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1.
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
2.
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.
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
4.
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
5.
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
6.
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
8.
Appl Microbiol Biotechnol ; 102(1): 93-103, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29143882

RESUMO

ß-N-Acetylglucosaminidases (GlcNAcases) hydrolyse N-acetylglucosamine-containing oligosaccharides and proteins. These enzymes produce N-acetylglucosamine (GlcNAc) and have a wide range of promising applications in the food, energy, and pharmaceutical industries, such as synergistic degradation of chitin with endo-chitinases and using GlcNAc to produce sialic acid, bioethanol, single-cell proteins, and pharmaceutical therapeutics. GlcNAcases also play an important role in the dynamic balance of cellular O-linked GlcNAc levels, catabolism of ganglioside storage in Tay-Sachs disease, and bacterial cell wall recycling and flagellar assembly. In view of these important biological functions and the wide range of industrial applications of GlcNAcases, this review aims to provide a better understanding of various advances for these enzymes. It focuses on enzymatic properties of GlcNAcases, including substrate specificity, catalytic activity, pH optimum, temperature optimum, thermostability, the effects of various metal ions and organic reagents, and transglycosylation.


Assuntos
Acetilglucosamina/metabolismo , Acetilglucosaminidase/genética , Acetilglucosaminidase/metabolismo , Acetilglucosaminidase/química , Sequência de Aminoácidos , Quitina/metabolismo , Quitinases/metabolismo , Clonagem Molecular , Estabilidade Enzimática , Etanol/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Filogenia , Especificidade por Substrato , Doença de Tay-Sachs/fisiopatologia , Temperatura
9.
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
12.
Brain Dev ; 37(1): 101-6, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24534057

RESUMO

AIM: To clarify the evolution of an augmented startle reflex in Tay-Sachs disease and compare the temporal relationship between this reflex and brainstem evoked potentials. SUBJECTS AND METHODS: Clinical and electrophysiological data from 3 patients with Tay-Sachs disease were retrospectively collected. RESULTS: The augmented startle reflex appeared between the age of 3 and 17 months and disappeared between the age of 4 and 6 years. Analysis of brainstem auditory evoked potentials revealed that poor segregation of peak I, but not peak III, coincided with the disappearance of the augmented startle reflex. A blink reflex with markedly high amplitude was observed in a patient with an augmented startle reflex. CONCLUSION: The correlation between the augmented startle reflex and the preservation of peak I but not peak III supports the theory that the superior olivary nucleus is dispensable for this reflex. The blink reflex with high amplitudes may represent augmented excitability of reticular formation at the pontine tegmentum in Tay-Sachs disease, where the pattern generators for the augmented startle and blink reflexes may functionally overlap.


Assuntos
Tronco Encefálico/fisiopatologia , Potenciais Evocados Auditivos/fisiologia , Reflexo de Sobressalto/fisiologia , Doença de Tay-Sachs/fisiopatologia , Criança , Pré-Escolar , Humanos , Lactente , Masculino
14.
Ann N Y Acad Sci ; 1233: 48-57, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21950975

RESUMO

Saccade-generating burst neurons (BN) are inhibited by omnipause neurons (OPN), except during saccades. OPN activity pauses before saccade onset and resumes at the saccade end. Microstimulation of OPN stops saccades in mid-flight, which shows that OPN can end saccades. However, OPN pause duration does not correlate well with saccade duration, and saccades are normometric after OPN lesions. We tested whether OPN were responsible for stopping saccades both in late-onset Tay-Sachs, which causes premature saccadic termination, and in individuals with cerebellar hypermetria. We studied gaze shifts between two targets at different distances aligned on one eye, which consist of a disjunctive saccade followed by vergence. High-frequency conjugate oscillations during the vergence movements that followed saccades were present in all subjects studied, indicating OPN silence. Thus, mechanisms other than OPN discharge (e.g., cerebellar caudal fastigial nucleus-promoting inhibitory BN discharge) must contribute to saccade termination.


Assuntos
Tronco Encefálico/fisiologia , Movimentos Sacádicos/fisiologia , Adulto , Animais , Tronco Encefálico/anatomia & histologia , Tronco Encefálico/fisiopatologia , Estudos de Casos e Controles , Ataxia Cerebelar/fisiopatologia , Feminino , Haplorrinos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos da Motilidade Ocular/etiologia , Transtornos da Motilidade Ocular/fisiopatologia , Estimulação Luminosa , Células Receptoras Sensoriais/fisiologia , Doença de Tay-Sachs/fisiopatologia , Adulto Jovem
16.
Clin Neuropathol ; 27(5): 302-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18808061

RESUMO

Autopsy studies of late-onset GM2 gangliosidosis are sparse and only one adult case is on record. The case of partial Hex A deficiency presented here started in childhood as spinal muscular atrophy which progressed slowly over 4 decades. Cognitive function remained intact throughout the entire course, but during the last few years of life allodynia supervened. The patient died at 44 years of age. In good correlation with clinical observations the autopsy findings showed the most severe accumulation of lipid and consequent regressive change in the anterior horns of the spinal cord. Extensive but less severe storage was found in other spinal cord neurons, brain stem and selected basal ganglia. Cerebral cortex was virtually spared by storage but was the site of excessive formation of lipofuscin which was also present in many other neurons in the CNS. Marked storage and ganglionic loss was also found in the dorsal root ganglia, and the fasciculus gracilis was severely depleted of myelinated fibers. Electron microscopy showed accumulated gangliosides almost exclusively in the form of single and coalescing zebra bodies. In conclusion, the pathology in this case of chronic GM2 gangliosidosis, though in part conforming with previous observations, differed in several aspects. First, the cerebral cortex was--with only a few exceptions--free of ganglioside storage. Also spared was the cerebellum. In addition, homogeneous accumulation of zebra bodies contrasted with heterogeneity of neuronal inclusions found in other chronic cases. Finally, the involvement of sensory neurons was prominent and potentially related to allodynia. Molecular study of HEXA gene in this patient showed an TATC1278/? genotype.


