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1.
Adv Exp Med Biol ; 1236: 225-244, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304075

RESUMO

Genetic model systems allow researchers to probe and decipher aspects of human disease, and animal models of disease are frequently specifically engineered and have been identified serendipitously as well. Animal models are useful for probing the etiology and pathophysiology of disease and are critical for effective discovery and development of novel therapeutics for rare diseases. Here we review the impact of animal model organism research in three examples of congenital metabolic disorders to highlight distinct advantages of model system research. First, we discuss phenylketonuria research where a wide variety of research fields and models came together to make impressive progress and where a nearly ideal mouse model has been central to therapeutic advancements. Second, we review advancements in Lesch-Nyhan syndrome research to illustrate the role of models that do not perfectly recapitulate human disease as well as the need for multiple models of the same disease to fully investigate human disease aspects. Finally, we highlight research on the GM2 gangliosidoses Tay-Sachs and Sandhoff disease to illustrate the important role of both engineered traditional laboratory animal models and serendipitously identified atypical models in congenital metabolic disorder research. We close with perspectives for the future for animal model research in congenital metabolic disorders.


Assuntos
Modelos Animais de Doenças , Erros Inatos do Metabolismo , Animais , Gangliosidoses GM2 , Humanos , Doenças Raras/congênito , Doença de Sandhoff , Doença de Tay-Sachs
2.
Ann Neurol ; 87(4): 609-617, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31995250

RESUMO

OBJECTIVE: GM2 gangliosidoses are lysosomal diseases due to biallelic mutations in the HEXA (Tay-Sachs disease [TS]) or HEXB (Sandhoff disease [SD]) genes, with subsequent low hexosaminidase(s) activity. Most patients have childhood onset, but some experience the first symptoms during adolescence/adulthood. This study aims to clarify the natural history of adult patients with GM2 gangliosidosis. METHODS: We retrospectively described 12 patients from a French cohort and 45 patients from the literature. RESULTS: We observed 4 typical presentations: (1) lower motoneuron disorder responsible for proximal lower limb weakness that subsequently expanded to the upper limbs, (2) cerebellar ataxia, (3) psychosis and/or severe mood disorder (only in the TS patients), and (4) a complex phenotype mixing the above 3 manifestations. The psoas was the first and most affected muscle in the lower limbs, whereas the triceps and interosseous were predominantly involved in the upper limbs. A longitudinal study of compound motor action potentials showed a progressive decrease in all nerves, with different kinetics. Sensory potentials were sometimes abnormally low, mainly in the SD patients. The main brain magnetic resonance imaging feature was cerebellar atrophy, even in patients without cerebellar symptoms. The prognosis was mainly related to gait disorder, as we showed that beyond 20 years of disease evolution, half of the patients were wheelchair users. INTERPRETATION: Improved knowledge of GM2 gangliosidosis in adults will help clinicians achieve correct diagnoses and better inform patients on the evolution and prognosis. It may also contribute to defining proper outcome measures when testing emerging therapies. ANN NEUROL 2020;87:609-617.


Assuntos
Doença de Sandhoff/fisiopatologia , Doença de Tay-Sachs/fisiopatologia , Potenciais de Ação , Adolescente , Adulto , Idade de Início , Idoso , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Criança , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Estudos de Coortes , Transtornos de Deglutição/fisiopatologia , Progressão da Doença , Disartria/fisiopatologia , Distonia/fisiopatologia , Eletrodiagnóstico , Eletromiografia , Feminino , Marcha Atáxica/fisiopatologia , Gangliosidoses GM2/diagnóstico por imagem , Gangliosidoses GM2/fisiopatologia , Gangliosidoses GM2/psicologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/fisiopatologia , Espasticidade Muscular/fisiopatologia , Debilidade Muscular/fisiopatologia , Condução Nervosa , Doença de Sandhoff/diagnóstico por imagem , Doença de Sandhoff/psicologia , Doença de Tay-Sachs/diagnóstico por imagem , Doença de Tay-Sachs/psicologia , Adulto Jovem
3.
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
4.
J Hum Genet ; 64(10): 985-994, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31388111

