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1.
BMJ Case Rep ; 12(9)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31519716

RESUMO

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.


Assuntos
Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/genética , Cadeia alfa da beta-Hexosaminidase/genética , Pré-Escolar , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/etiologia , Humanos , Masculino , Mutação/genética , Paquistão/epidemiologia , Cuidados Paliativos/métodos , Doença de Tay-Sachs/fisiopatologia , Sequenciamento Completo do Exoma/métodos
3.
Methods Mol Biol ; 1885: 233-250, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30506202

RESUMO

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 GM2 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-ß-glucosamine (4-MUG) and 4-methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-ß-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.


Assuntos
Testes Genéticos , Diagnóstico Pré-Natal/métodos , Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/genética , Alelos , Contaminação por DNA , Análise Mutacional de DNA , Eletroforese Capilar , Testes Genéticos/métodos , Testes Genéticos/normas , Genótipo , Humanos , Mutação , Reação em Cadeia da Polimerase , Diagnóstico Pré-Natal/normas , Doença de Tay-Sachs/metabolismo , Cadeia alfa da beta-Hexosaminidase/genética , Cadeia alfa da beta-Hexosaminidase/metabolismo
7.
J Christ Nurs ; 34(4): 246-249, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28902054

RESUMO

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.


Assuntos
Triagem de Portadores Genéticos/ética , Testes Genéticos/ética , Judeus/genética , Judaísmo , Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/etnologia , Humanos , Doença de Tay-Sachs/genética , Estados Unidos
8.
Pract Neurol ; 17(5): 396-399, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28739864

RESUMO

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 GM2 gangliosidosis, and white cell enzyme analysis showed markedly reduced enzymatic activity of ß-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.


Assuntos
Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/fisiopatologia , Adulto , Idade de Início , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Creatina Quinase/sangue , Diagnóstico Diferencial , Eletrocardiografia , Humanos , Imagem por Ressonância Magnética , Masculino , Doença de Tay-Sachs/sangue , Tomografia Computadorizada por Raios X
10.
Genet Test Mol Biomarkers ; 20(9): 504-9, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27362553

RESUMO

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_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.


Assuntos
Ensaios Enzimáticos/métodos , Triagem de Portadores Genéticos/métodos , Doença de Tay-Sachs/enzimologia , Doença de Tay-Sachs/genética , Cadeia alfa da beta-Hexosaminidase/genética , Cadeia alfa da beta-Hexosaminidase/metabolismo , Afro-Americanos/genética , Grupos Étnicos/genética , Testes Genéticos/métodos , Heterozigoto , Hispano-Americanos/genética , Humanos , Judeus/genética , Mutação , Cidade de Nova Iorque/epidemiologia , Reprodutibilidade dos Testes , Análise de Sequência de DNA , Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/epidemiologia
11.
Fam Syst Health ; 33(4): 422-5, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26641873

RESUMO

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


Assuntos
Relações Profissional-Família , Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/terapia , Adulto , Características Culturais , Feminino , Humanos , Lactente , Recém-Nascido , México , Minnesota , Gravidez
12.
Twin Res Hum Genet ; 18(5): 613-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26323370

RESUMO

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.


Assuntos
DNA/genética , Gêmeos Dizigóticos , Gêmeos Monozigóticos , Transplante de Medula Óssea , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/terapia , Feminino , Testes Genéticos , Humanos , Lactente , Masculino , Médicos , Doença de Tay-Sachs/diagnóstico , Trombocitopenia/diagnóstico , Trombocitopenia/terapia , Estudos em Gêmeos como Assunto
14.
Mol Genet Metab ; 114(2): 274-80, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25557439

RESUMO

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-1ß, 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.


Assuntos
Biomarcadores/líquido cefalorraquidiano , Gangliosidoses/diagnóstico , Inflamação/diagnóstico , Adolescente , Biomarcadores/sangue , Sistema Nervoso Central/metabolismo , Quimiocina CCL2/líquido cefalorraquidiano , Quimiocina CCL4/líquido cefalorraquidiano , Quimiocina CXCL5/líquido cefalorraquidiano , Criança , Pré-Escolar , Feminino , Gangliosidoses/metabolismo , Gangliosidose GM1/diagnóstico , Gangliosidose GM1/metabolismo , Humanos , Lactente , Masculino , Receptores Tipo II do Fator de Necrose Tumoral/líquido cefalorraquidiano , Doença de Sandhoff/diagnóstico , Doença de Sandhoff/metabolismo , Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/metabolismo , Fatores de Transcrição/líquido cefalorraquidiano
15.
J Paediatr Child Health ; 51(3): 271-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24923490

RESUMO

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.


