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1.
Mult Scler Relat Disord ; 32: 64-65, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31035122

RESUMEN

Diagnosis of biotinidase deficiency is rare and usually made in infancy, through newborn screening or after presenting symptoms. We present the case of 19-year old male with progressive optic atrophy and in a second phase spinal cord syndrome unresponsive to immunosuppressive therapies. After diagnosis of profound biotinidase deficiency, oral biotin substitution was started with partial visual improvement and normalization of gait. This case highlights the possibility of late-onset biotinidase deficiency and its treatable character.


Asunto(s)
Deficiencia de Biotinidasa/diagnóstico por imagen , Deficiencia de Biotinidasa/tratamiento farmacológico , Atrofia Óptica/diagnóstico por imagen , Atrofia Óptica/tratamiento farmacológico , Enfermedades de la Médula Espinal/diagnóstico por imagen , Enfermedades de la Médula Espinal/tratamiento farmacológico , Biotina/administración & dosificación , Deficiencia de Biotinidasa/genética , Humanos , Masculino , Atrofia Óptica/genética , Enfermedades de la Médula Espinal/genética , Adulto Joven
2.
Mol Psychiatry ; 22(6): 874-883, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-27113998

RESUMEN

A recent genome-wide association meta-analysis for Alzheimer's disease (AD) identified 19 risk loci (in addition to APOE) in which the functional genes are unknown. Using Drosophila, we screened 296 constructs targeting orthologs of 54 candidate risk genes within these loci for their ability to modify Tau neurotoxicity by quantifying the size of >6000 eyes. Besides Drosophila Amph (ortholog of BIN1), which we previously implicated in Tau pathology, we identified p130CAS (CASS4), Eph (EPHA1), Fak (PTK2B) and Rab3-GEF (MADD) as Tau toxicity modulators. Of these, the focal adhesion kinase Fak behaved as a strong Tau toxicity suppressor in both the eye and an independent focal adhesion-related wing blister assay. Accordingly, the human Tau and PTK2B proteins biochemically interacted in vitro and PTK2B co-localized with hyperphosphorylated and oligomeric Tau in progressive pathological stages in the brains of AD patients and transgenic Tau mice. These data indicate that PTK2B acts as an early marker and in vivo modulator of Tau toxicity.


Asunto(s)
Quinasa 2 de Adhesión Focal/genética , Proteínas tau/metabolismo , Enfermedad de Alzheimer/genética , Animales , Biomarcadores , Modelos Animales de Enfermedad , Drosophila/genética , Quinasa 2 de Adhesión Focal/metabolismo , Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Factores de Riesgo , Proteínas tau/genética
3.
Mol Psychiatry ; 18(11): 1225-34, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23399914

RESUMEN

Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Predisposición Genética a la Enfermedad/genética , Proteínas Nucleares/genética , Proteínas Supresoras de Tumor/genética , Proteínas tau/metabolismo , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Proteínas de Drosophila/deficiencia , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Endofenotipos , Expresión Génica/genética , Humanos , Ratones , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Proteínas Nucleares/biosíntesis , Placa Amiloide/patología , Polimorfismo de Nucleótido Simple/genética , Sinaptosomas/patología , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/biosíntesis , Proteínas tau/antagonistas & inhibidores
4.
J Neurol Neurosurg Psychiatry ; 81(1): 90-3, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20019223

