. We report the first Jordanian Arab TSD patient diagnosed by deficient β-hexosaminidase A activity. HEXA mutation analysis revealed homozygosity for a nonsense mutation, c.78G>A (p.W26X). Previously reported in Arab patients, this mutation is a candidate for TSD screening in Arab populations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Tay-Sachs disease is a rare autosomal recessive neurodegenerative disorder that results from mutations in the HEXA gene, leading to β-hexosaminidase A (HexA) α subunit deficiency. An unusual variant of Tay-Sachs disease is known as the B1 variant. Previous studies indicated that, in northern Portugal, this is not only the most common variant but also one of the most prevalent lysosomal storage diseases. Additionally, this variant might also show a higher prevalence in populations of Portuguese and Spanish ancestry. A single mutation is invariably present in at least one of the alleles of B1 variant patients, HEXA mutation c.533G >A. To implement a method for c.533G >A testing in individuals and populations, we have optimized two distinct mutation analysis techniques, one based on restriction fragment length polymorphism analysis and the other based on allelic discrimination. We present the comparison of both methods and their advantages. Mutation screening by allelic discrimination proved to be particularly useful for the studying of large samples of individuals. It is time saving and highly reproducible, and under the conditions used, its cost is lower than the cost of polymerase chain reaction-based restriction fragment length polymorphism analysis.

Sandhoff disease is a GM2 gangliosidosis that is rare in Thailand. The authors report a Thai family with two children known to have infantile form of Sandhoff disease. The index case exhibited mitral valve prolapse with mitral regurgitation as an early sign, which is a rare presentation in Sandhoff disease. Thereafter the patient had developmental regression, startle reaction, and cherry red spots. The diagnosis was confirmed by biochemical analysis.

A screening programme for Tay Sachs disease (TSD) carrier status was introduced in high schools in Victoria, Australia in 1997, and was expanded to screen for six other genetic conditions common in the Ashkenazi Jewish population in 2008. The aim of this study was to evaluate the current programme and compare it with an evaluation of the programme when screening was offered for TSD alone. All students from Jewish high schools in Melbourne who offered the programme in 2009 were invited to participate in the study. A purpose-designed questionnaire explored the following domains: knowledge (disease and genetics), reasons for screening, anxiety, and predicted negative feelings if found to be a carrier. Two hundred and seventy-three students were offered screening, and 272 (99.6%) completed the questionnaire. Only two students chose not to have screening. Two hundred and seventy-one students were in the penultimate year of high school (99.6%) and 222 were of Ashkenazi Jewish descent (82.5%). The main reasons for choosing screening were the desire to know carrier status and convenience. Knowledge level decreased and negative feelings increased in the current cohort compared to that when screening was offered for TSD alone. We conclude that the current programme is efficient, although increasing the number of conditions resulted in a decrease in knowledge and increase in predicted negative feelings if found to be a carrier of one of the conditions. This has implications for multi-disease screening programmes that will increase in frequency as more conditions can be screened for and costs diminish.

Genetic testing for Tay-Sachs and Canavan disease is particularly important for Ashkenazi Jews, because both conditions are more frequent in that population. This comparative case study was possible because of different patenting and licensing practices. The role of DNA testing differs between Tay-Sachs and Canavan diseases. The first-line screening test for Tay-Sachs remains an enzyme activity test rather than genotyping. Genotyping is used for preimplantation diagnosis and confirmatory testing. In contrast, DNA-based testing is the basis for Canavan screening and diagnosis. The HEXA gene for Tay-Sachs was cloned at the National Institutes of Health, and the gene was patented but has not been licensed. The ASPA gene for Canavan disease was cloned and patented by Miami Children's Hospital. Miami Children's Hospital did not inform family members and patient groups that had contributed to the gene discovery that it was applying for a patent, and pursued restrictive licensing practices when a patent issued in 1997. This led to intense controversy, litigation, and a sealed, nonpublic 2003 settlement that apparently allowed for nonexclusive licensing. A survey of laboratories revealed a possible price premium for ASPA testing, with per-unit costs higher than for other genetic tests in the Secretary's Advisory Committee on Genetics, Health, and Society case studies. The main conclusion from comparing genetic testing for Tay-Sachs and Canavan diseases, however, is that patenting and licensing conducted without communication with patients and advocates cause mistrust and can lead to controversy and litigation, a negative model to contrast with the positive model of patenting and licensing for genetic testing of cystic fibrosis.