Assuntos
Testes Genéticos/economia , Judeus/genética , Cuidado Pré-Concepcional/métodos , Diagnóstico Pré-Natal/métodos , Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/epidemiologia , Adulto , Austrália/epidemiologia , Criança , Feminino , Testes Genéticos/métodos , Humanos , Incidência , Cooperação Internacional , Masculino , Cuidado Pré-Concepcional/economia , Gravidez , Diagnóstico Pré-Natal/economia , Doença de Tay-Sachs/genética
16.
Rev. cuba. pediatr ; 86(4): 529-534, oct.-dic. 2014. ilus
Artigo em Espanhol | LILACS, CUMED | ID: lil-730328

RESUMO

La enfermedad de Tay-Sachs es un trastorno neurodegenerativo progresivo de herencia autosómica recesiva. Se debe a la deficiencia de la enzima β-hexosaminidasa A, que provoca una acumulación de gangliósidos GM2 en los lisosomas. Se incluye dentro de las esfingolipidosis. De las esfingolipidosis que presentan mancha rojo cereza en la mácula, la enfermedad de Tay-Sachs es la única en la que no se evidencia hepatoesplenomegalia. La variante más frecuente se inicia en la lactancia. Se presenta un lactante del sexo masculino al que se le realizó el diagnóstico de esta entidad a los 8 meses de edad. A partir de los 4 meses comenzó a presentar una reacción de sobresalto. A los 6 meses comenzó a perder habilidades previamente adquiridas y crisis epilépticas mioclónicas. Se constató una disminución de la actividad específica de la enzima hexosaminidasa A en leucocitos.


Tay-Sachs disease is a progressive autosomal recessive inherited neurodegenerative disorder caused by Beta-hexosaminidase A enzyme deficiency that in turn provokes GM2 ganglioside accumulation in the lysosomes. It is included in the sphyngolipidoses classification. Among the sphyngolipidoses that present with cherry-red spot in the macula, Tay-Sachs disease is the only one that does not show hepatosplenomegaly. The most frequent variant begins at the breast-feeding phase. This report presented a male nursling who was diagnosed with Tay-Sachs disease at the age of 8 months. At 4 months of age, he had begun getting some fright reactions. At 6 months-old, he began losing his previously acquired skills and suffering myoclonic seizures. The cause was the reduced specific activity of the hexosaminidase A enzyme in leukocytes.


Assuntos
Humanos , Masculino , Doença de Tay-Sachs/complicações , Doença de Tay-Sachs/diagnóstico , Hexosaminidase A
17.
Rev. cuba. pediatr ; 86(4): 529-534, oct.-dic. 2014.
Artigo em Espanhol | CUMED | ID: cum-58726

RESUMO

La enfermedad de Tay-Sachs es un trastorno neurodegenerativo progresivo de herencia autosómica recesiva. Se debe a la deficiencia de la enzima β-hexosaminidasa A, que provoca una acumulación de gangliósidos GM2 en los lisosomas. Se incluye dentro de las esfingolipidosis. De las esfingolipidosis que presentan mancha rojo cereza en la mácula, la enfermedad de Tay-Sachs es la única en la que no se evidencia hepatoesplenomegalia. La variante más frecuente se inicia en la lactancia. Se presenta un lactante del sexo masculino al que se le realizó el diagnóstico de esta entidad a los 8 meses de edad. A partir de los 4 meses comenzó a presentar una reacción de sobresalto. A los 6 meses comenzó a perder habilidades previamente adquiridas y crisis epilépticas mioclónicas. Se constató una disminución de la actividad específica de la enzima hexosaminidasa A en leucocitos(AU)


Tay-Sachs disease is a progressive autosomal recessive inherited neurodegenerative disorder caused by Beta-hexosaminidase A enzyme deficiency that in turn provokes GM2 ganglioside accumulation in the lysosomes. It is included in the sphyngolipidoses classification. Among the sphyngolipidoses that present with cherry-red spot in the macula, Tay-Sachs disease is the only one that does not show hepatosplenomegaly. The most frequent variant begins at the breast-feeding phase. This report presented a male nursling who was diagnosed with Tay-Sachs disease at the age of 8 months. At 4 months of age, he had begun getting some fright reactions. At 6 months-old, he began losing his previously acquired skills and suffering myoclonic seizures. The cause was the reduced specific activity of the hexosaminidase A enzyme in leukocytes(AU)


Assuntos
Humanos , Masculino , Lactente , Doença de Tay-Sachs/complicações , Doença de Tay-Sachs/diagnóstico , Hexosaminidase A
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