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2.
J Neurol ; 254(7): 846-8, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17431704

RESUMEN

Given the known roles of TGFbeta2 in both regulating the immune system and promoting the survival of dopaminergic neurons, it is feasible that genetic variations in TGFB2 might play an aetiological role in neurological diseases such as Multiple Sclerosis (MS) and Parkinson's disease (PD). Hence we performed an indirect association analysis of TGFB2 using 8 haplotype-tagging SNPs in a population of 937 MS patients, 538 PD cases and 2022 controls. We found no evidence for association with susceptibility or progression of MS, but have demonstrated a trend towards association of the 5' region of the gene with susceptibility to PD. Further analysis of TGFB2 is warranted in other PD cohorts.


Asunto(s)
Esclerosis Múltiple/genética , Enfermedad de Parkinson/genética , Factor de Crecimiento Transformador beta2/genética , Humanos , Polimorfismo de Nucleótido Simple
3.
Neurology ; 68(5): 376-83, 2007 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-17261686

RESUMEN

BACKGROUND: Familial factors influence susceptibility to multiple sclerosis (MS) but it is unknown whether there are additional effects on the natural history of the disease. METHOD: We evaluated 1,083 families with > or =2 first-degree relatives with MS for concordance of age at onset, clinical course, and disease severity and investigated transmission patterns of these clinical features in affected parent-child pairs. RESULTS: There is concordance for age at onset for all families (correlation coefficient 0.14; p < 0.001), as well as for affected siblings (correlation coefficient 0.15; p < 0.001), and affected parent-child pairs (correlation coefficient 0.12; p = 0.03) when each is evaluated separately. Concordance for year of onset is present among affected siblings (correlation coefficient 0.18; p < 0.001) but not the parent-child group (correlation coefficient 0.08; p = 0.15). The clinical course is similar between siblings (kappa 0.12; p < 0.001) but not affected parents and their children (kappa -0.04; p = 0.09). This influence on the natural history is present in all clinical subgroups of relapsing-remitting, and primary and secondary progressive MS, reflecting a familial effect on episodic and progressive phases of the disease. There is no concordance for disease severity within any of the considered family groups (correlation coefficients: all families analyzed together, 0.02, p = 0.53; affected sibling group, 0.02, p = 0.61; affected parent-child group, 0.02, p = 0.69). Furthermore, there are no apparent transmission patterns of any of the investigated clinical features in affected parent-child pairs and no evidence for anticipation or effects of genetic loading. CONCLUSION: Familial factors do not significantly affect eventual disease severity. However, they increase the probability of a progressive clinical course, either from onset or after a phase of relapsing remitting disease. The familial effect is more likely to reflect genetic than environmental conditions. The results are relevant for counseling patients and have implications for the design of studies seeking to identify factors that influence the natural history of the disease.


Asunto(s)
Familia , Heterocigoto , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/genética , Medición de Riesgo/métodos , Adulto , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Internacionalidad , Masculino , Persona de Mediana Edad , Linaje , Prevalencia , Factores de Riesgo
5.
J Neurol Neurosurg Psychiatry ; 77(5): 665-7, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16614029

RESUMEN

The LRRK2 G2019S mutation is the commonest genetic cause of Parkinson's disease (PD) identified to date, although estimates of its prevalence in idiopathic disease vary considerably. Our objectives were to determine G2019S mutation frequency in an unselected, community based cohort of idiopathic PD cases from the UK and to describe phenotypic characteristics among carriers. The mutation was present in two of 519 cases (0.4%) and none of 887 control individuals. The true prevalence of the mutation in idiopathic disease, its penetrance, and the phenotypic heterogeneity of associated cases have important implications for genetic screening in the clinical field.


Asunto(s)
Sustitución de Aminoácidos/genética , Análisis Mutacional de ADN , Exones , Glicina/genética , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Serina/genética , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Estudios de Cohortes , Inglaterra , Femenino , Frecuencia de los Genes , Genes Dominantes , Tamización de Portadores Genéticos , Pruebas Genéticas , Genotipo , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Fenotipo
6.
Neurology ; 64(7): 1144-51, 2005 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-15824338

RESUMEN

BACKGROUND: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. METHODS: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. RESULTS: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. CONCLUSION: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.


