Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation

Background and Purpose-CADASIL is an autosomal dominant arteriopathy, chara cterized by multiple brain infarcts, cognitive decline, and finally dementi a, which is caused by mutations in Notch3 gene encoding a Notch3 receptor p rotein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutatio n resulting in R133C amino acid substitution, in comparison to 9 age-matche d heterozygous patients with the same mutation. Methods-The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were a nalyzed electron microscopically. Results-The homozygous patient had his first-ever stroke at age 28 years. T his is markedly earlier than the average, but the patient's heterozygous so n had his first transient ischemic attack-like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years ol der. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (conflue nt grade D) white matter MRI changes. Positron emission tomography showed m arkedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozyg ous case was, however, slower than in the most severely affected heterozygo us patient. Conclusions-Our homozygous patient's phenotype is within the clinical spect rum of CADASIL, although at its severe end. Thus, CADASIL may follow the cl assic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.