RESUMEN

BACKGROUND: m.14487T>C, a missense mutation (p.M63V) affecting the ND6 subunit of complex I of the mitochondrial respiratory chain, has been reported in isolated childhood cases with Leigh syndrome (LS) and progressive dystonia. Adult-onset phenotypes have not been reported. OBJECTIVES: To determine the clinical-neurological spectrum and associated mutation loads in an extended m.14487T>C family. METHODS: A genotype-phenotype correlation study of a Belgian five-generation family with 12 affected family members segregating m.14487T>C was carried out. Clinical and mutation load data were available for nine family members. Biochemical analysis of the respiratory chain was performed in three muscle biopsies. RESULTS: Heteroplasmic m.14487T>C levels (36-52% in leucocytes, 97-99% in muscle) were found in patients with progressive myoclonic epilepsy (PME) and dystonia or progressive hypokinetic-rigid syndrome. Patients with infantile LS were homoplasmic (99-100% in leucocytes, 100% in muscle). We found lower mutation loads (between 8 and 35% in blood) in adult patients with clinical features including migraine with aura, Leber hereditary optic neuropathy, sensorineural hearing loss and diabetes mellitus type 2. Despite homoplasmic mutation loads, complex I catalytic activity was only moderately decreased in muscle tissue. INTERPRETATION: m.14487T>C resulted in a broad spectrum of phenotypes in our family. Depending on the mutation load, it caused severe encephalopathies ranging from infantile LS to adult-onset PME with dystonia. This is the first report of PME as an important neurological manifestation of an isolated mitochondrial complex I defect.


Asunto(s)
Enfermedad de Leigh/genética , Epilepsias Mioclónicas Progresivas/genética , NADH Deshidrogenasa/genética , Adulto , Edad de Inicio , Bélgica , Niño , ADN Mitocondrial/genética , Trastornos Distónicos/genética , Familia , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Mutación Missense/genética , Linaje , Fenotipo , Adulto Joven
5.
Neurology ; 63(1): 173-5, 2004 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-15249634

RESUMEN

The authors previously reported that genetic variation in the gene coding for nicastrin (NCSTN) modified risk for familial early-onset Alzheimer disease (AD) in a Dutch population-based sample. Risk was highest in patients without an APOE epsilon4 allele. Here, they evaluated if NCSTN polymorphisms increased risk of AD in the eastern Finnish population. A significant difference in one haplotype was observed in AD patients without the APOE epsilon4 allele.


Asunto(s)
Enfermedad de Alzheimer/genética , Glicoproteínas de Membrana/genética , Polimorfismo de Nucleótido Simple , Anciano , Enfermedad de Alzheimer/epidemiología , Secretasas de la Proteína Precursora del Amiloide , Apolipoproteínas E/genética , Femenino , Finlandia/epidemiología , Genes Dominantes , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos/genética , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Presenilina-1 , Presenilina-2
6.
J Neurol Neurosurg Psychiatry ; 75(8): 1166-70, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15258222

RESUMEN

OBJECTIVES: The most common familial early onset dementia mutations are found in the genes involved in Alzheimer's disease; the amyloid precursor protein (APP) and the presenilin 1 and 2 (PSEN1 and 2) genes; the prion protein gene (PRNP) may be involved. METHODS: Following identification of a two-octapeptide repeat insertion in PRNP, we conducted a meta-analysis to investigate the relation of number of PRNP octapeptide repeats with age at disease onset and duration of illness; identifying 55 patients with PRNP octapeptide repeat insertions. We used a linear mixed effects model to assess the relation of number of repeats with age at disease onset, and studied the effect of the number of inserted octapeptide repeats on disease duration with a Cox proportional hazards regression analysis. RESULTS: We found an increasing number of repeats associated with younger age at onset (p < 0.001). Duration of the disease decreased significantly with the length of the octapeptide repeat (p < 0.001) when adjusting for age at onset. CONCLUSIONS: Our findings show significant inverse associations of the length of the PRNP octapeptide repeat with age at disease onset and disease duration in the spongiform encephalopathies.