Asunto(s)
Evaluación de la Discapacidad , Esclerosis Múltiple/diagnóstico , Índice de Severidad de la Enfermedad , Adulto , Edad de Inicio , Estudios de Cohortes , Estudios Transversales , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Francia/epidemiología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Modelos Neurológicos , Modelos Estadísticos , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/fisiopatología , Valor Predictivo de las Pruebas , Pronóstico , Recurrencia , Reproducibilidad de los Resultados
7.
J Neuroimmunol ; 143(1-2): 25-30, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14575910

RESUMEN

In 1996, we reported the results of a linkage genome screen based on 129 UK multiple sclerosis multiplex families, together with follow-up typing of interesting regions in a second set of families. We have now completed screening the remainder of the genome in this second set of United Kingdom families by typing 242 microsatellite markers. These data have been analysed together with those previously published, resulting in the largest currently available whole genome linkage dataset from a single population in multiple sclerosis. Four new regions of potential linkage (chromosomes 10p, 11p, 19p, 20p) not previously described were identified. In the combined analysis of all 226 families, a total of five regions of suggestive linkage are seen (chromosomes 1p, 6p, 14q, 17q, Xq), where only one would have been expected to occur by chance alone.


Asunto(s)
Ligamiento Genético , Pruebas Genéticas/métodos , Genoma Humano , Esclerosis Múltiple/genética , Alelos , Electroforesis en Gel de Poliacrilamida , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Prueba de Histocompatibilidad , Humanos , Masculino , Repeticiones de Microsatélite , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/inmunología , Reacción en Cadena de la Polimerasa , Hermanos , Reino Unido/epidemiología
8.
J Neuroimmunol ; 143(1-2): 60-4, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14575915

RESUMEN

The association of multiple sclerosis with alleles/haplotypes from the HLA region on chromosome 6p21 is well established although the remainder of the genome remains relatively unexplored. We have completed a genome-wide screen for linkage disequilibrium in a cohort of Australian multiple sclerosis patients positive for HLA-DRB1*1501. A total of 4346 microsatellite markers provided through the "Genetic Analysis of Multiple sclerosis in EuropeanS" (GAMES) collaborative were analysed in DNA separately pooled from cases (n=217) and controls (n=187). Associations were found in four genomic regions (12q15, 16p13, 18p11 and 19q13) previously identified in linkage genome screens. Three additional regions of novel association were also identified (11q12, 11q23 and 14q21). Further analysis of these regions is required to establish whether the associations observed are due to epistatic interaction with the HLA locus.


Asunto(s)
Alelos , Pruebas Genéticas , Genoma Humano , Antígenos HLA-DR/genética , Desequilibrio de Ligamiento/genética , Esclerosis Múltiple/genética , Adulto , Australia/epidemiología , Estudios de Casos y Controles , Femenino , Pruebas Genéticas/métodos , Pruebas Genéticas/estadística & datos numéricos , Genotipo , Cadenas HLA-DRB1 , Prueba de Histocompatibilidad/estadística & datos numéricos , Humanos , Masculino , Repeticiones de Microsatélite/genética , Esclerosis Múltiple/epidemiología
9.
J Neurol ; 250(8): 943-7, 2003 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12928913

RESUMEN

Osteopontin transcription is increased in the central nervous system of patients with multiple sclerosis and rats with experimental allergic encephalomyelitis; where expression correlates with disease severity. We typed four single nucleotide polymorphisms located in exons 6 and 7 of the osteopontin gene in a large cohort of 1056 multiple sclerosis patients and 325 controls. We did not find significant allelic differences of the screened polymorphisms between the cases and controls and there was no allelic association with disease severity. Despite strong theoretical reasons to consider osteopontin as a potential candidate, the results of our study argue against the gene being a susceptibility locus for either the development or clinical severity of MS.


