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Phenotypic comparison of individuals with homozygous or heterozygous mutation of NOTCH3 in a large CADASIL family

Al-Shaar, Hussam Abou ; Qadi, Najeeb ; Ahmed, Mohammed ; Meyer, Brian F ; Bohlega, Saeed

Journal of the neurological sciences, 2016-08, Vol.367, p.239-243 [Periódico revisado por pares]

Netherlands: Elsevier B.V

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  • Título:
    Phenotypic comparison of individuals with homozygous or heterozygous mutation of NOTCH3 in a large CADASIL family
  • Autor: Al-Shaar, Hussam Abou ; Qadi, Najeeb ; Ahmed, Mohammed ; Meyer, Brian F ; Bohlega, Saeed
  • Assuntos: Adolescent ; Adult ; Aged ; Brain - diagnostic imaging ; CADASIL ; CADASIL - diagnostic imaging ; CADASIL - genetics ; CADASIL - physiopathology ; CADASIL - psychology ; Child ; Family ; Female ; Heterozygote ; Heterozygous ; Homozygote ; Homozygous ; Humans ; Male ; Middle Aged ; Mutation ; Neurology ; NOTCH3 ; Pedigree ; Phenotype ; Receptor, Notch3 - genetics ; Stroke ; Young Adult
  • É parte de: Journal of the neurological sciences, 2016-08, Vol.367, p.239-243
  • Notas: ObjectType-Case Study-2
    SourceType-Scholarly Journals-1
    ObjectType-Feature-4
    content type line 23
    ObjectType-Report-1
    ObjectType-Article-3
  • Descrição: Abstract Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy caused by mutations in NOTCH3 , very rarely homoallelic. Objective. To describe the clinical, radiological, and neuropsychological features in an extended CADASIL family including members with either a homozygous or heterozygous NOTCH3 R1231C mutation. Methods The pedigree included 3 generations of a family with 13 affected individuals. The patients were examined clinically and radiologically. Neuropsychological testing was performed on the proband. Sequencing of the entire coding DNA sequence (CDS) and flanking regions of NOTCH3 was undertaken using PCR amplification and direct Sanger sequencing. Results Homozygous C3769T mutation, predicting R1231C in exon 22 of NOTCH3 was found in 7 family members. Six other family members harbored the same in the heterozygous state. Homozygous individuals showed a more severe phenotype and earlier onset compared to their heterozygous counterparts. Radiological abnormalities were also more severe among homozygous patients and appeared at an earlier age. Conclusion This study reports the largest number of patients with homozygous NOTCH3 mutation. The phenotype and imaging features of homozygous individuals is within the spectrum of CADASIL, although slightly at the severe end when compared to heterozygotes carrying the same mutation. Both genetic modifiers and environmental factors may play an essential role in modification and alteration of the clinical phenotype and white matter changes among CADASIL patients.
  • Editor: Netherlands: Elsevier B.V
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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