RESUMEN
Inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and/or frontotemporal dementia (FTD) (IBMPFD) was recently identified as rare autosomal dominant disorder due to mutations in VCP gene. However, VCP mutations have also been documented in patients with amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth type 2 (CMT2) disease, and hereditary spastic paraplegia (HSP), underlining the heterogeneity of the phenotypes due to VCP mutations. In this study, we reported a novel missense heterozygous variant c.1184A > C (p.D395A) in exon 10 of VCP gene identified in three patients (two sisters and one brother) belonging to an Italian family. The patients underwent a detailed clinical evaluation including medical history, neurological examination, and neuropsychological assessment. Brain's morphologic and functional analysis was also performed. The whole picture was consistent with the criteria of behavioral variant frontotemporal dementia (bvFTD) without IBM and PBD. Our report confirms the high degree of heterogeneity of VCP disease. A VCP analysis should be considered for the genetic screening of familial bvFTD with an early onset also in absence of IBM or PDB signs.
RESUMEN
BACKGROUND: Several genetic variants playing a key role in cholesterol levels, blood pressure, and vascular dysfunction influence the risk of Alzheimer's disease (AD) and vascular dementia (VaD). The many meta-analysis studies carried out on large numbers of samples in different populations have not provided clear results to date, because a trans-ethnic shift of risk genotypes in different populations is often observed. OBJECTIVES: To determine genotypes allele frequencies of the polymorphisms most frequently identified to be correlated with cardio-cerebrovascular disease and AD in a Southern Italy population and to investigate their possible association with dementia. METHODS: The genotype and allele frequencies of 13 cardio-cerebrovascular risk polymorphisms were assessed and their possible association with dementia was investigated in a case-control study, including 221 consecutive unrelated subjects diagnosed with dementia (120 subjects affected by AD, 55 by frontotemporal dementia, and 33 by vascular dementia) and 218 matched controls of Calabrian origin. RESULTS: Carriers of at least one APOEÉ4 allele resulted to be at higher risk of AD [OR(95% CI)â=â2.721(1.477-5.011)] and VaD [OR(95% CI)â=â6.205(2.356-16.342)] compared to non-carriers. Individuals with the IV genotype of the CETP polymorphism were more likely to have AD [OR(95% CI)â=â2.427(1.364-4.319)] and VaD [OR(95% CI)â=â3.649(1.455-9.152)] compared to subjects with the II-VV genotypes. CONCLUSION: CETP I405V polymorphism is likely a risk factor for AD and VaD in our cohort, independent of APOEÉ4 status. Unmodifiable genetic risk factors should be taken into account to promote a healthy lifestyle to prevent dementia.
Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Proteínas de Transferencia de Ésteres de Colesterol/genética , Demencia Vascular/genética , Demencia Frontotemporal/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Humanos , Italia , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Factores de RiesgoRESUMEN
BACKGROUND: Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance. OBJECTIVE: To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus. METHODS: We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients. RESULTS: Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222âS mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2. CONCLUSIONS: Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.
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Proteínas Portadoras/genética , Demencia/genética , Glicoproteínas/genética , Glicoproteínas de Membrana/genética , Mutación/genética , Anciano , Animales , Encéfalo/diagnóstico por imagen , Análisis Mutacional de ADN , Demencia/diagnóstico por imagen , Demencia/patología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Proteína Niemann-Pick C1 , Tomografía Computarizada de Emisión de Fotón Único , Proteínas de Transporte VesicularRESUMEN
We identified the novel PSEN1 pathogenic mutation M84V in 3 patients belonging to a large kindred affected by autosomal dominant Alzheimer's disease (AD). The clinical phenotype was characterized by early onset dementia in 14 affected subjects over 3 generations. Detailed clinical, imaging and genetic assessment was performed. We highlighted the presence of unusual symptoms such as frontal executive syndrome, psychosis and spastic paraparesis in these patients. Spastic paraparesis has been reported in other PSEN1 mutations in adjacent codons, suggesting that the position of the genetic defect may affect the clinical expression, although this phenotype can occur in mutations throughout the whole PSEN1 gene. Brain magnetic resonance imaging showed diffuse cortical atrophy, but also atrophy of cerebellar lobules, mainly involving Crus I, in 2 patients without cerebellar motor deficits. These neuroimaging results were consistent with recent findings about the association between sporadic AD and distinct and circumscribed cerebellar atrophy. The present work acknowledged the novel PSEN1 pathogenic mutation M84V and might contribute to the ongoing debate about the involvement of cerebellum in AD.