Asunto(s)
Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Sialoglicoproteínas/genética , Alelos , Distribución de Chi-Cuadrado , Exones , Femenino , Humanos , Masculino , Esclerosis Múltiple/metabolismo , Osteopontina , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Nucleótido Simple/genética , Índice de Severidad de la Enfermedad , Sialoglicoproteínas/metabolismo
10.
Brain Res Bull ; 61(3): 229-34, 2003 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-12909292

RESUMEN

Recent years have witnessed considerable advances in our understanding of monogenic neurodegenerative diseases, such as hereditary motor sensory neuropathy and Huntington's Chorea. Progress has been slower in the genetic dissection of other more common neurological diseases with a complex mode of inheritance. The identification of relevant genes in some, such as Alzheimer's disease (AD) or Parkinson's disease (PD), has been facilitated by characteristic pathological findings and autosomal dominant inheritance in a proportion of early onset families. Attempts to identify relevant genes for multiple sclerosis have highlighted the role of the major histocompatibility complex, but so far failed to unequivocally implicate other immunologic or structural candidate genes. Six linkage-based whole genome screens have been completed in multiple sclerosis and several regions of interest have been identified. As technology and progress in the human genome project advance, it has become clear that future studies of common neurological diseases will depend critically on the availability of large sample sizes and will have to address issues of disease heterogeneity.


Asunto(s)
Esclerosis Múltiple/genética , Enfermedades del Sistema Nervioso/genética , Predisposición Genética a la Enfermedad , Genoma Humano , Humanos
11.
Genes Immun ; 3(8): 464-9, 2002 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-12486604

RESUMEN

The role of genetic factors in determining susceptibility to multiple sclerosis is well established but, despite the global distribution of the disease, systematic efforts to locate susceptibility genes have concentrated exclusively on populations from the Northern Hemisphere. We performed a genome wide screen of linkage in the Australian population using a panel of 397 microsatellite markers in 54 affected sibling-pairs. Multipoint linkage analysis revealed four regions of suggestive linkage (on chromosomes 2p13, 4q26-28, 6q26 and Xp11) and 18 additional regions of potential linkage (at 1q43-44, 3q13-24, 4q24, 4q31-34, 5q11-13, 6q27, 7q33-35, 8p23-21, 9q21, 13q31-32, 16p13, 16p11, 16q23-24, 17p13, 18p11, 20p12-11, Xp21-11 and Xq23-28). Our results contribute to the available data adding new provisional regions of linkage as well as increasing support for areas previously implicated in genetic susceptibility to multiple sclerosis.


Asunto(s)
Mapeo Cromosómico/métodos , Ligamiento Genético/genética , Genoma Humano , Esclerosis Múltiple/genética , Hermanos , Australia , Frecuencia de los Genes/genética , Humanos , Repeticiones de Microsatélite/genética
12.
J Neurol Neurosurg Psychiatry ; 72(2): 184-7, 2002 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11796767

RESUMEN

BACKGROUND: The association between multiple sclerosis and class II alleles of the major histocompatibility complex, in particular the DRB1*1501-DQB1*0602 haplotype, is well established but their role in determining specific features of this clinically heterogeneous disease is unknown as few studies involving large sample sizes have been performed. METHODS: 729 patients with multiple sclerosis were typed for the HLA DR15 phenotype. All patients underwent clinical assessment and a detailed evaluation of their clinical records was undertaken. RESULTS: The presence of DR15 was associated with younger age at diagnosis and female sex but there was no association with disease course (relapsing-remitting or secondary progressive v primary progressive type), disease outcome, specific clinical features (opticospinal v disseminated form), diagnostic certainty (clinically and laboratory supported definite v clinically probable multiple sclerosis), and paraclinical investigations including the presence of oligoclonal bands in the CSF or characteristic abnormalities on MRI imaging of the central nervous system. CONCLUSION: Even though DR15 carriers are more likely to be female and prone to an earlier disease onset, the results indicate that there is no association with other specific clinical outcomes or laboratory indices examined here. This suggests that DR15 exerts a susceptibility rather than disease modifying effect in multiple sclerosis.


