RESUMO
CADASIL is a cerebrovascular disease caused by mutations in the NOTCH3 gene. Most mutations result in a gain or loss of cysteine residue in one of the 34 epidermal growth factor-like repeats in the extracellular domain of the Notch3 protein, thus sparing the number of cysteine residues. To date, more than 130 different mutations in the NOTCH3 gene have been reported in CADASIL patients, of which 95% are missense point mutations. Many polymorphisms have also been identified in the NOTCH3 coding sequence, some of them leading to amino acid substitutions. The aim of the present study was to analyze the NOTCH3 gene in a large group of patients affected by leukoencephalopathy and to investigate the presence of genetic variants. The molecular analysis revealed several nucleotide alterations. In particular, we identified 20 different mutations, 22 polymorphisms, and 8 genetic variants of unknown pathological significance never reported previously. We hope that this NOTCH3 gene mutational analysis, performed in such a significant number of unrelated and related patients affected by leukoencephalopathy, will help in molecular screening for the NOTCH3 gene, thus contributing to enlargement of the NOTCH3 gene variation database.
Assuntos
CADASIL/genética , Receptores Notch/genética , Análise Mutacional de DNA , Humanos , Mutação , Polimorfismo Genético , Receptor Notch3RESUMO
The distal hereditary motor neuropathy (dHMN) is a rare genetically and clinically heterogeneous disorder characterized by weakness and wasting of distal limb muscles in absence of overt sensory abnormalities. Recently, pyramidal signs have been also described in some patients with dominant or recessive dHMN, and two different loci have been identified in families affected by dHMN complicated with pyramidal dysfunction. We investigated an Italian family affected by an autosomal dominant dHMN complicated by pyramidal signs in order to map a new gene locus. The disease maps to a novel locus in a 26-cM region flanked by D4S1552 and D4S2930 on chromosome 4q34.3-35.2. Three candidate genes (SNX25, CASP3 and TUBB4Q) located in the critical region were screened for the presence of mutations by heteroduplex analysis. No mutations have been detected in the analyzed genes. In conclusion, the new private genetic locus we reported further confirms the wide heterogeneity of dHMN.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 4/genética , Neuropatia Hereditária Motora e Sensorial/genética , Feminino , Heterogeneidade Genética , Ligação Genética , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Masculino , LinhagemAssuntos
Encéfalo/patologia , CADASIL/genética , Mutação INDEL/genética , Mutação de Sentido Incorreto/genética , Receptores Notch/genética , Adulto , CADASIL/diagnóstico , CADASIL/fisiopatologia , Feminino , Lobo Frontal/patologia , Humanos , Imageamento por Ressonância Magnética , Linhagem , Fenótipo , Receptor Notch3 , Lobo Temporal/patologiaRESUMO
Mutations in the Angiogenin gene (ANG) linked to 14q11.2 have been recently discovered to be associated with Amyotrophic Lateral Sclerosis (ALS) in Irish and Scottish populations. In our study we investigated the role of ANG gene in ALS patients from southern Italy. We found a novel mutation in the signal peptide of the ANG gene in a sporadic patient with ALS (SALS). The molecular analysis of the ANG gene also demonstrated an allelic association with the rs11701 single nucleotide polymorphism (SNP) in familial ALS (FALS) but not in SALS patients. Our finding supports the evidence that the ANG gene is involved in ALS.