RESUMO

Tay-Sachs disease (TSD) (OMIM) is a neurodegenerative lysosomal storage disorder caused due to mutations in the HEXA gene. To date, nearly 190 mutations have been reported in HEXA gene. Here, we have characterized 34 enzymatically confirmed TSD families to investigate the presence of novel as well as known variants in HEXA gene. Overall study detected 25 variants belonging to 31 affected TSD patients and 3 carrier couples confirmed by enzyme study. Of these 17 patients harbors 15 novel variants, including seven missense variants [p.V206L, p.Y213H, p.R252C, p.F257S, p.C328G, p.G454R, and p.P475R], four nonsense variant [p.S9X, p.E91X, p.W420X, and p.W482X], two splice site variants [c.347-1G>A and c.460-1G>A], and two small deletion [c.1349delC (p.A450VfsX3) and c.52delG (p.G18Dfs*82)]. While remaining 17 patients harbors 10 previously reported variants that includes six missense variants [p.M1T, p.R170Q, p.D322Y, p.D322N, p.E462V, and p.R499C], one nonsense variant [p.Q106X], two splice site variants [c.1073+1G>A and c.459+4A>G] and one 4 bp insertion [c.1278insTATC (p.Y427IfsX5)]. In conclusion, Indian infantile TSD patients provide newer insight into the molecular heterogeneity of the TSD. Combining present study and our earlier studies, we have observed that 67% genotypes found in Indian TSD patients are novel, which are associated with severe infantile phenotypes, while rest 33% genotypes found in our cohort were previously reported in various populations. In addition, higher frequency of the p.E462V and c.1278insTATC mutations in the present study further support and suggest the prevalence of p.E462V mutation in the Indian population.


Assuntos
Doença de Tay-Sachs/genética , Cadeia alfa da beta-Hexosaminidase/genética , Alelos , Pré-Escolar , Códon sem Sentido , Demografia , Feminino , Estudos de Associação Genética , Humanos , Índia , Lactente , Masculino , Mutação de Sentido Incorreto , Deleção de Sequência , Doença de Tay-Sachs/enzimologia , Doença de Tay-Sachs/fisiopatologia , Cadeia alfa da beta-Hexosaminidase/química
5.
Neuroscience ; 414: 128-140, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31283907

RESUMO

Tay-Sachs disease (TSD) is a GM2 gangliosidosis lysosomal storage disease caused by a loss of lysosomal hexosaminidase-A (HEXA) activity and characterized by progressive neurodegeneration due to the massive accumulation of GM2 ganglioside in the brain. Here, we generated iPSCs derived from patients with TSD, and found similar potential for neural differentiation between TSD-iPSCs and normal iPSCs, although neural progenitor cells (NPCs) derived from the TSD-iPSCs exhibited enlarged lysosomes and upregulation of the lysosomal marker, LAMP1, caused by the accumulation of GM2 ganglioside. The NPCs derived from TSD-iPSCs also had an increased incidence of oxidative stress-induced cell death. TSD-iPSC-derived neurons showed a decrease in exocytotic activity with the accumulation of GM2 ganglioside, suggesting deficient neurotransmission in TSD. Our findings demonstrated that NPCs and mature neurons derived from TSD-iPSCs are potentially useful cellular models of TSD and are useful for investigating the efficacy of drug candidates in the future.


Assuntos
Células-Tronco Pluripotentes Induzidas/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Terminações Pré-Sinápticas/fisiologia , Doença de Tay-Sachs/fisiopatologia , Humanos , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Células-Tronco Neurais/fisiologia , Neuritos/fisiologia , Sinapsinas/metabolismo , Doença de Tay-Sachs/metabolismo , Regulação para Cima/fisiologia
7.
J Neurol ; 266(8): 1953-1959, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31076878

RESUMO

BACKGROUND: Tay-Sachs disease (TSD) is an inherited neurodegenerative disorder caused by a lysosomal ß-hexosaminidase A deficiency due to mutations in the HEXA gene. The late-onset form of disease (LOTS) is considered rare, and only a limited number of cases have been reported. The clinical course of LOTS differs substantially from classic infantile TSD. METHODS: Comprehensive data from 14 Czech patients with LOTS were collated, including results of enzyme assays and genetic analyses. RESULTS: 14 patients (9 females, 5 males) with LOTS were diagnosed between 2002 and 2018 in the Czech Republic (a calculated birth prevalence of 1 per 325,175 live births). The median age of first symptoms was 21 years (range 10-33 years), and the median diagnostic delay was 10.5 years (range 0-29 years). The main clinical symptoms at the time of manifestation were stammering or slurred speech, proximal weakness of the lower extremities due to anterior horn cell neuronopathy, signs of neo- and paleocerebellar dysfunction and/or psychiatric disorders. Cerebellar atrophy detected through brain MRI was a common finding. Residual enzyme activity was 1.8-4.1% of controls. All patients carried the typical LOTS-associated c.805G>A (p.Gly269Ser) mutation on at least one allele, while a novel point mutation, c.754C>T (p.Arg252Cys) was found in two siblings. CONCLUSION: LOTS seems to be an underdiagnosed cause of progressive distal motor neuron disease, with variably expressed cerebellar impairment and psychiatric symptomatology in our group of adolescent and adult patients. The enzyme assay of ß-hexosaminidase A in serum/plasma is a rapid and reliable tool to verify clinical suspicions.


