RESUMEN
Mutations in the progranulin (GRN) gene have recently been reported as a cause of the frontotemporal dementia (FTD) syndrome. We performed a clinical, neuropathological and molecular genetic study of two families with FTD and the same novel mutation in GRN. Age of onset ranged from 35 to 75 years and all individuals progressed to a severe dementia syndrome with a mean disease duration of approximately 6-10 years. Variable clinical presentations included language impairment, behaviour change or parkinsonism. Seven total autopsies in the families (five in Family 1, two in Family 2) showed gross and microscopic evidence of neuronal loss in the neocortex, striatum, hippocampus and substantia nigra. All cases with material available for immunohistochemistry had cytoplasmic and intranuclear ubiquitin positive, tau negative inclusions that stained best with an antibody to the TDP43 protein. In addition, all but one had evidence of distinctive tau pathology. Two cases in Family 1 also had alpha-synuclein (SNCA) pathology, one with diffuse neocortical inclusions and neurites and unusual striatal cytoplasmic inclusions. Affected persons in both families had the same mutation in GRN (c.709-2A>G). A minigene construct showed that this mutation alters splicing of exon 7 and results in reduced mRNA message in brain. A single GRN mutation in these two families was associated with variable clinical presentations consistent with the FTD syndrome. All cases had ubiquitin/TDP43 immuno-positive inclusions and most had additional tau pathology. Two cases had SNCA pathology. These findings suggest a link between mutations in GRN and aggregation of tau, TDP43 and SNCA.
Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/genética , Mutación , Enfermedad de Pick/genética , Adulto , Edad de Inicio , Anciano , Western Blotting/métodos , Encéfalo/patología , Estudios de Casos y Controles , Cuerpo Estriado/química , Cuerpo Estriado/patología , Proteínas de Unión al ADN/análisis , Femenino , Genotipo , Hipocampo/química , Hipocampo/patología , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neocórtex/química , Neocórtex/patología , Linaje , Enfermedad de Pick/metabolismo , Enfermedad de Pick/patología , Progranulinas , Análisis de Secuencia de ADN , Sustancia Negra/química , Sustancia Negra/patología , Ubiquitina/análisis , alfa-Sinucleína/análisis , Proteínas tau/análisisRESUMEN
Described is a large family with an autosomal dominant dementia associated with an H187R mutation in the prion protein gene (PRNP). Clinical features include neuropsychiatric disturbances in childhood and adolescence, dementia in young adulthood with frontotemporal manifestations, and long disease duration. Neuropathology revealed atrophy and mild gliosis, whereas prion protein analysis revealed an abnormal conformer with unusual sensitivity to protease digestion. Mutations in PRNP may cause neuropsychiatric disorders that predate dementia by many years.
Asunto(s)
Demencia/genética , Discapacidad Intelectual/genética , Trastornos Mentales/genética , Enfermedades por Prión/genética , Priones/genética , Adolescente , Adulto , Edad de Inicio , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Niño , Análisis Mutacional de ADN , Demencia/complicaciones , Demencia/fisiopatología , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/fisiopatología , Masculino , Trastornos Mentales/complicaciones , Trastornos Mentales/fisiopatología , Persona de Mediana Edad , Mutación/genética , Neuronas/metabolismo , Neuronas/patología , Linaje , Enfermedades por Prión/complicaciones , Enfermedades por Prión/fisiopatología , Priones/metabolismoRESUMEN
parkin Mutations are the most common identified cause of Parkinson's disease (PD). It has been suggested that patients with young-onset PD be screened for parkin mutations as a part of their clinical work-up. The aim of this study was to assess parkin mutation frequency in a clinical setting, correlate genotype with phenotype, and evaluate the current justification for clinical parkin testing. Patients were selected from a movement disorder clinic based on diagnosis of PD and onset age =40 years. parkin was genotyped by sequence and dosage analysis for all 12 exons. Key relatives and controls were screened for identified mutations. Mutations were found in 7/39 patients. Two patients were compound heterozygous; five were heterozygous. Mutations included deletions in exons 2, 3, and 8, duplications in exons 2-4, and 9, and P437L substitution. Seventy-eight percent of mutations were deletions/multiplications. A novel substitution (R402W) was found in one patient and in one control. None of the point mutations found in patients were detected in 96 controls. parkin phenotypes were consistent with idiopathic PD. In conclusion, parkin mutations are common in the clinic setting: 10% of PD patients had early-onset and 18% of them had parkin mutations. However, if parkin is recessive, only 5% of early-onset cases who had compound mutations could be attributed to this locus. Mutation frequency was 0.12 (95% CI 0.04-0.19). parkin cases can present as typical idiopathic PD, distinguishable only by molecular testing. Seventy percent of parkin cases were heterozygous. It is unclear whether heterozygous mutations are pathogenic. parkin-based diagnosis and counseling require a better understanding of the mode of inheritance, penetrance, and carrier frequencies.