Asunto(s)
Antígenos HLA-DR/genética , Esclerosis Múltiple Crónica Progresiva/genética , Esclerosis Múltiple Recurrente-Remitente/genética , Fenotipo , Adolescente , Adulto , Factores de Edad , Alelos , Estudios de Cohortes , Evaluación de la Discapacidad , Tamización de Portadores Genéticos , Predisposición Genética a la Enfermedad/genética , Subtipos Serológicos HLA-DR , Humanos , Masculino , Esclerosis Múltiple Crónica Progresiva/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Pronóstico , Factores Sexuales
13.
J Neurol Neurosurg Psychiatry ; 71(1): 97-9, 2001 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-11413271

RESUMEN

The clinical and radiological overlap between multiple sclerosis and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; MIM 125310) raises the possibility of diagnostic confusion and suggests that pleiotropic effects of the Notch3 gene might include influencing susceptibility to multiple sclerosis. To investigate these possibilities three microsatellites markers closely flanking the Notch 3 gene in 745 simplex families with multiple sclerosis were genotyped and exon 3 and exon 4 of the gene were directly sequenced in a subset of the index members from these families (n=93). No evidence for association was found in any of the three markers and none of the commoner mutations causing CADASIL were found in the sequenced patients.


Asunto(s)
Demencia por Múltiples Infartos/genética , Esclerosis Múltiple/genética , Proteínas Proto-Oncogénicas/genética , Receptores de Superficie Celular , Adulto , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Reacción en Cadena de la Polimerasa , Receptor Notch3 , Receptores Notch
14.
Brain ; 123 ( Pt 6): 1102-11, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10825350

RESUMEN

Previous studies examining an association with other autoimmune diseases have suggested the existence of a generalized autoimmune diathesis in patients with multiple sclerosis. We investigated the prevalence of autoimmune disease in first-degree relatives of probands with multiple sclerosis using a case-control method. The results show an excess of autoimmune disease within these families, but no significant association was seen with non-autoimmune diseases. The higher risk in multiplex than simplex families suggests an effect of genetic loading. While the increase in risk applies to each autoimmune disease, autoimmune thyroid disease (and Graves' disease in particular) contributes disproportionately to the excess risk. There was no increase in autoimmune disease within patients with multiple sclerosis themselves when compared with the index controls or population data. We conclude that autoimmune disease is more common in first-degree relatives of patients with multiple sclerosis and hypothesize that common genetic susceptibility factors for autoimmunity co-exist with additional disease specific genetic or environmental factors, which determine clinical phenotype in the individual.


Asunto(s)
Enfermedades Autoinmunes/epidemiología , Salud de la Familia , Esclerosis Múltiple/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/genética , Estudios de Casos y Controles , Recolección de Datos , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/genética , Núcleo Familiar , Prevalencia , Psoriasis/epidemiología , Psoriasis/genética , Factores de Riesgo , Reino Unido/epidemiología
15.
Mult Scler ; 6(2): 121-3, 2000 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-10773858

RESUMEN

The notion that cervical lymphatic surgery may influence the development of multiple sclerosis has been suggested before. Recent work in experimental allergic encephalomyelitis lends further support to this idea. We, therefore conducted a case:control study of tonsillectomy in multiple sclerosis. We found no evidence to suggest that tonsillectomy affects susceptibility to multiple sclerosis. This result supports previous studies, which have largely failed to show any link between prior tonsillectomy and the subsequent development of multiple sclerosis. In addition, we failed to show any effect of tonsillectomy on the extent of cerebral demyelination as assessed clinically or with magnetic resonance imaging.