Assuntos
Cerebelo/diagnóstico por imagem , Transtornos Mentais/diagnóstico por imagem , Atrofia Muscular/diagnóstico por imagem , Doença de Tay-Sachs/diagnóstico por imagem , Adolescente , Adulto , Idade de Início , Estudos de Coortes , República Tcheca/epidemiologia , Feminino , Humanos , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , Atrofia Muscular/epidemiologia , Atrofia Muscular/psicologia , Doença de Tay-Sachs/epidemiologia , Doença de Tay-Sachs/psicologia , Adulto Jovem
8.
SLAS Discov ; 24(3): 295-303, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30616450

RESUMO

Tay-Sachs disease is an inherited lysosomal storage disease resulting from mutations in the lysosomal enzyme, ß-hexosaminidase A, and leads to excessive accumulation of GM2 ganglioside. Tay-Sachs patients with the infantile form do not live beyond 2-4 years of age due to rapid, progressive neurodegeneration. Enzyme replacement therapy is not a therapeutic option due to its inability to cross the blood-brain barrier. As an alternative, small molecules identified from high-throughput screening could provide leads suitable for chemical optimization to target the central nervous system. We developed a new high-throughput phenotypic assay utilizing infantile Tay-Sachs patient cells based on disrupted lysosomal calcium signaling as a monitor of diseased phenotype. The assay was validated in a pilot screen on a collection of Food and Drug Administration-approved drugs to identify compounds that could reverse or attenuate the disease. Pyrimethamine, a known pharmacological chaperone of ß-hexosaminidase A, was identified from the primary screen. The mechanism of action of pyrimethamine in reversing the defective lysosomal phenotype was by improving autophagy. This new high-throughput screening assay in patient cells will enable the screening of larger chemical compound collections. Importantly, this approach could lead to identification of new molecular targets previously unknown to impact the disease and accelerate the discovery of new treatments for Tay-Sachs disease.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Lisossomos/fisiologia , Bibliotecas de Moléculas Pequenas/análise , Doença de Tay-Sachs/fisiopatologia , Autofagia , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Lisossomos/metabolismo , Projetos Piloto , Estudo de Prova de Conceito , Bibliotecas de Moléculas Pequenas/uso terapêutico , Doença de Tay-Sachs/tratamento farmacológico , Doença de Tay-Sachs/metabolismo
9.
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
10.
BMJ Case Rep ; 11(1)2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30567231

RESUMO

Lysosomal storage disorders or lipidoses are a wide spectrum of inherited diseases caused by deficiency of a specific lysosomal hydrolase. About 134 mutations have been described so far and this number is gradually increasing with newer mutations being reported. We report a 28-month-old child who presented to us with neurodevelopment regression, seizures and cherry red spot in both eyes. His hexosaminidase A enzyme activity was reduced and genetic testing revealed a homozygous novel variation in HEXA (hexosaminidase A) gene in the DNA sample of the patient.


Assuntos
Hexosaminidase A/genética , Mutação , Doença de Tay-Sachs/genética , Pré-Escolar , Humanos , Índia , Masculino
11.
J Mol Med (Berl) ; 96(12): 1359-1373, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30341570

