RESUMO
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have recently been reported in patients with severe neurodevelopmental disorder characterized by early-onset seizures, infantile spasms, severe psychomotor impairment and very recently, in patients with Rett syndrome (RTT)-like phenotype. Although the involvement of CDKL5 in specific biological pathways and its neurodevelopmental role have not been completely elucidated, the CDKL5 appears to be physiologically related to the MECP2 gene. Here we report on the clinical and CDKL5 molecular investigation in a very unusual RTT case, with severe, early-neurological involvement in which we have shown in a previous report, a novel P388S MECP2 mutation [Conforti et al. (2003); Am J Med Genet A 117A: 184-187]. The patient has had severe psychomotor delay since the first month of life and infantile spasms since age 5 months. Moreover, at age 5 years the patient suddenly presented with renal failure. The severe pattern of symptoms in our patient, similar to a CDKL5 phenotype, prompted us to perform an analysis of the CDKL5, which revealed a novel missense mutation never previously described. The X-inactivation assay was non-informative. In conclusion, this report reinforces the observation that the CDKL5 phenotype overlaps with RTT and that CDKL5 analysis is recommended in patients with a seizure disorder commencing during the first months of life.
Assuntos
Mutação de Sentido Incorreto , Proteínas Serina-Treonina Quinases/genética , Síndrome de Rett/enzimologia , Síndrome de Rett/genética , Adolescente , Idade de Início , Cromossomos Humanos X/genética , Análise Mutacional de DNA , Epilepsia/enzimologia , Epilepsia/genética , Feminino , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , FenótipoRESUMO
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 Notch3Assuntos
Encéfalo/patologia , CADASIL/diagnóstico , CADASIL/genética , Predisposição Genética para Doença/genética , Mutação/genética , Receptores Notch/genética , Adulto , Idade de Início , Idoso , Substituição de Aminoácidos/genética , Encéfalo/metabolismo , Encéfalo/fisiopatologia , CADASIL/fisiopatologia , Artérias Cerebrais/metabolismo , Artérias Cerebrais/patologia , Artérias Cerebrais/fisiopatologia , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/genética , Hemorragia Cerebral/fisiopatologia , Análise Mutacional de DNA , Imagem de Difusão por Ressonância Magnética , Feminino , Frequência do Gene/genética , Marcadores Genéticos , Testes Genéticos , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Receptor Notch3 , Estudos Retrospectivos , Adulto JovemRESUMO
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 , LinhagemRESUMO
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.