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1.
Neuropediatrics ; 50(4): 248-252, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31064022

RESUMEN

BACKGROUND: Fucosidosis is a rare lysosomal disorder caused by mutations in the FUCA1 gene. We describe here a novel homozygous mutation in FUCA1 in an Indian fucosidosis case. Furthermore, we summarize the clinical and genetic findings in the most recently reported individuals with fucosidosis. CASE: The proband is an 8-year-old boy born to consanguineous parents. He had generalized dystonia and bilateral spasticity as well as coarse facies, dysostosis multiplex, recurrent infections, angiokeratoma corporis diffusum, and visceromegaly. Whole exome sequencing analysis detected a homozygous canonical splice variant in the FUCA1 gene [Chr1(GRCh37):g.24172346C > T; NM_000147.4:c.1261-1G > A], not previously reported as causative of a human phenotype. Low levels of α-fucosidase in patient leukocytes and a positive qualitative urine based thin layer chromatography test for fucosidosis confirmed the diagnosis. Our literature review identified 89 cases of fucosidosis since the last major review. We show that dystonia is a rare manifestation (12%) and that only a small minority of cases receive treatment with transplantation (3.37%). CONCLUSION: We report a novel homozygous mutation in FUCA1 as the cause of severe neurological phenotype including generalized dystonia. Early recognition of fucosidosis may be important for consideration of promising treatment options, such as bone marrow transplantation.


Asunto(s)
Distonía/etiología , Fucosidosis/complicaciones , Mutación , alfa-L-Fucosidasa/genética , Niño , Distonía/genética , Fucosidosis/genética , Humanos , Masculino , Fenotipo
2.
Neurogenetics ; 17(4): 265-270, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27679996

RESUMEN

We performed whole genome sequencing (WGS) in nine families from India with early-onset hereditary spastic paraplegia (HSP). We obtained a genetic diagnosis in 4/9 (44 %) families within known HSP genes (DDHD2 and CYP2U1), as well as perixosomal biogenesis disorders (PEX16) and GM1 gangliosidosis (GLB1). In the remaining patients, no candidate structural variants, copy number variants or predicted splice variants affecting an extended candidate gene list were identified. Our findings demonstrate the efficacy of using WGS for diagnosing early-onset HSP, particularly in consanguineous families (4/6 diagnosed), highlighting that two of the diagnoses would not have been made using a targeted approach.


Asunto(s)
Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Secuenciación Completa del Genoma , Familia 2 del Citocromo P450/genética , Femenino , Heterocigoto , Homocigoto , Humanos , India , Masculino , Proteínas de la Membrana/genética , Mutación , Linaje , Fosfolipasas/genética , beta-Galactosidasa/genética
3.
Neurol India ; 62(2): 149-52, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24823723

RESUMEN

BACKGROUND: Parkinson's disease (PD) is a disabling neurological disorder characterized by progressive degeneration of dopaminergic neurons. Mutations analysis within the α-synuclein gene (SNCA) on chromosome 4 has been reported in the last decade. OBJECTIVE: To elucidate the possible role of SNCA gene in the pathogenesis of PD in Indian population specifically in north Karnataka. MATERIALS AND METHODS: The study subjects included 100 clinically diagnosed PD patients and 100 ethnically matched healthy controls. Isolated deoxyribonucleic acid (DNA) samples from both were subjected to exon-specific polymerase chain reaction (PCR) amplification and amplicons were subjected to capillary-based direct DNA sequencing. RESULT: No mutations were observed in SNCA gene of PD samples in comparison with control samples. CONCLUSION: These findings support the hypothesis that the SNCA gene mutations might be population specific and may not be playing role in causing PD in all the populations.