Asunto(s)
Demencia/genética , Demencia/patología , Priones/genética , Secuencias Repetitivas de Ácidos Nucleicos , Edad de Inicio , Progresión de la Enfermedad , Humanos , Fenotipo , Análisis de Regresión , Factores de Tiempo
8.
J Neurol Neurosurg Psychiatry ; 74(8): 1148-51, 2003 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12876259

RESUMEN

OBJECTIVE: The authors conducted a prospective study of neurodegenerative and vascular dementia in Belgium. Strict diagnostic inclusion criteria were used to include well defined patients and controls. The results of apolipoprotein E (APOE) genotype effect on risk and clinical characteristics are presented. METHODS: APOE genotyping was performed in patients with probable Alzheimer's disease (AD) (n=504), frontotemporal dementia (FTD) (n=47), vascular dementia (VaD) (n=152), mixed dementia (n=132), mild cognitive impairment (MCI) (n=44), Parkinson's disease (PD) (n=30), dementia with Lewy bodies (DLB) (n=17), and multisystem atrophy (MSA)/progressive supranuclear palsy (PSP) (n=12). RESULTS: The APOE allele frequencies of this Belgian control population (epsilon 2: 6.9%; epsilon 3: 76.2%; epsilon 4: 16.9%) did not differ from those reported for other white populations. AD, MCI, and mixed dementia patients had higher APOE epsilon 4 (32.9%, 38.6%, and 28.4% respectively) and lower APOE epsilon 3 (62.2%, 53.4%, and 66.3%) frequencies compared with controls, whereas only AD and mixed dementia patients had lower APOE epsilon 2 frequencies (4.9% and 5.3%). Apart from a borderline significant different distribution of APOE allele frequencies in VaD patients compared with controls, no other differences were detected. The influence of APOE epsilon 4 on clinical features of dementia was limited to lower age at onset in AD patients and a less pronounced negative correlation between age at onset and number of epsilon 4 alleles in MCI and mixed dementia patients. CONCLUSIONS: This study confirmed the risk association between APOE epsilon 4 and AD. The observation that APOE epsilon 4 is associated with mixed dementia reflected the role of AD in the aetiopathogenesis of this condition. Although MCI is an aetiologically heterogeneous syndrome, the increased APOE epsilon 4 frequencies indicated that a large proportion of the MCI patients included in the study might be predisposed to develop AD.


Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Demencia Vascular/genética , Demencia/genética , Genotipo , Enfermedades Neurodegenerativas/genética , Adulto , Anciano , Alelos , Enfermedad de Alzheimer/diagnóstico , Apolipoproteína E2 , Apolipoproteína E4 , Bélgica , Demencia/diagnóstico , Demencia Vascular/diagnóstico , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genética de Población , Humanos , Imagen por Resonancia Magnética , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Enfermedades Neurodegenerativas/diagnóstico , Estudios Prospectivos , Valores de Referencia
9.
Neuromuscul Disord ; 13(2): 133-42, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12565911

RESUMEN

Autosomal recessive progressive external ophthalmoplegia is a mitochondrial disease characterized by accumulation of multiple large-scale deletions of mitochondrial DNA. We previously reported missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma in two nuclear families compatible with autosomal recessive progressive external ophthalmoplegia. Here, we report a novel POLG missense mutation (R627W) in a sporadic patient and we provide genetic support that all these POLG mutations are actually causal and recessive. The novel patient presented with sensory ataxic neuropathy and has the clinical triad of sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO). This is the first finding of a genetic cause of Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis and it implies that this disorder may actually be a variant of autosomal recessive progressive external ophthalmoplegia. Sensory neuropathy is the initial feature in Belgian compound heterozygote autosomal recessive progressive external ophthalmoplegia patients, all carrying the POLG A467T mutation, which occurs at a frequency of 0.6% in the Belgian population.


Asunto(s)
Ataxia/genética , ADN Polimerasa Dirigida por ADN/genética , Mutación Missense , Oftalmoplejía Externa Progresiva Crónica/genética , Adolescente , Adulto , Anciano , Arginina/genética , Ataxia/etiología , ADN Polimerasa gamma , ADN Polimerasa Dirigida por ADN/ultraestructura , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Genes Recesivos , Heterocigoto , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Datos de Secuencia Molecular , Músculo Esquelético/química , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Oftalmoplejía Externa Progresiva Crónica/complicaciones , Linaje , Succinato Deshidrogenasa/metabolismo , Triptófano/genética
10.
Mol Psychiatry ; 7(10): 1064-74, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12476321