RESUMO

Tay-Sachs disease (TSD) is a lethal lysosomal storage disease (LSD) caused by mutations in the HexA gene, which can lead to deficiency of ß-hexosaminidase A (HexA) activity and consequent accumulation of its substrate, GM2 ganglioside. Recent reports that progranulin (PGRN) functions as a chaperone of lysosomal enzymes and its deficiency is associated with LSDs, including Gaucher disease and neuronal ceroid lipofuscinosis, prompted us to screen the effects of recombinant PGRN on lysosomal storage in fibroblasts from 11 patients affected by various LSDs, which led to the isolation of TSD in which PGRN demonstrated the best effects in reducing lysosomal storage. Subsequent in vivo studies revealed significant GM2 accumulation and the existence of typical TSD cells containing zebra bodies in both aged and ovalbumin-challenged adult PGRN-deficient mice. In addition, HexA, but not HexB, was aggregated in PGRN-deficient cells. Furthermore, recombinant PGRN significantly reduced GM2 accumulation and lysosomal storage in these animal models. Mechanistic studies indicated that PGRN bound to HexA through granulins G and E domain and increased the enzymatic activity and lysosomal delivery of HexA. More importantly, Pcgin, an engineered PGRN derivative bearing the granulin E domain, also effectively bound to HexA and reduced the GM2 accumulation. Collectively, these studies not only provide new insights into the pathogenesis of TSD but may also have implications for developing PGRN-based therapy for this life-threatening disorder. KEY MESSAGES: GM2 accumulation and the existence of typical TSD cells containing zebra bodies are detected in both aged and ovalbumin-challenged adult PGRN deficient mice. Recombinant PGRN significantly reduces GM2 accumulation and lysosomal storage both in vivo and in vitro, which works through increasing the expression and lysosomal delivery of HexA. Pcgin, an engineered PGRN derivative bearing the granulin E domain, also effectively binds to to HexA and reduces GM2 accumulation.


Assuntos
Gangliosídeos/metabolismo , Hexosaminidase A/metabolismo , Lisossomos/metabolismo , Progranulinas/metabolismo , Doença de Tay-Sachs/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Progranulinas/genética , Células RAW 264.7 , Proteínas Recombinantes/farmacologia
12.
Orphanet J Rare Dis ; 13(1): 152, 2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-30220252

RESUMO

BACKGROUND: Tay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by autosomal recessive mutations in the HEXA gene on chromosome 15 that encodes ß-hexosaminidase. Deficiency in HEXA results in accumulation of GM2 ganglioside, a glycosphingolipid, in lysosomes. Currently, there is no effective treatment for TSD. RESULTS: We generated induced pluripotent stem cells (iPSCs) from two TSD patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). The TSD neural stem cells exhibited a disease phenotype of lysosomal lipid accumulation. The Tay-Sachs disease NSCs were then used to evaluate the therapeutic effects of enzyme replacement therapy (ERT) with recombinant human Hex A protein and two small molecular compounds: hydroxypropyl-ß-cyclodextrin (HPßCD) and δ-tocopherol. Using this disease model, we observed reduction of lipid accumulation by employing enzyme replacement therapy as well as by the use of HPßCD and δ-tocopherol. CONCLUSION: Our results demonstrate that the Tay-Sachs disease NSCs possess the characteristic phenotype to serve as a cell-based disease model for study of the disease pathogenesis and evaluation of drug efficacy. The enzyme replacement therapy with recombinant Hex A protein and two small molecules (cyclodextrin and tocopherol) significantly ameliorated lipid accumulation in the Tay-Sachs disease cell model.


Assuntos
Células-Tronco Neurais/citologia , Doença de Tay-Sachs/tratamento farmacológico , Doença de Tay-Sachs/terapia , 2-Hidroxipropil-beta-Ciclodextrina/uso terapêutico , Diferenciação Celular/fisiologia , Linhagem Celular , Terapia de Reposição de Enzimas/métodos , Feminino , Imunofluorescência , Gangliosidoses GM2/metabolismo , Hexosaminidase A/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Masculino , Repetições de Microssatélites/genética , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/fisiologia , Pichia/metabolismo , Espectrometria de Massas em Tandem , Doença de Tay-Sachs/genética , Doença de Tay-Sachs/metabolismo , Tocoferóis/uso terapêutico
15.
BMC Med Genet ; 19(1): 109, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973161

RESUMO

BACKGROUND: Tay-Sachs disease (TSD) is a sphingolipid storage disorder caused by mutations in the HEXA gene. To date, nearly 170 mutations of HEXA have been described, including only one 7.6 kb large deletion. METHODS: Multiplex Ligation-dependent Probe Amplification (MLPA) study was carried out in 5 unrelated patients for copy number changes where heterozygous and/or homozygous disease causing mutation/s could not be identified in the coding region by sequencing of HEXA gene. RESULTS: The study has identified the presence of a homozygous deletion of exon-2 and exon-3 in two patients, two patient showed compound heterozygosity with exon 1 deletion combined with missense mutation p.E462V and one patient was identified with duplication of exon-1 with novel variants c.1527-2A > T as a second allele. CONCLUSION: This is the first report of deletion/duplication in HEXA gene providing a new insight into the molecular basis of TSD and use of MLPA assay for detecting large copy number changes in the HEXA gene.