Assuntos
Esclerose Lateral Amiotrófica/genética , Predisposição Genética para Doença/genética , Neurônios Motores/metabolismo , Mutação/genética , Ribonuclease Pancreático/genética , Adulto , Idoso , Substituição de Aminoácidos/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/fisiopatologia , Mapeamento Cromossômico , Cromossomos Humanos Par 14/genética , Citoproteção/genética , Análise Mutacional de DNA , Feminino , Ligação Genética/genética , Marcadores Genéticos/genética , Testes Genéticos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Neurônios Motores/patologia , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Ribonuclease Pancreático/químicaAssuntos
Braço/fisiopatologia , Doença dos Neurônios Motores/fisiopatologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular/fisiopatologia , Mutação/genética , Superóxido Dismutase/genética , Idoso , Braço/inervação , Análise Mutacional de DNA , Progressão da Doença , Lateralidade Funcional/genética , Humanos , Masculino , Doença dos Neurônios Motores/enzimologia , Doença dos Neurônios Motores/genética , Neurônios Motores/enzimologia , Neurônios Motores/patologia , Debilidade Muscular/enzimologia , Debilidade Muscular/genética , Debilidade Muscular/fisiopatologia , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Atrofia Muscular/enzimologia , Atrofia Muscular/genética , Condução Nervosa/genética , Nervos Periféricos/patologia , Nervos Periféricos/fisiopatologia , Reflexo Anormal/genética , Superóxido Dismutase-1RESUMO
BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant disease characterised by the development of multiple nervous system tumours, ocular abnormalities, and skin tumours. Although classically considered a disease of adults, initial signs and/or symptoms may be evident in childhood and are often unrecognised. OBJECTIVES: The aim of this study was to identify the earliest clinical presentations of NF2 and to characterise the clinical course and outcome in children with NF2. METHODS: We have performed a retrospective (years 1990-1998) and prospective (years 1998-2004) study of 24 patients (10 males, 14 females; currently aged 4 to 22 years) fulfilling the revised (Manchester) NF2 criteria seen at the Universities of Catania and Rome, Italy. RESULTS: Causes of referral prior to a definitive diagnosis of NF2 were: 1) Ophthalmologic problems: early onset lens opacities (n = 3); strabismus (n = 3) and amblyopia (n = 3) (due to underlying cranial nerves and/or brain tumours); 2) Otolaryngology problems: hearing loss and tinnitus (n = 2) in early teens disregarded or treated as ear infections; hoarse (n = 1) or bitonal (n = 1) voice; 3) Neurological dysfunction: seizures secondary to intracranial meningioma (n = 1) or vestibular schwannomas (VS) (n = 1), neurological dysfunction related to brainstem and/or spinal cord tumours (n = 7), isolated and multiple cranial nerve deficits (n = 10), and peripheral neuropathy secondary to schwannomas (n = 4); 4) Skin manifestations: schwannomas misdiagnosed as neurofibromas because of associated café-au-lait spots (n = 2); café-au-lait spots (n = 8) and skin tumours (n = 3). A family history was relevant in 20 % of the patients. Molecular genetic analysis of the NF2 gene revealed typical truncating mutations in all the 5 familial cases and in 2/10 sporadic cases analysed. CONCLUSIONS: Children with NF2 often first come to medical attention because of ocular, subtle skin, or neurological problems the significance of which is realised when they later present with more classical symptoms due to bilateral VS or other intracranial tumours. The clinical course at this young age is highly variable, depending on tumour burden, early surgical intervention, surgical outcome after tumour resection, and complications.
Assuntos
Neurofibromatose 2/fisiopatologia , Otorrinolaringopatias/etiologia , Adolescente , Adulto , Encéfalo/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Saúde da Família , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Doenças do Sistema Nervoso/etiologia , Neurofibromatose 2/genética , Neurofibromatose 2/patologia , Transtornos da Motilidade Ocular/genética , Transtornos da Motilidade Ocular/patologia , Transtornos da Motilidade Ocular/fisiopatologia , Otorrinolaringopatias/genética , Otorrinolaringopatias/patologia , Estudos Prospectivos , Estudos Retrospectivos , Medula Espinal/patologiaRESUMO
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to accumulating neurologic deficits and dementia. CADASIL has been linked to nucleotide substitutions and deletions in the Notch3 gene. All the mutations described until now lead to unpaired cysteine residue in the epidermal growth factor-like repeats. The authors report a family with CADASIL carrying a deletion in the Notch3 gene that did not involve a cysteine residue.
Assuntos
CADASIL/genética , Proteínas Proto-Oncogênicas/genética , Receptores de Superfície Celular/genética , Deleção de Sequência , Adulto , Idoso , CADASIL/patologia , Cromatografia Líquida de Alta Pressão , Cisteína/química , Éxons/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Dobramento de Proteína , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/química , Receptor Notch3 , Receptores de Superfície Celular/química , Receptores Notch , Sequências Repetitivas de Aminoácidos , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: To investigate the possible occurrence of a conversion event in three patients with adult-onset spinal muscular atrophy (SMA) type IV, which represents the mildest form within the spectrum of the SMA phenotype. MATERIAL AND METHODS: We observed three patients with adult onset SMA and apparent isolated deletion of telomeric survival motor neuron (SMN1) exon 7. To distinguish between a deletion and a sequence conversion event of exon 7, these patients were analyzed in greater detail by a simple PCR-based assay. RESULTS: Analysis by DdeI digestion showed products for both telomeric and centromeric copies of exon 8. These findings indicated a gene conversion event as the site for primer R111 was retained at least in one of two alleles. CONCLUSIONS: These results provide first evidence that a conversion event may be also associated with adult-onset SMA, and further support the notion that a gene conversion event is usually associated with a milder SMA phenotype and a later onset of disease.