RESUMEN

We report the results of a genome-wide search in a four-generation pedigree with autosomal dominant early-onset dementia (mean onset age: 64.9 years, range 53-79 years). In this family we previously excluded the known Alzheimer's disease genes based on linkage analysis and mutation screening of the amyloid precursor protein gene (exons 16 and 17) and the presenilin 1 and 2 genes. In addition we excluded mutations in the prion protein gene and exons 9-13 of the microtubule associated protein tau (MAPT) gene. We obtained conclusive linkage with chromosome 17q21 markers with a maximum multi-point LOD score of 5.51 at D17S951 and identified a candidate region of 4.8 cM between D17S1787 and D17S958 containing MAPT. Recent clinical and neuropathological follow-up of the family showed that the phenotype most closely resembled frontotemporal dementia (FTD) characterized by dense ubiquitin-positive neuronal inclusions that were tau negative. Extensive mutation analysis of MAPT identified 38 sequence variations in exons, introns, untranslated regions and the 5' regulatory sequence, however none was comprised within the disease haplotype. Although our findings do not entirely exclude a mutation in a yet unanalyzed region of MAPT, the apparent absence of MAPT mutations combined with the lack of tau pathology is highly suggestive for another defective gene at 17q21 responsible for FTD in this family.


Asunto(s)
Precursor de Proteína beta-Amiloide/genética , Cromosomas Humanos Par 17 , Demencia/genética , Lóbulo Frontal/patología , Eliminación de Gen , Proteínas tau/genética , Anciano , Mapeo Cromosómico , Demencia/patología , Femenino , Marcadores Genéticos , Genoma Humano , Humanos , Masculino , Persona de Mediana Edad , Linaje
11.
Am J Med Genet ; 114(5): 570-3, 2002 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-12116196

RESUMEN

The apolipoprotein E (APOE) gene is involved in lipid transport. A common polymorphism in this gene with the APOE*2, APOE*3, and APOE*4 alleles influences plasma levels of apolipoprotein E and cholesterol. Besides its role in lipid transport, the APOE*4 allele is a genetic risk factor for Alzheimer disease (AD). Recently, a polymorphism in the APOE promoter region was found to be involved in plasma apolipoprotein E levels and was found associated with AD. We studied the effect of this -491A/T promoter polymorphism on plasma apolipoprotein E levels and risk for AD in a population-based case-control study. We found that there was a modest but statistically significant effect of the -491A/T polymorphism on plasma apolipoprotein E levels independent of the APOE genotype. The lowest plasma levels were measured for the AA genotype, highest levels for the TT genotype, and intermediate levels for the heterozygotes. There was a small effect of the -491 AA genotype on AD risk that disappeared after adjusting for APOE genotypes. Our data suggest that the -491A/T polymorphism has an APOE genotype-independent effect on plasma apolipoprotein E levels but no APOE-independent effect on AD risk.


Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Alelos , Enfermedad de Alzheimer/sangre , Apolipoproteínas E/sangre , ADN/genética , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Regiones Promotoras Genéticas/genética , Factores de Riesgo
12.
Brain ; 124(Pt 12): 2383-92, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11701593

