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C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke

J F Arboleda-Velasquez1, F Lopera, E Lopez

  • 1Center for Neurological Diseases, Brigham and Women's Hospital-Harvard Medical School, Boston, MA, USA.

Neurology
|July 24, 2002
PubMed

Insights

A novel C455R mutation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) causes unusually early-onset strokes. This finding impacts understanding of CADASIL genetic causes and disease progression.

Area of Science:

  • Neurology
  • Genetics
  • Vascular Biology

Background:

  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cerebrovascular disorder.
  • CADASIL is primarily caused by mutations in the NOTCH3 gene, affecting epidermal growth factor-like repeats.

Purpose of the Study:

  • To investigate a novel mutation in a Colombian kindred with early-onset CADASIL.
  • To characterize the clinical presentation and genetic basis of this CADASIL variant.

Main Methods:

  • Genetic sequencing to identify mutations in the NOTCH3 gene.
  • Clinical evaluation of affected individuals, including age of stroke onset.
  • Comparison with known CADASIL mutations and population data.

Main Results:

  • A novel C455R mutation in the NOTCH3 gene was identified in a Colombian kindred.
  • Patients with the C455R mutation experienced stroke at a significantly earlier median age (31 years) compared to other CADASIL populations.
  • This contrasts with a second Colombian kindred carrying an R1031C mutation, also presenting with CADASIL.

Conclusions:

  • The novel C455R mutation is associated with a severe, early-onset phenotype of CADASIL.
  • This discovery expands the spectrum of NOTCH3 mutations causing CADASIL.
  • Understanding genotype-phenotype correlations is crucial for CADASIL diagnosis and management.

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