Asunto(s)
Mutación , Enfermedad de Parkinson/genética , Ubiquitina-Proteína Ligasas/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , ADN/química , ADN/genética , Análisis Mutacional de ADN , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/patología , Linaje , FenotipoRESUMEN
BACKGROUND: DNA testing of persons at risk for hereditary, degenerative neurologic diseases is relatively new. Only anecdotal reports of such testing in familial Alzheimer disease (FAD) exist, and little is know about the personal and social impact of such testing. METHODS: In a descriptive, observational study, individuals at 50% risk for autosomal dominant, early-onset FAD or frontotemporal dementia with parkinsonism linked to chromosome 17 underwent DNA testing for the genetic mutations previously identified in affected family members. Individuals were followed up for (1/2) to 3 years and were interviewed regarding attitudes toward the testing process and the impact of the results. RESULTS: Twenty-one (8.4%) of 251 persons at risk for FAD or frontotemporal dementia requested genetic testing. The most common reasons for requesting testing were concern about early symptoms of dementia, financial or family planning, and relief from anxiety. Twelve individuals had positive DNA test results, and 6 of these had early symptoms of dementia; 8 had negative results; and 1 has not yet received results. Of 14 asymptomatic individuals completing testing, 13 believed the testing was beneficial. Two persons reported moderate anxiety and 1 reported moderate depression. As expected, persons with negative test results had happier experiences overall, but even they had to deal with ongoing anxiety and depression. Thus far, there have been no psychiatric hospitalizations, suicide attempts, or denials of insurance. CONCLUSIONS: Genetic testing in early-onset FAD and frontotemporal dementia can be completed successfully. Most individuals demonstrate effective coping skills and find the testing to be beneficial, but long-term effects remain unknown.
Asunto(s)
Enfermedad de Alzheimer/genética , Demencia/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Adulto , Anciano , Enfermedad de Alzheimer/diagnóstico , Precursor de Proteína beta-Amiloide/genética , ADN/análisis , Demencia/diagnóstico , Femenino , Lóbulo Frontal , Asesoramiento Genético , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Presenilina-1 , Presenilina-2 , Lóbulo Temporal , Proteínas tau/genéticaRESUMEN
BACKGROUND: A Guam variant of amyotrophic lateral sclerosis (ALS-G) and parkinsonism dementia complex (PDC-G) are found in the Chamorro people of Guam. Both disorders have overlapping neuropathologic findings, with neurofibrillary tangles in spinal cord and brain. The cause of ALS-G-PDC-G is unknown, although inheritance and environment appear important. Because neurofibrillary tangles containing tau protein are present in ALS-G-PDC-G, and because mutations in the tau gene (TAU) cause autosomal dominant frontotemporal dementia, TAU was examined as a candidate gene for ALS-G-PDC-G. METHODS: TAU was evaluated by DNA sequence analysis in subjects with ALS-G-PDC-G, by linkage analysis of TAU polymorphisms in an extended pedigree from the village of Umatac, and by evaluation of linkage disequilibrium with polymorphic markers flanking and within TAU. RESULTS: Linkage disequilibrium between ALS-G-PDC-G and the TAU polymorphism CA3662 was observed. For this 2-allele system, PDC and ALS cases were significantly less likely than Guamanian controls to have the 1 allele (4.9% and 2% vs 11.5%, respectively; Fisher exact P =.007). DNA sequence analysis of TAU coding regions did not demonstrate a mutation responsible for ALS-G-PDC-G. Analysis of TAU genotypes in an extended pedigree of subjects from Umatac showed obligate recombinants between TAU and ALS-G-PDC-G. Linkage analysis of the Umatac pedigree indicates that TAU is not the major gene for ALS-G-PDC-G. CONCLUSIONS: The genetic association between ALS-G-PDC-G implicates TAU in the genetic susceptibility to ALS-G-PDC-G. TAU may be a modifying gene increasing risk for ALS-G-PDC-G in the presence of another, as yet, unidentified gene.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Demencia/genética , Predisposición Genética a la Enfermedad , Trastornos Parkinsonianos/genética , Proteínas tau/genética , Adulto , Anciano , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/fisiopatología , Demencia/diagnóstico , Demencia/fisiopatología , Femenino , Frecuencia de los Genes , Guam , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/fisiopatología , Linaje , Polimorfismo Genético , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Mutations in the tau gene have been reported in families with frontotemporal dementia (FTD) linked to chromosome 17. It remains uncertain how commonly such mutations are found in patients with FTD or non-Alzheimer dementia with or without a positive family history. OBJECTIVE: To determine the frequency of tau mutations in patients with non-Alzheimer dementia. PATIENTS AND METHODS: One hundred one patients with non-Alzheimer, nonvascular dementia, most thought to have FTD. Of these, 57 had a positive family history of dementia. Neuropathologic findings were available in 32. The tau gene was sequenced for all exons including flanking intronic DNA, portions of the 3' and 5' untranslated regions, and at least 146 base pairs in the intron following exon 10. RESULTS: Overall, the frequency of the tau mutations was low, being 5.9% (6/101) in the entire group. No mutations were found in the 44 sporadic cases. However, 6 (10.5%) of the 57 familial cases and 4 (33%) of the 12 familial cases with tau pathologic findings had mutations in the tau gene. The most common mutation was P301L. CONCLUSIONS: We conclude that tau mutations are uncommon in a neurology referral population with non-Alzheimer dementia, even in those with a clinical diagnosis of FTD. However, a positive family history and/or tau pathologic findings increase the likelihood of a tau mutation. There must be other genetic and nongenetic causes of FTD and non-Alzheimer dementia, similar to the etiologic heterogeneity present in Alzheimer disease.