Asunto(s)
Predisposición Genética a la Enfermedad , Mutación/genética , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética , Adulto , Análisis Mutacional de ADN/métodos , Regulación de la Expresión Génica , Humanos , India , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico
4.
Cureus ; 15(9): e45347, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37849584

RESUMEN

INTRODUCTION: Nitric oxide (NO) overproduction has been found to have neurotoxic effects on the brain. Moreover, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced, the suppression of the NO-synthesizing enzymes, such as neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS), has neuroprotective benefits in Parkinson's disease (PD). These findings imply that NOS may have a role in regulating the nigral dopaminergic neurons' tolerance to environmental stressors in PD. OBJECTIVE: In the present study, we investigated variations in the NOS1 gene that may raise the likelihood of PD. METHODS: PD patients who visited the neurology departments of several medical colleges and hospitals in North Karnataka, India, between 2009 and 2011 were included in the study. The detailed clinic pathological details were obtained from 100 PD patients. Genomic DNA was isolated using the kit method followed by the evaluation of the quality and quantity of isolated gDNA. Polymerase chain reaction (PCR) amplification of exon 29 was performed, and sequencing was performed using the Applied Biosystems ABI 3500 Sanger sequencing platform. RESULTS: The present study is comprised of 100 PD patients, which includes 65 males and 35 females. There were 64 sporadic, 34 idiopathic, and two familial PD cases. The majority (67.1%) of PD cases were from metropolitan areas. Community-based segregation showed that the maximum cases were from Hindu Lingayat. A proportion (90.8%) of the patients had tremors, 32.7% of them displayed slowness in their daily tasks, and 8.1% of them had dyskinesia. Molecular analysis showed two untranslated region (UTR) variations g.151787 del T (rs1434015950) and g.151745 C>T (rs2682826) in our study group. CONCLUSION: The absence of mutations in the targeted NOS1 gene in the PD patients from North Karnataka shows the involvement of other genes in the molecular pathophysiology. Thus, it is crucial to screen other possible genes using cutting-edge technology to obtain a clear picture of the genetics of PD.

5.
Front Neurol ; 11: 524, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32655481

RESUMEN

Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our "hub-spoke" model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.

6.
Parkinsonism Relat Disord ; 69: 111-118, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31731261

RESUMEN

INTRODUCTION: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. METHODS: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. RESULTS: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). CONCLUSION: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.


Asunto(s)
Trastornos Distónicos/diagnóstico , Trastornos Distónicos/genética , Secuenciación Completa del Genoma/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Adulto Joven
7.
Neurology ; 79(21): 2115-21, 2012 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-23077024

RESUMEN

OBJECTIVE: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). METHODS: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. RESULTS: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. CONCLUSIONS: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders.


Asunto(s)
Ataxia/genética , Corea/genética , Proteínas de la Membrana/genética , Migraña con Aura/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Adolescente , Adulto , Anciano , Ataxia/diagnóstico , Niño , Corea/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Migraña con Aura/diagnóstico , Linaje , Adulto Joven
9.
Postgrad Med J ; 67(793): 1011-2, 1991 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-1775407

RESUMEN

A 14 year old boy developed the syndrome of Bickerstaff's brainstem encephalitis during the course of bacteriologically proved typhoid fever. The clinical course and the results of various neurological investigations are detailed. This report adds a further manifestation to the published neuropsychiatric complications of typhoid fever.


Asunto(s)
Encefalitis/complicaciones , Salmonella typhi , Fiebre Tifoidea/complicaciones , Adolescente , Ampicilina/uso terapéutico , Quimioterapia Combinada , Electroencefalografía , Encefalitis/diagnóstico , Encefalitis/tratamiento farmacológico , Humanos , Masculino , Combinación Trimetoprim y Sulfametoxazol/uso terapéutico , Fiebre Tifoidea/tratamiento farmacológico
10.
J Neurol Neurosurg Psychiatry ; 56(2): 209-10, 1993 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-8437013

RESUMEN

A patient manifested pathological laughter heralding the onset of brainstem stroke leading to a "locked-in" state. The pathological laughter did not recur. MRI revealed a bilateral ventral pontine infarct. The clinico-anatomical correlations of this rare phenomenon of fou rire prodromique are discussed.


