RESUMO
We describe 10 patients from a large family with early onset motor and sensory neuropathy. Six were still living at the time of the study. In all cases, early motor milestones had been achieved. Mean age at onset of symptoms was 34 months; these included progressive distal and proximal muscle weakness of lower limbs. Pes equinovarus developed in all patients during childhood. Slight facial weakness was present in four patients, and one of them also had bilateral facial synkinesia. Intellectual function was normal in all cases. There was no evidence of thickened peripheral nerves. All three adult patients (mean age, 27 years) were seriously handicapped and wheelchair-bound. Death occurred in the fourth to fifth decade of life and the duration of the illness varied from 27 to 39 years. Motor nerve conduction velocities ranged from 15 to 17 m/sec in the upper limbs of the youngest patients, and were undetectable in the adult patients. Sensitive action potentials were almost always absent. In all patients, auditory evoked potentials showed abnormally delayed interpeak I-III latencies. The most prominent pathologic finding was a highly unusual myelin abnormality consisting of irregular redundant loops and folding of the myelin sheath. The genealogic study gave strong evidence of autosomal-recessive inheritance. The molecular analysis failed to demonstrate either duplication in the chromosome 17p11.2-12, point mutations in the four exons of the PMP-22 (17p11.2) and the six exons of the Po (1q21-q25) genes, or linkage to chromosome 8q13-21.1.
Assuntos
Neuropatia Hereditária Motora e Sensorial/genética , Bainha de Mielina/patologia , Adulto , Idade de Início , Tronco Encefálico/fisiopatologia , Criança , Pré-Escolar , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 8 , Consanguinidade , Desoxirribonuclease HpaII , Pessoas com Deficiência , Potenciais Evocados Auditivos , Feminino , Genes Recessivos , Ligação Genética , Neuropatia Hereditária Motora e Sensorial/patologia , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Microscopia Eletrônica , Proteína P0 da Mielina/genética , Proteínas da Mielina/genética , Bainha de Mielina/ultraestrutura , Condução Nervosa , Linhagem , Nervos Periféricos/fisiopatologia , Polimorfismo Conformacional de Fita Simples , Mapeamento por Restrição , Nervo Sural/patologia , Nervo Sural/ultraestruturaRESUMO
A recent study has shown a mutation at codon 713 of the amyloid precursor protein (APP) gene in a schizophrenic patient. We have analyzed the MaeIII restriction site caused by that mutation in Italian and Russian families with schizophrenia. No mutations were observed suggesting that the APP713 mutation is unlikely to be linked to the pathogenesis of such a psychiatric disorder.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Esquizofrenia/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Sequência de Bases , DNA/análise , Humanos , Itália , Dados de Sequência Molecular , Mutação , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Reação em Cadeia da Polimerase , Mapeamento por Restrição , Federação Russa , Esquizofrenia/metabolismoRESUMO
Mutations in the beta-amyloid precursor protein (APP) gene have been associated with both familial Alzheimer disease (FAD) and with hereditary cerebral haemorrhage. The polymerase chain reaction was used to both amplify and sequence exon 4 of the APP gene from genomic DNA of subjects with FAD and normal control subjects. A novel, rare, conservative DNA sequence variant was discovered at nucleotide 459 of codon 153 (valine) in exon 4 of the APP gene in an affected member of a large FAD pedigree. Segregation studies indicate that this mutation is likely to be non-pathogenic, but must be recognized and discriminated from pathogenic mutations during sequencing studies of the APP gene in patients with FAD.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Éxons , Mutação , Precursor de Proteína beta-Amiloide/metabolismo , Sequência de Bases , DNA/genética , Humanos , Dados de Sequência MolecularRESUMO
In an Italian kindred (family N), early onset Alzheimer's disease has been transmitted in a Mendelian autosomal fashion since the early 18th century. The age at death of affected members of the family varies widely, and was taken as an index of the age of expression, a measure of phenotypic variability. Either a gamma or a log-normal algorithm provides the best fit for the age at death distribution. Subsets of family N widely different as to time and place have the same age at death of patients: Environment appears to play a negligible role in the expression of disease. Pairwise correlation between an affected parent and child is zero: The disease is monogenic (no major expression gene). The same stochastic distribution of age of expression, but with late onset, and after correction for death from other causes, is compatible with the epidemiology of Alzheimer's disease in general. Mendelian genetics is a possible model for Alzheimer's disease etiology.
Assuntos
Doença de Alzheimer/genética , Regulação da Expressão Gênica/fisiologia , Fenótipo , Adulto , Fatores Etários , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Atrofia , Encéfalo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Fatores de RiscoRESUMO
We have recently discovered in Torino (Italy) a new pedigree with early-onset Alzheimer's disease. The index patient is a woman who, at the age of 43 years, showed progressive memory impairment and ideomotor apraxia. Several relatives of the patient have had a history of dementia. The ancestors of the patient were from Calabria (southern Italy) and members of the family emigrated to the north of Italy, to France, and to the United States. Up to now, the new kindred comprises 1950 members, distributed in eight generations. Thirty members affected with Alzheimer's disease have been identified. Neuropathologic confirmation of antemortem clinically diagnosed Alzheimer's disease has been achieved for one patient. The pedigree is consistent with autosomal dominant inheritance. The clinical course of the disease is fairly uniform: the first symptom is memory loss, beginning around age 40 years. Psychiatric symptoms like hallucinations and delusions follow. At a later stage of the disease, several patients developed myoclonus and generalized epileptic seizures and eventually died with profound dementia. The "Torino family" shows several genealogic and clinical similarities with other large multigenerational familial Alzheimer's disease pedigrees originating from the Calabria region.
Assuntos
Doença de Alzheimer/genética , Adulto , Fatores Etários , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Testes Neuropsicológicos , LinhagemAssuntos
Homozigoto , Teorema de Bayes , Consanguinidade , Feminino , Ataxia de Friedreich/genética , Humanos , Masculino , Mutação , Linhagem , Recombinação GenéticaRESUMO
Probable heterogeneity of Alzheimer's disease is still debated. Many authors report heterogeneity on phenotypic and/or genetic level. We have tried to reveal if variability exists also in an Italian kindred (family N) with early onset Alzheimer's disease in which the illness has been transmitted in a mendelian autosomal fashion since the early eighteenth century. The only parameter that varies widely is the age at death of affected members and it was taken as an index of expression, a measure of phenotypic variability. Extension of this concept will be discussed.
Assuntos
Doença de Alzheimer/genética , Fenótipo , Adulto , Idoso , Doença de Alzheimer/mortalidade , Cromossomos Humanos Par 21 , Triagem de Portadores Genéticos , Humanos , Longevidade/genética , Pessoa de Meia-IdadeRESUMO
Several kindreds (N, C, To and RB) with familial Alzheimer disease (FAD) from the same small area of Calabria are currently under study. Recently two of us (F.M. and L.F-S.) identified a family in Milan (FJ01) made up of 3 siblings whose parents were of Calabrian origin. Through a subsequent systematic or blanket genealogical study a link has been traced between kindreds To and FJ01. We discuss the relevance of these results to genetic studies.
Assuntos
Doença de Alzheimer/genética , Adulto , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Feminino , Humanos , Masculino , LinhagemRESUMO
Some cases of Alzheimer's disease are inherited as an autosomal dominant trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcripts encoded within this region. One of these transcripts (S182) corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease. Because these changes occurred in conserved domains of this gene, and are not present in normal controls, they are likely to be causative of AD3.