RESUMEN
Since 1994, a population-based study of frontotemporal dementia (FTD) in The Netherlands has aimed to ascertain all patients with FTD, and first prevalence estimates based on 74 patients were reported in 1998. Here, we present new prevalence estimates after expansion of our FTD population to 245 patients, with emphasis on the prevalence in the province Zuid-Holland where the main study centre is located. All neurologists and physicians in nursing homes received a yearly postal enquiry about suspected FTD cases. FTD was diagnosed in 245 patients according to the Lund-Manchester criteria, supported by neuroimaging and neuropsychology. tau mutation analysis was performed in a subgroup of 154 patients (63%), and 40 out of 98 patients (41%) who died during follow-up were autopsied during the course of the study. The prevalence of FTD in the province Zuid-Holland was 3.6 per 100,000 at age 50-59 years, 9.4 per 100,000 at age 60-69 years and 3.8 per 100,000 at age 70-79 years. The median age at onset of the 245 patients (51% female) was 58.0 years (range 33-80 years). Dementia in one or more first-degree family members was found in 43% of patients and mutation analysis of the tau gene showed mutations in 34 patients (19 P301L, five L315R, four G272V, four R406W, one Delta K280 and one S320F), all with a positive family history for dementia (14% of the total population, 32% of patients with a positive family history). Pathological findings in the 40 autopsied patients consisted of dementia lacking distinctive histology in 22%, FTD with ubiquitin-positive inclusions in 33%, Pick's disease in 15% and tauopathy in the remaining 30% of patients, with tau mutations identified in more than half of the latter patients. We conclude that the prevalence of FTD in The Netherlands is higher than previously reported, confirming that FTD is more common than was previously thought. The finding of tau mutations in 32% of patients with a positive family history for dementia justifies mutation screening in FTD patients with a positive family history, while tau mutations in non-familiar cases are rare.
Asunto(s)
Demencia/epidemiología , Adulto , Distribución por Edad , Anciano , Demencia/genética , Demencia/patología , Femenino , Estudios de Seguimiento , Lóbulo Frontal/patología , Predisposición Genética a la Enfermedad , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Mutación , Países Bajos/epidemiología , Prevalencia , Lóbulo Temporal/patología , Proteínas tau/genéticaRESUMEN
Gilles de la Tourette syndrome (GTS) is a sporadic or inherited complex neuropsychiatric disorder characterized by involuntary motor and vocal tics. There is comorbidity with disorders like obsessive compulsive disorder and attention deficit hyperactivity disorder. Until now linkage analysis has pointed to a number of chromosomal locations, but has failed to identify a clear candidate gene(s). We have investigated a GTS family with a complex chromosomal insertion/translocation involving chromosomes 2 and 7. The affected father [46,XY,inv(2) (p23q22),ins(7;2) (q35-q36;p21p23)] and two affected children [46,XX,der(7)ins(7;2)(q35-q36;p21p23) and 46,XY,der(7)ins(7;2)(q35-q36;p213p23)] share a chromosome 2p21-p23 insertion on chromosome 7q35-q36, thereby interrupting the contactin-associated protein 2 gene (CNTNAP2). This gene encodes a membrane protein located in a specific compartment at the nodes of Ranvier of axons. We hypothesize that disruption or decreased expression of CNTNAP2 could lead to a disturbed distribution of the K(+) channels in the nervous system, thereby influencing conduction and/or repolarization of action potentials, causing unwanted actions or movements in GTS.
Asunto(s)
Proteínas de la Membrana , Proteínas del Tejido Nervioso/genética , Trastorno Obsesivo Compulsivo/genética , Síndrome de Tourette/genética , Preescolar , Cromosomas Humanos Par 2 , Cromosomas Humanos Par 7 , Comorbilidad , Femenino , Humanos , Cariotipificación , Masculino , Trastorno Obsesivo Compulsivo/complicaciones , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/fisiopatología , Linaje , Síndrome de Tourette/complicaciones , Síndrome de Tourette/diagnóstico , Síndrome de Tourette/fisiopatología , Translocación GenéticaRESUMEN
The DJ-1 gene encodes a ubiquitous, highly conserved protein. Here, we show that DJ-1 mutations are associated with PARK7, a monogenic form of human parkinsonism. The function of the DJ-1 protein remains unknown, but evidence suggests its involvement in the oxidative stress response. Our findings indicate that loss of DJ-1 function leads to neurodegeneration. Elucidating the physiological role of DJ-1 protein may promote understanding of the mechanisms of brain neuronal maintenance and pathogenesis of Parkinson's disease.
Asunto(s)
Mutación , Proteínas Oncogénicas/genética , Trastornos Parkinsonianos/genética , Alelos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Secuencia de Bases , Encéfalo/metabolismo , Células COS , Núcleo Celular/metabolismo , Cromosomas Humanos Par 1 , Clonación Molecular , Citoplasma/metabolismo , ADN Complementario , Exones , Genes Recesivos , Humanos , Péptidos y Proteínas de Señalización Intracelular , Datos de Secuencia Molecular , Proteínas Oncogénicas/química , Proteínas Oncogénicas/metabolismo , Estrés Oxidativo , Células PC12 , Trastornos Parkinsonianos/metabolismo , Linaje , Mapeo Físico de Cromosoma , Mutación Puntual , Proteína Desglicasa DJ-1 , Estructura Secundaria de Proteína , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Eliminación de Secuencia , TransfecciónRESUMEN
Preaxial polydactyly (PPD) is a common limb malformation in human. A number of polydactylous mouse mutants indicate that misexpression of Shh is a common requirement for generating extra digits. Here we identify a translocation breakpoint in a PPD patient and a transgenic insertion site in the polydactylous mouse mutant sasquatch (Ssq). The genetic lesions in both lie within the same respective intron of the LMBR1/Lmbr1 gene, which resides approximately 1 Mb away from Shh. Genetic analysis of Ssq reveals that the Lmbr1 gene is incidental to the phenotype and that the mutation directly interrupts a cis-acting regulator of Shh. This regulator is most likely the target for generating PPD mutations in human.
Asunto(s)
Intrones , Proteínas de la Membrana/genética , Polidactilia/genética , Transactivadores/genética , Animales , Clonación Molecular , Cruzamientos Genéticos , Proteínas Hedgehog , Heterocigoto , Humanos , Hibridación Fluorescente in Situ , Ratones , Mutación , Fenotipo , Recombinación Genética , Mapeo Restrictivo , Translocación GenéticaRESUMEN
Benign hereditary chorea (BHC) (MIM 118700) is an autosomal dominant movement disorder. The early onset of symptoms (usually before the age of 5 years) and the observation that in some BHC families the symptoms tend to decrease in adulthood suggests that the disorder results from a developmental disturbance of the brain. In contrast to Huntington disease (MIM 143100), BHC is non-progressive and patients have normal or slightly below normal intelligence. There is considerable inter- and intrafamilial variability, including dysarthria, axial dystonia and gait disturbances. Previously, we identified a locus for BHC on chromosome 14 and subsequently identified additional independent families linked to the same locus. Recombination analysis of all chromosome 14-linked families resulted initially in a reduction of the critical interval for the BHC gene to 8.4 cM between markers D14S49 and D14S278. More detailed analysis of the critical region in a small BHC family revealed a de novo deletion of 1.2 Mb harboring the TITF-1 gene, a homeodomain-containing transcription factor essential for the organogenesis of the lung, thyroid and the basal ganglia. Here we report evidence that mutations in TITF-1 are associated with BHC.