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Enfermedad de Alzheimer/genética , Cerebelo/patología , Función Ejecutiva , Genes Dominantes/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Mutación , Paraparesia Espástica/genética , Presenilina-1/genética , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Atrofia , Cerebelo/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Paraparesia Espástica/diagnóstico por imagen , Linaje , Trastornos Psicóticos/diagnóstico por imagen , Trastornos Psicóticos/genética , SíndromeRESUMEN
The rebuilding of the N family, a large Italian kindred affected by early-onset autosomal dominant Alzheimer's disease (AD), provided an important contribution to the discovery of Presenilin 1 (PSEN1), the main gene responsible for familial AD. This pedigree was identified with the help of medical records from the archives of the Psychiatric Hospital of Girifalco, Italy. The clinical record of Angela R., an ancestor of the N family, dating back to 1904, showed a clinical picture of Angela R., consistent with a diagnosis of non-amnestic probable AD, matching the "dysexecutive" phenotype described in her descendants. The a posteriori diagnosis of AD is supported by the evidence of the causative genetic mutation PSEN1-Met146Leu as well as neuropathological AD features in her genealogically proven descendants. The clinical case of Angela R. was recorded at the same time of Alzheimer's description of Auguste D. Its discovery crucially contributed to the genealogical reconstruction of the N family, linking came from different branches, which until then were unrelated, to the same kindred. The archives of the Girifalco Hospital represented a valuable source of medical and historical information and were essential to the research on Italian-American AD families that finally led to the identification of new genes.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/historia , Salud de la Familia , Mutación/genética , Presenilina-1/genética , Femenino , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Italia , MasculinoRESUMEN
Prion protein gene mutations have been associated with clinical pictures mimicking neurodegenerative diseases different from inherited prion diseases (IPD). We report a novel missense P39L mutation in the N-terminal domain of prion protein in 2 patients affected by frontotemporal lobar degeneration syndrome, negative for mutations in genes causative of dementia. Neither the first carrier, a 67-year-old male in which the onset was a progressive non-fluent aphasia, nor the second carrier, a 78-year-old male affected by frontotemporal dementia and parkinsonism, showed any clinical or instrumental findings suggestive of IPD. Genetic screening of healthy controls and in silico analysis provide support for the potential pathogenicity of this variant. Patient phenotypes, unclassifiable as prion disease, may depend on the location of the mutation in the N-terminal domain, outside the amyloid core of pathologic prion protein, although further functional studies are required to determine whether and how this mutation exerts its pathogenic effect. However, genetic screening of prion protein gene becomes relevant in familial degenerative dementia, particularly in geographical areas with high IPD prevalence.
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Degeneración Lobar Frontotemporal/diagnóstico , Degeneración Lobar Frontotemporal/genética , Mutación Missense , Priones/genética , Estructura Terciaria de Proteína/genética , Anciano , Femenino , Estudios de Asociación Genética , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , SíndromeAsunto(s)
Síndrome de Alagille/genética , Sustitución de Aminoácidos , Proteínas de Unión al Calcio/genética , Codón sin Sentido , Codón/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/genética , Preescolar , Codón de Terminación , Exones , Salud de la Familia , Femenino , Heterocigoto , Humanos , Proteína Jagged-1 , Masculino , Mutación Puntual , Proteínas Serrate-JaggedAsunto(s)
Síndrome de Alagille/genética , Sustitución de Aminoácidos , Proteínas de Unión al Calcio/genética , Codón/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/genética , Mutación Missense , Preescolar , Exones , Salud de la Familia , Femenino , Heterocigoto , Humanos , Proteína Jagged-1 , Masculino , Mutación Puntual , Proteínas Serrate-JaggedAsunto(s)
Síndrome de Alagille/genética , Proteínas de Unión al Calcio/genética , Codón/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/genética , Mutación , Cromatografía Líquida de Alta Presión , Codón de Terminación , Exones , Salud de la Familia , Femenino , Humanos , Lactante , Proteína Jagged-1 , Masculino , Análisis de Secuencia de ADN , Proteínas Serrate-JaggedRESUMEN
We investigated the association between TOMM40 rs10524523, age of onset, and memory performance in patients with the PSEN1 M146L mutation in a large familial Alzheimer's disease Calabrian kindred, with a wide variability of onset not attributable to APOE. APOE33/TOMM40VL/VL patients showed a tendency for an earlier age at onset compared to those with APOE33/TOMM40VL/S and APOE33/TOMM40S/S. Moreover, TOMM40VL/VL patients had better memory performance, when compared to TOMM40S/S but not to TOMM40VL/S patients, so there is not a dose-dependent effect. Our results suggest that, in the presence of the PSEN1 mutation, the slight difference in age of onset together with memory performance could be influenced by TOMM40 genotypes.