Asunto(s)
Esclerosis Múltiple/etiología , Esclerosis Múltiple/genética , Tonsilectomía/efectos adversos , Adenoidectomía/efectos adversos , Adulto , Distribución por Edad , Encéfalo/patología , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/epidemiología , Vaina de Mielina/patología , Fenotipo , Estudios Prospectivos , Valores de Referencia , Distribución por Sexo
17.
Neurology ; 45(10): 1859-63, 1995 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-7477982

RESUMEN

Assessments of genetically determined variations in the T-cell antigen receptor in multiple sclerosis (MS) have yielded conflicting results. We used three restriction fragment length polymorphisms (RFLPs) and a polymorphic microsatellite repeat as markers for the T-cell receptor (TCR) beta locus (7q32-35) in multiplex MS families. Affected sibling-pair analysis of the RFLP data failed to show evidence for linkage (127 families) whereas analysis of the microsatellite data (86 families) provided weak evidence for linkage with a maximum lod score of 0.98 (p < 0.05). We repeated the analysis in those families (n = 53) in which the affected sibling pairs were concordant for the HLA haplotype DR15/DQ6. This altered the proportion of affected siblings sharing 0, 1, 2 RFLP haplotypes from 0.24, 0.50, and 0.26 (p = NS) before stratification to 0.16, 0.41, and 0.43 (p < 0.05) in the DR15/DQ6 positive pairs alone; for the microsatellite data, sharing altered from 0.16, 0.50, and 0.34 (p < 0.05) in all pairs to 0.07, 0.49, and 0.44 (p < 0.01) in the DR15/DQ6 concordant siblings.


Asunto(s)
Esclerosis Múltiple/genética , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Adulto , Anciano , Secuencia de Bases , ADN Satélite/análisis , Femenino , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Polimorfismo de Longitud del Fragmento de Restricción , Secuencias Repetitivas de Ácidos Nucleicos
18.
J Neurol ; 242(10): 677-82, 1995 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8568530

RESUMEN

A haplotype marker consisting of three biallelic restriction fragment length polymorphism (RFLP) loci from the VH-2 variable gene family was examined in 124 families with sibling pairs concordant for multiple sclerosis, 178 unrelated patients and 159 unaffected controls to investigate the role of the immunoglobulin heavy chain gene cluster in susceptibility to multiple sclerosis. Evidence for linkage was assessed using the affected sibling pair method of identity by descent, modified to allow for haplotype sharing on a probabilistic basis in families where haplotypes could not be assigned with certainty. The estimated probabilities of affected siblings sharing 0, 1 or 2 haplotypes were Z0 = 0.20, Z1 = 0.45, Z2 = 0.35. This deviation from the expected sharing probabilities of Z0 = 0.25, Z1 = 0.5, Z2 = 0.25 provides evidence for weak linkage (P < 0.05; equivalent to a lod score of 0.84); however, no significant allelic or haplotypic association was observed. Linkage without a population association suggests that a gene encoded on 14q confers susceptibility to multiple sclerosis, although this is not any of the existing VH-2 polymorphisms.


Asunto(s)
Genes de Inmunoglobulinas , Ligamiento Genético , Marcadores Genéticos , Haplotipos , Familia de Multigenes , Esclerosis Múltiple/genética , Alelos , Susceptibilidad a Enfermedades , Frecuencia de los Genes , Humanos , Funciones de Verosimilitud
19.
Eye (Lond) ; 9 ( Pt 6): 760-2, 1995.
Artículo en Inglés | MEDLINE | ID: mdl-8849546

RESUMEN

A number of anticoagulants are found in plasma, helping to maintain the balance between thrombosis and haemorrhage. Two of the most important are antithrombin and protein C, which inactivates factors V and VIII. Deficiencies are well-recognised predisposing factors for systemic thrombosis. To establish whether the factor V or Cambridge II antithrombin mutations were present with an increased frequency in patients with idiopathic central retinal vein occlusion (CRVO) we screened 50 such patients. DNA was isolated and the regions of the gene encoding for factor V and antithrombin were amplified by means of the polymerase chain reaction. Following digestion with restriction enzymes the products were electrophoresed in agarose gels. We identified a single patient with the factor V mutation and none with the antithrombin mutation. These findings suggest that resistance to activated protein C and antithrombin mutations does not play a major role in CRVO.


Asunto(s)
Antitrombinas/genética , Factor V/genética , Mutación , Oclusión de la Vena Retiniana/genética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa
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