Clinical and genetic features in a family with CADASIL and high lipoprotein (a) values

Area of Science:

• Neurology
• Genetics
• Vascular Biology

Background:

• Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic disorder affecting small blood vessels in the brain.
• Elevated Lipoprotein(a) [Lp(a)] is a known risk factor for cardiovascular and cerebrovascular diseases.

Observation:

• A family presented with CADASIL and unusually high Lp(a) levels.
• The index patient exhibited stenoses in large intracranial arteries, atypical for CADASIL.
• Affected individuals, including children, showed early signs of cerebral microangiopathy, white matter lesions, and lacked typical CADASIL symptoms like migraine or cognitive decline.

Findings:

• A specific mutation (S118C in exon 4 of Notch3) was identified as the cause of CADASIL in this family.
• The mechanism for elevated Lp(a) was linked to the size of kringle IV type 2 repetitions.
• The study correlated the Notch3 mutation with elevated Lp(a) levels.

Implications:

• This research highlights a potential link between elevated Lp(a) and the cerebrovascular phenotype in CADASIL.
• The findings expand the understanding of CADASIL's genetic basis and clinical variability.
• Early detection of microangiopathy in children suggests the need for proactive monitoring and management strategies.