Homozygosity and severity of phenotypic presentation in a CADASIL family

Area of Science:

• Genetics and Neurology
• Molecular Medicine

Background:

• Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is typically caused by heterozygous NOTCH3 gene mutations.
• Homozygous CADASIL mutations are rare, with limited data on their clinical presentation and potential phenotypic variations.

Observation:

• A consanguineous Italian family with a homozygous p.Cys183Ser NOTCH3 mutation was studied.
• The index patient, a 44-year-old male, presented with early-onset stroke, severe leukoencephalopathy, and cognitive decline.
• Five heterozygous relatives showed variable phenotypes, including late-onset stroke or asymptomatic disease.

Findings:

• The homozygous mutation in this family resulted in a severe and early-onset CADASIL phenotype.
• Heterozygous carriers of the same mutation exhibited milder or absent clinical symptoms, suggesting a dose-dependent effect.
• Skin biopsies confirmed Granular Osmiophilic Material (GOMs) deposition, a hallmark of CADASIL.

Implications:

• This case underscores the importance of considering homozygous mutations in rare genetic disorders.
• Understanding genotype-phenotype correlations in CADASIL is crucial for accurate diagnosis and prognosis.
• The study contributes to the knowledge of genetic variations influencing the severity of inherited cerebrovascular diseases.