RESUMEN

The dense-cored plaques are considered the pathogenic type of amyloid deposition in Alzheimer's disease brains because of their predominant association with dystrophic neurites. Nevertheless, in > 90% of cases of Alzheimer's disease amyloid is also deposited in cerebral blood vessel walls (congophilic amyloid angiopathy; CAA) but its role in Alzheimer's disease pathogenesis remains enigmatic. Here, we report a family (family GB) in which early-onset Alzheimer's disease was caused by a novel presenilin 1 mutation (L282V). This was unusually severe CAA reminiscent of the Flemish amyloid precursor protein (A692G) mutation we reported previously, which causes Alzheimer's disease and/or cerebral haemorrhages. In family GB, however, the disease presented as typical progressive Alzheimer's disease in the absence of strokes or stroke-like episodes. Similarly, neuroimaging studies and neuropathological examination favoured a degenerative over a vascular dementia. Interestingly, an immunohistochemical study revealed that, similar to causing dense-cored amyloid plaques, CAA also appeared capable of instigating a strong local dystrophic and inflammatory reaction. This was suggested by the observed neuronal loss, the presence of tau- and ubiquitin-positive neurites, micro- and astrogliosis, and complement activation. Together, these data suggest that, like the dense-cored neuritic plaques, CAA might represent a pathogenic lesion that contributes significantly to the progressive neurodegeneration that occurs in Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Angiopatía Amiloide Cerebral Familiar/genética , Angiopatía Amiloide Cerebral Familiar/patología , Proteínas de la Membrana/genética , Adulto , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/análisis , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/metabolismo , Línea Celular , Angiopatía Amiloide Cerebral Familiar/diagnóstico por imagen , Salud de la Familia , Resultado Fatal , Femenino , Lóbulo Frontal/química , Lóbulo Frontal/patología , Genotipo , Humanos , Inmunohistoquímica , Riñón/citología , Masculino , Persona de Mediana Edad , Mutagénesis Sitio-Dirigida , Mutación , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , Presenilina-1 , Cintigrafía
13.
Neurosci Lett ; 313(1-2): 69-72, 2001 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-11684342

RESUMEN

We investigated the risk associated with the codon 129 polymorphism in the prion protein gene (PRNP) and apolipoprotein E gene (APOE) isoforms for development of Creutzfeldt-Jakob disease (CJD) (n=126) and the possible influences on the disease pathology and its most important clinical characteristics. The PRNP M129V (PRNP129) polymorphism was determined using both DNA extracted from formalin fixed and paraffin embedded brain tissue (n=59) and leukocyte extracted DNA (n=67). In the latter group also the PRNP open reading frame and the APOE genotype were analysed and compared to a neurologically unaffected, age and sex matched control group (n=79). We found that methionine homozygosity of the PRNP129 increases the risk for developing CJD. PRNP129 also influenced the prion accumulation patterns in brain. The APOE 4 allele was an independent risk factor for developing CJD. We further observed a significant dose dependent APOE 4 effect on the number and type of amyloid-beta plaques in the brain of CJD patients.


Asunto(s)
Apolipoproteínas E/genética , Síndrome de Creutzfeldt-Jakob/genética , Priones/genética , Anciano , Apolipoproteína E4 , Síndrome de Creutzfeldt-Jakob/epidemiología , Síndrome de Creutzfeldt-Jakob/patología , Femenino , Fijadores , Formaldehído , Predisposición Genética a la Enfermedad , Genotipo , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Placa Amiloide/patología , Polimorfismo Genético , Estudios Retrospectivos , Factores de Riesgo
14.
Neurosci Lett ; 313(1-2): 105-7, 2001 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-11684351

RESUMEN

The beta-site of beta-amyloid precursor protein cleaving enzyme (BACE) cleaves the beta-amyloid (Abeta) precursor protein at the N-terminal end of Abeta, allowing for the production of Abeta by C-terminal gamma-secretase cleavage. We hypothesized that over-activity of BACE might lead to the overproduction of Abeta, hence causing Alzheimer's disease (AD). Molecular genetic analyses of BACE in 9 autosomal dominant AD families and a population-based sample of 101 presenile AD cases did not identify genetic linkage, pathogenic mutations or genetic association with BACE, suggesting that BACE is not genetically involved in the etiology of AD.