Asunto(s)
Tronco Encefálico/irrigación sanguínea , Infarto Cerebral/fisiopatología , Risa/fisiología , Adulto , Infarto Cerebral/diagnóstico , Dominancia Cerebral/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética , Examen Neurológico , Puente/irrigación sanguínea , Cuadriplejía/diagnóstico , Cuadriplejía/fisiopatología , Flujo Sanguíneo Regional/fisiología
11.
J Neural Transm (Vienna) ; 109(9): 1189-94, 2002 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12203045

RESUMEN

Familial Paroxysmal Kinesigenic Dyskinesia (PKD) is an autosomal dominant condition characterized by attacks of dystonia or chorea triggered by sudden movements. Recently two separate loci for PKD, Episodic Kinesigenic Dyskinesia 1 (EKD1) and Episodic Kinesigenic Dyskinesia 2 (EKD2), have been mapped to chromosome 16 but the causative genes have not been identified. The Na(+)/H(+) exchanger gene (NHE5) involved in regulating intracellular pH lies in the EKD2 region. The coding region of the NHE5 gene in familial PKD was sequenced. We did not identify any mutations in the exons, intron/exon boundaries or the 5' and 3'UTR. This excludes mutations in the coding region of the NHE5 gene as a cause for familial PKD, but does not rule out a possible role of sequence variants in introns or regulatory regions.


Asunto(s)
Corea/genética , Mutación/genética , Intercambiadores de Sodio-Hidrógeno/genética , Regiones no Traducidas 3'/genética , Regiones no Traducidas 5'/genética , Ganglios Basales/metabolismo , Ganglios Basales/fisiopatología , Secuencia de Bases/genética , Corea/metabolismo , Corea/fisiopatología , Cromosomas Humanos Par 16/genética , ADN/análisis , ADN/genética , Análisis Mutacional de ADN , Exones/genética , Femenino , Heterocigoto , Humanos , Concentración de Iones de Hidrógeno , Líquido Intracelular/metabolismo , Intrones/genética , Masculino , Proteínas de la Membrana , Linaje , Intercambiadores de Sodio-Hidrógeno/metabolismo
12.
Brain ; 123 ( Pt 10): 2040-5, 2000 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11004121

RESUMEN

Paroxysmal kinesigenic choreoathetosis (PKC) is a rare paroxysmal movement disorder characterized by recurrent and brief attacks of choreiform or dystonic movements triggered or exacerbated by sudden voluntary movements. Some patients with PKC also have a history of infantile afebrile convulsions. PKC can be sporadic, or familial with autosomal dominant inheritance. PKC has been mapped to the pericentromeric region of human chromosome 16 in several Japanese families and in an African-American family, to regions which overlap by 9.8 cM (centiMorgan). Both regions overlap by 3.4 cM with a region containing a gene responsible for 'infantile convulsions and paroxysmal choreoathetosis' (ICCA). We have identified a second PKC locus (EKD2) on the long arm of chromosome 16 in a large Indian family with PKC. A maximum two-point LOD score of 3.66 (recombination fraction = 0.00, penetrance = 0.80) was obtained between PKC and D16S419. Haplotype and recombinant analysis localized EKD2 to a 15.8 cM region between D16S685 and D16S503. This region does not overlap with that identified in Japanese families, or with the ICCA locus. These results exclude one locus on chromosome 16 which causes both the ICCA and PKC syndromes; this suggests that there may be a cluster of genes on human chromosome 16 which lead to paroxysmal disorders.


Asunto(s)
Atetosis/genética , Corea/genética , Cromosomas Humanos Par 16 , Familia de Multigenes/genética , Adolescente , Adulto , Niño , Mapeo Cromosómico , Salud de la Familia , Ligamiento Genético , Marcadores Genéticos , Haplotipos , Humanos
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