Assuntos
Deleção de Sequência/genética , Doença de Tay-Sachs/genética , Cadeia alfa da beta-Hexosaminidase/genética , Éxons/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Índia , Lactente , Masculino , Mutação de Sentido Incorreto/genética
16.
Hormones (Athens) ; 17(3): 415-418, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29943104

RESUMO

Tay-Sachs disease is an autosomal recessive type of lysosomal storage disorder. The disease is very rare in Turkey, with an incidence of 0.54/100,000. The clinical manifestations of Tay-Sachs disease include progressive developmental delay, seizures, deafness, blindness, spasticity, and dystonia, which are caused by the accumulation of gangliosides in the central nervous system. To date, only one case indicating the association between Tay-Sachs disease and central precocious puberty has been reported. Although the mechanism of this association is not clear, it is thought to be due to ganglioside accumulation in the central nervous system or the inhibition of the hypothalamic inhibiting pathway. Herein, we report two patients with genetically proven Tay-Sachs disease who developed central precocious puberty during follow-up. Pubertal development in patients affected by Tay-Sachs disease should be carefully assessed.


Assuntos
Puberdade Precoce/etiologia , Doença de Tay-Sachs/complicações , Criança , Pré-Escolar , Feminino , Humanos , Puberdade Precoce/metabolismo , Doença de Tay-Sachs/metabolismo , Doença de Tay-Sachs/fisiopatologia
17.
Curr Gene Ther ; 18(2): 68-89, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29618308

RESUMO

Tay-Sachs disease, caused by impaired ß-N-acetylhexosaminidase activity, was the first GM2 gangliosidosis to be studied and one of the most severe and earliest lysosomal diseases to be described. The condition, associated with the pathological build-up of GM2 ganglioside, has acquired almost iconic status and serves as a paradigm in the study of lysosomal storage diseases. Inherited as a classical autosomal recessive disorder, this global disease of the nervous system induces developmental arrest with regression of attained milestones; neurodegeneration progresses rapidly to cause premature death in young children. There is no effective treatment beyond palliative care, and while the genetic basis of GM2 gangliosidosis is well established, the molecular and cellular events, from diseasecausing mutations and glycosphingolipid storage to disease manifestations, remain to be fully delineated. Several therapeutic approaches have been attempted in patients, including enzymatic augmentation, bone marrow transplantation, enzyme enhancement, and substrate reduction therapy. Hitherto, none of these stratagems has materially altered the course of the disease. Authentic animal models of GM2 gangliodidosis have facilitated in-depth evaluation of innovative applications such as gene transfer, which in contrast to other interventions, shows great promise. This review outlines current knowledge pertaining the pathobiology as well as potential innovative treatments for the GM2 gangliosidoses.


Assuntos
Transplante de Medula Óssea , Terapia de Reposição de Enzimas , Terapia Genética , Doença de Sandhoff/genética , Doença de Sandhoff/terapia , Doença de Tay-Sachs/genética , Doença de Tay-Sachs/terapia , Animais , Modelos Animais de Doenças , Glicoesfingolipídeos/metabolismo , Humanos , Lactente , Lisossomos/enzimologia , Lisossomos/genética , Lisossomos/patologia , Camundongos , Mutação , Doenças Raras , Doença de Sandhoff/enzimologia , Doença de Sandhoff/patologia , Doença de Tay-Sachs/enzimologia , Doença de Tay-Sachs/patologia , beta-N-Acetil-Hexosaminidases/genética
18.
Cochrane Database Syst Rev ; 3: CD010849, 2018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29537064