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Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad , Proteínas de Transporte de Membrana/genética , Mutación/genética , Polimorfismo Genético/genética , Presenilina-1/genética , Adulto , Edad de Inicio , Enfermedad de Alzheimer/complicaciones , Femenino , Genotipo , Humanos , Leucina/genética , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/genética , Metionina/genética , Persona de Mediana Edad , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Pruebas NeuropsicológicasRESUMEN
The objectives of this study were to estimate frontotemporal dementia (FTD) prevalence, identify FTD-related mutations, and correlate FTD phenotype with mutations in a southern Italian population. The study population consisted of subjects ≥ 50 years of age residing in the Community of Biv. on January 1, 2004, and a door-to-door 2-phase design was used. Genetic and biochemical analyses were done on samples collected from 32 patients. Prevalence rates were 0.6 for Alzheimer's disease, 0.4 for vascular dementia (VD), 3.5 for FTD, 0.2 for Parkinson dementia, and 1.2 for unspecified dementia. Three GRN (1 known and 2 novel) mutations with reduced plasma protein levels were found associated to 3 distinct phenotypes (behavioral, affective, and delirious type). We report an unusually high FTD prevalence in the investigated population, but a low prevalence of Alzheimer's disease. We confirm the heterogeneity of FTD phenotype associated with different GRN mutations.
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Demencia Frontotemporal/epidemiología , Demencia Frontotemporal/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Mutación/genética , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Proteína C9orf72 , Estudios de Cohortes , Proteínas de Unión al ADN/metabolismo , Demencia Vascular/epidemiología , Demencia Vascular/genética , Femenino , Demencia Frontotemporal/sangre , Pruebas Genéticas , Encuestas Epidemiológicas , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Progranulinas , Proteínas/metabolismo , ARN Mensajero/metabolismo , Proteína FUS de Unión a ARN/metabolismo , Proteínas tau/metabolismoRESUMEN
We have investigated a 34-year-old female who had mild clinical and electrophysiological features of demyelinating peripheral neuropathy. She presented a novel frameshift mutation (V160fsX3) in the exon 4 of the Myelin Protein Zero (MPZ) gene. Clinical and genetic studies performed on her family revealed the same mutation in her oligosymptomatic mother and sister. Our report expands the number of MPZ mutations and indicates that mutations in exon 4 may cause a mild Charcot-Marie-Tooth type 1B phenotype.
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Proteína P0 de la Mielina/genética , Adulto , Enfermedad de Charcot-Marie-Tooth/genética , Femenino , Pruebas Genéticas , Humanos , Mutación , Linaje , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
CHARGE syndrome is an autosomal dominant disorder characterized by features represented in its acronym: Coloboma, Heart defect, Atresia of the choanae, Retarded growth and development, Genital abnormalities, Ear anomalies/deafness. We report two patients with a diagnosis of typical CHARGE syndrome and one with atypical clinical diagnosis. All the three patients had uni- or bilateral choanal atresia and sensorineural hearing loss. The patients were screened for CHD7 gene mutations. Three novel occurring de novo heterozygous mutations were identified: a mutation in the donor splice site of intron 24, a missense mutation in exon 2 and a deletion in exon 11.