Assuntos
Encéfalo/patologia , Medula Espinal/patologia , Doença de Tay-Sachs/patologia , Adulto , Idade de Início , Criança , Doença Crônica , Progressão da Doença , Feminino , Hexosaminidase A/genética , Humanos , Doença de Tay-Sachs/genética , Doença de Tay-Sachs/fisiopatologia
17.
Subcell Biochem ; 49: 567-88, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18751927

RESUMO

A review is presented of the major clinical features of a number of glycolipidoses including Fabry, Gaucher, Tay-Sachs, metachromatic leukodystrophy as well as CeroidLipofucinosis and Sjogren-Larsson syndrome. The possibilities offered by lipidomics for diagnosis and follow-up after enzyme replacement therapy are presented from a practical perspective. The contribution of HPLC coupled with tandem mass spectrometry has considerably simplified the detection and assay of abnormal metabolites. Corresponding internal standards consisting of weighed mixtures of the stable-isotope labeled metabolites required to calibrate and quantitate lipid components of these orphan diseases standards have yet to become commercially available. A lipidomics approach has been found to compare favorably with DNA-sequence analysis for the rapid diagnosis of pre-birth syndromes resulting from these multiple gene defects. The method also seems to be suitable for screening applications in terms of a high throughput combined with a low rate of false diagnoses based on the wide differences in metabolite concentrations found in affected patients as compared with normal subjects. The practical advantages of handling samples for lipidomic diagnoses as compared to enzyme assay are presented for application to diagnosis during pregnancy.


Assuntos
Terapia Enzimática , Genômica/métodos , Lipidoses/diagnóstico , Lipídeos/química , Doença de Fabry/diagnóstico , Doença de Fabry/fisiopatologia , Doença de Fabry/terapia , Doença de Gaucher/diagnóstico , Doença de Gaucher/fisiopatologia , Doença de Gaucher/terapia , Humanos , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/fisiopatologia , Leucodistrofia Metacromática/terapia , Lipidoses/enzimologia , Lipidoses/terapia , Lipofuscinoses Ceroides Neuronais/diagnóstico , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Lipofuscinoses Ceroides Neuronais/terapia , Síndrome de Sjogren-Larsson/diagnóstico , Síndrome de Sjogren-Larsson/fisiopatologia , Síndrome de Sjogren-Larsson/terapia , Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/fisiopatologia , Doença de Tay-Sachs/terapia
18.
Prog Brain Res ; 171: 563-6, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18718354

RESUMO

Saccades normally place the eye on target with one smooth movement. In late-onset Tay-Sachs (LOTS), intrasaccadic transient decelerations occur that may result from (1) premature omnipause neuron (OPN) re-activation due to malfunction of the latch circuit that inhibits OPNs for the duration of the saccade or (2) premature inhibitory burst neuron (IBN) activation due to fastigial nucleus (FN) dysregulation by the dorsal cerebellar vermis. Neuroanatomic analysis of a LOTS brain was performed. Purkinje cells were absent and gliosis of the granular cell layer was present in the dorsal cerebellar vermis. Deep cerebellar nuclei contained large inclusions. IBNs were present with small inclusions. The sample did not contain the complete OPN region; however, neurons in the OPN region contained massive inclusions. Pathologic findings suggest that premature OPN re-activation and/or inappropriate firing of IBNs may be responsible for interrupted saccades in LOTS. Cerebellar clinical dysfunction, lack of saccadic slowing, and significant loss of cerebellar cells suggest that the second cause is more likely.


Assuntos
Cerebelo/patologia , Cerebelo/fisiopatologia , Neurônios/fisiologia , Movimentos Sacádicos/fisiologia , Animais , Cerebelo/anatomia & histologia , Cerebelo/fisiologia , Músculos Oculomotores/fisiologia , Doença de Tay-Sachs/patologia , Doença de Tay-Sachs/fisiopatologia , Vias Visuais/fisiologia
19.
Prog Brain Res ; 171: 567-70, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18718355

RESUMO

In late-onset Tay-Sachs disease (LOTS), saccades are interrupted by one or more transient decelerations. Some saccades reaccelerate and continue on before eye velocity reaches zero, even in darkness. Intervals between successive decelerations are not regularly spaced. Peak decelerations of horizontal and vertical components of oblique saccades in LOTS is more synchronous than those in control subjects. We hypothesize that these decelerations are caused by dysregulation of the fastigial nuclei (FN) of the cerebellum, which fire brain stem inhibitory burst neurons (IBNs).


Assuntos
Núcleos Cerebelares/fisiopatologia , Movimentos Sacádicos/fisiologia , Doença de Tay-Sachs/fisiopatologia , Núcleos Cerebelares/patologia , Núcleos Cerebelares/fisiologia , Humanos , Estimulação Luminosa , Células de Purkinje/fisiologia , Doença de Tay-Sachs/patologia , Vias Visuais/fisiologia
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