RESUMO

BACKGROUND: Globally, about five per cent of children are born with congenital or genetic disorders. The most common autosomal recessive conditions are thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease, with higher carrier rates in specific patient populations. Identifying and counselling couples at genetic risk of the conditions before pregnancy enables them to make fully informed reproductive decisions, with some of these choices not being available if genetic counselling is only offered in an antenatal setting. This is an update of a previously published review. OBJECTIVES: To assess the effectiveness of systematic preconception genetic risk assessment to improve reproductive outcomes in women and their partners who are identified as carriers of thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease in healthcare settings when compared to usual care. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Registers. In addition, we searched for all relevant trials from 1970 (or the date at which the database was first available if after 1970) to date using electronic databases (MEDLINE, Embase, CINAHL, PsycINFO), clinical trial databases (National Institutes of Health, Clinical Trials Search portal of the World Health Organization, metaRegister of controlled clinical trials), and hand searching of key journals and conference abstract books from 1998 to date (European Journal of Human Genetics, Genetics in Medicine, Journal of Community Genetics). We also searched the reference lists of relevant articles, reviews and guidelines and also contacted subject experts in the field to request any unpublished or other published trials.Date of latest search of the registers: 20 June 2017.Date of latest search of all other sources: 16 November 2017. SELECTION CRITERIA: Any randomised or quasi-randomised controlled trials (published or unpublished) comparing reproductive outcomes of systematic preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease when compared to usual care. DATA COLLECTION AND ANALYSIS: We identified 25 papers, describing 16 unique trials which were potentially eligible for inclusion in the review. However, after assessment, no randomised controlled trials of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease were found. MAIN RESULTS: No randomised controlled trials of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease were included. One ongoing trial has been identified which may potentially eligible for inclusion once completed. AUTHORS' CONCLUSIONS: As no randomised controlled trials of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis, or Tay-Sachs disease were found for inclusion in this review, the research evidence for current policy recommendations is limited to non-randomised studies.Information from well-designed, adequately powered, randomised trials is desirable in order to make more robust recommendations for practice. However, such trials must also consider the legal, ethical, and cultural barriers to implementation of preconception genetic risk assessment.


Assuntos
Anemia Falciforme/genética , Fibrose Cística/genética , Triagem de Portadores Genéticos , Cuidado Pré-Concepcional , Doença de Tay-Sachs/genética , Talassemia/genética , Feminino , Humanos , Medição de Risco
20.
Exp Neurol ; 299(Pt A): 26-41, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28974375

RESUMO

Tay-Sachs disease is a severe lysosomal storage disorder caused by mutations in Hexa, the gene that encodes for the α subunit of lysosomal ß-hexosaminidase A (HEXA), which converts GM2 to GM3 ganglioside. Unexpectedly, Hexa-/- mice have a normal lifespan and show no obvious neurological impairment until at least one year of age. These mice catabolize stored GM2 ganglioside using sialidase(s) to remove sialic acid and form the glycolipid GA2, which is further processed by ß-hexosaminidase B. Therefore, the presence of the sialidase (s) allows the consequences of the Hexa defect to be bypassed. To determine if the sialidase NEU3 contributes to GM2 ganglioside degradation, we generated a mouse model with combined deficiencies of HEXA and NEU3. The Hexa-/-Neu3-/- mice were healthy at birth, but died at 1.5 to 4.5months of age. Thin-layer chromatography and mass spectrometric analysis of the brains of Hexa-/-Neu3-/- mice revealed the abnormal accumulation of GM2 ganglioside. Histological and immunohistochemical analysis demonstrated cytoplasmic vacuolation in the neurons. Electron microscopic examination of the brain, kidneys and testes revealed pleomorphic inclusions of many small vesicles and complex lamellar structures. The Hexa-/-Neu3-/- mice exhibited progressive neurodegeneration with neuronal loss, Purkinje cell depletion, and astrogliosis. Slow movement, ataxia, and tremors were the prominent neurological abnormalities observed in these mice. Furthermore, radiographs revealed abnormalities in the skeletal bones of the Hexa-/-Neu3-/- mice. Thus, the Hexa-/-Neu3-/- mice mimic the neuropathological and clinical abnormalities of the classical early-onset Tay-Sachs patients, and provide a suitable model for the future pre-clinical testing of potential treatments for this condition.


Assuntos
Gangliosidoses GM2/genética , Hexosaminidase B/genética , Neuraminidase/genética , Doença de Tay-Sachs/genética , Animais , Química Encefálica/genética , Vesículas Citoplasmáticas/patologia , Gangliosidoses GM2/metabolismo , Gliose/genética , Gliose/patologia , Glicoesfingolipídeos/metabolismo , Coxeadura Animal/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuraminidase/deficiência , Neurônios/patologia , Células de Purkinje/patologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Doença de Tay-Sachs/patologia
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