Asunto(s)
Enfermedad de Alzheimer/genética , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Edad de Inicio , Secretasas de la Proteína Precursora del Amiloide , Precursor de Proteína beta-Amiloide/metabolismo , Endopeptidasas , Genes Dominantes , Ligamiento Genético , Genotipo , Humanos , Persona de Mediana Edad , Polimorfismo Genético
15.
Brain ; 124(Pt 10): 1939-47, 2001 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11571212

RESUMEN

At least 13 loci responsible for autosomal dominant cerebellar ataxia (ADCA) have been identified. Spinocerebellar ataxia 1, 2, 3, 6 and 7 are caused by translated CAG repeat expansions. However, in France, >30% of ADCAs are not explained by the known genes. Recently, analysis of the TATA box-binding protein (TBP) gene, one of the transcription factors known to contain a CAG/CAA repeat, in patients with progressive cerebellar ataxia revealed one sporadic case with 63 repeats. We examined this gene in 162 index cases with ADCA. An expanded repeat with 46 repeat units was detected in a single index case from Belgium. In this family, two affected members and six unaffected, but at-risk, individuals carried expanded alleles. Interestingly, the expanded repeat was stable during transmission. The main clinical features in six patients were cerebellar ataxia, dementia and behavioural disturbances with onset in their fourth to sixth decade. The main neuropathological finding was severe neuronal loss and gliosis in the Purkinje cell layer. Immunohistochemical analysis showed neuronal intranuclear inclusions containing expanded polyglutamine, indicating that this disease shares several features with other polyglutamine diseases. This study demonstrates that CAG/CAA repeat expansion in the TBP gene causes ADCA with dementia and/or psychiatric manifestations.


Asunto(s)
Ataxia Cerebelosa/genética , Proteínas de Unión al ADN/genética , TATA Box/genética , Factores de Transcripción/genética , Expansión de Repetición de Trinucleótido/genética , Adulto , Anciano , Atrofia , Encéfalo/patología , Ataxia Cerebelosa/patología , Femenino , Gliosis/genética , Gliosis/patología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Linaje , Proteína de Unión a TATA-Box
18.
Nat Genet ; 28(3): 211-2, 2001 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-11431686

RESUMEN

Progressive external ophthalmoplegias (PEO) characterized by accumulation of large-scale mitochondrial DNA (mtDNA) deletions are rare human diseases. We mapped a new locus for dominant PEO at 15q22-q26 in a Belgian pedigree and identified a heterozygous mutation (Y955C) in the polymerase motif B of the mtDNA polymerase gamma (POLG). We identified three additional POLG missense mutations compatible with recessive PEO In two nuclear families. POLG is the only DNA polymerase responsible for mtDNA replication.


Asunto(s)
ADN Mitocondrial/genética , ADN Polimerasa Dirigida por ADN/genética , Oftalmoplejía Externa Progresiva Crónica/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Bélgica , Cromosomas Humanos Par 15/genética , ADN Polimerasa gamma , Femenino , Heterocigoto , Humanos , Escala de Lod , Masculino , Datos de Secuencia Molecular , Mutación , Mutación Missense , Oftalmoplejía Externa Progresiva Crónica/enzimología , Oftalmoplejía Externa Progresiva Crónica/epidemiología , Linaje , Eliminación de Secuencia , Homología de Secuencia de Aminoácido
19.
J Neurol ; 248(11): 935-9, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11757955

RESUMEN

We have previously reported a significant association between early-onset Alzheimer's disease (EOAD) and an allele in the promoter of presenilin 1 (PSEN1) significantly decreasing PSEN1 expression in vitro. For late-onset Alzheimer's disease (LOAD), numerous studies have reported inconsistent associations with a PSEN1 intronic polymorphism. We therefore hypothesized that linkage disequilibrium between the intronic PSEN1 polymorphism and the functional promoter polymorphism might explain the conflicting reports in LOAD. We analysed both variations in 356 LOAD patients and 230 controls in a population-based case-control study. In addition, we re-analysed all published literature on the PSEN1 intronic polymorphism in a meta-analysis. No significant association was found with the PSEN1 intronic or promoter polymorphism in our case-control sample. In the meta-analysis no major differences between patients and controls were found for the PSEN1 intronic variation. Together, our results do not support a major role for variable expression of PSEN1 in LOAD.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/biosíntesis , Edad de Inicio , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Proteínas de la Membrana/análisis , Polimorfismo Genético , Presenilina-1 , Factores de Riesgo
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