Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy affecting an African American man: identification of a novel 15-base pair NOTCH3 duplication.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the best characterized genetic cause of vascular dementia and stroke and has been extensively reported in European and Asian populations.
OBJECTIVE: To report the pathological and genetic analysis of CADASIL in an African American man with a 15-base pair NOTCH3 duplication.
DESIGN: Case report.
SETTING: University hospital. PATIENT: A 78-year-old man with dementia, recurrent strokes, a family history of similar neurological disease, and white matter abnormalities seen on brain magnetic resonance imaging. MAIN OUTCOME MEASURES: Brain pathology and genetic analysis of NOTCH3.
RESULTS: The patient's brain showed widespread arteriopathy in large and small arteries. Using electron microscopy, granular osmiophilic material typical of CADASIL was identified abutting the plasma membrane of smooth muscle cells. Brain extracts contained elevated NOTCH3 protein levels. Sequencing of the NOTCH3 gene revealed a novel 15-base pair heterozygous duplication in exon 7, which is predicted to direct expression of a protein that contains 5 extra amino acids, including a cysteine residue.
CONCLUSIONS: To our knowledge, this is the first reported pathological and genetic analysis of an African American patient with CADASIL. The mutation in NOTCH3 is the longest duplication within this gene yet reported.