Assuntos
Deleção de Genes , Atrofia Muscular Espinal/genética , Proteínas do Tecido Nervoso/genética , Adulto , Idade de Início , Idoso , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Éxons , Humanos , Masculino , Atrofia Muscular Espinal/patologia , Fenótipo , Reação em Cadeia da Polimerase , Proteínas de Ligação a RNA , Proteínas do Complexo SMN , Índice de Gravidade de Doença , Proteína 1 de Sobrevivência do Neurônio Motor , Telômero/genéticaRESUMO
Hereditary spastic paraplegias are neurodegenerative disorders characterized clinically by progressive spasticity of the lower limbs. They are inherited as autosomal dominant, autosomal recessive, and X-linked traits. Four Italian families with autosomal recessive pure spastic paraplegia are reported. We show evidence of linkage to the SPG5 locus on chromosome 8p and our data reduce the candidate interval for SPG5 to the11-cM interval spanned by D8S285 and D8S544. We also report the search for mutations in five genes located in the region and their exclusion as candidates for SPG5.
Assuntos
Cromossomos Humanos Par 8 , Escore Lod , Paraplegia/genética , Adulto , Saúde da Família , Feminino , Genes Recessivos , Marcadores Genéticos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary syndrome caused by mutations of the Notch3 gene, usually localized to exons 3 and 4. OBJECTIVES: To report a novel pathogenetic mutation occurring in exon 6 of the Notch3 gene, a location not previously recognized in patients with CADASIL, and to report the results of magnetic resonance spectroscopy in CADASIL. METHODS: Mutation analysis of the Notch3 gene was performed in 2 patients belonging to a large kindred manifesting CADASIL, as well as in 7 clinically unaffected members of the family and 200 control chromosomes. Proton magnetic resonance spectroscopy was used to estimate metabolite resonance intensities in the 2 affected subjects. RESULTS: Sequence analysis of the Notch3 gene showed a new missense mutation CGC-->TGC in codon 332 of exon 6, resulting in the replacement of an arginine residue with a cysteine. This mutation was never observed in the 7 unaffected members of the family and the 200 control chromosomes examined. Proton magnetic resonance spectroscopy showed a diffuse decrease in cerebral N-acetylaspartate, indicating the presence of widespread axonal damage. CONCLUSIONS: Our findings emphasize the role of direct DNA sequence analysis for the diagnosis of CADASIL. Moreover, the results of proton magnetic resonance spectroscopy suggest that widespread axonal damage may be an early finding of the disease.
Assuntos
Demência por Múltiplos Infartos/genética , Saúde da Família , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas/genética , Receptores de Superfície Celular , Adulto , Encéfalo/patologia , Demência por Múltiplos Infartos/patologia , Éxons , Feminino , Genes Dominantes , Humanos , Itália , Espectroscopia de Ressonância Magnética , Masculino , Linhagem , Receptor Notch3 , Receptores NotchRESUMO
A 9-year-old girl, who had no family history of neurologic diseases in the first-degree relatives, had a 3-year history of progressive myoclonus epilepsy (PME). A thorough laboratory investigation was normal. As two sisters of her paternal grandmother were said to have Huntington's disease (HD), the authors looked for HD and found a CAG repeat expansion of 115 repeats. This diagnosis should be considered in addition to other causes in patients with PME. Moreover, the current case further supports the notion that HD should be considered even when a family history is not obvious.
Assuntos
Doença de Huntington/diagnóstico , Epilepsias Mioclônicas Progressivas/diagnóstico , Criança , Eletroencefalografia , Feminino , Humanos , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Epilepsias Mioclônicas Progressivas/fisiopatologiaRESUMO
The authors report a large pedigree from southern Italy with Charcot-Marie-Tooth disease type 2A (CMT2A). The clinical picture was uniform and characterized by distal muscular weakness and atrophy in the lower limbs, reduced or absent tendon reflexes mainly in the lower limbs, and mild sensory impairment in the feet. Significant linkage to the CMT2A locus on chromosome 1p35-p36 was detected. Based on informative recombination in affected individuals, the authors mapped the CMT2A gene between D1S160 and D1S170.