Cerebral Microbleedings and Late Stroke Onset in a CADASIL Family with Rare Deletion in Exon 5 of the NOTCH3 Gene

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL) is a rare hereditary non-atherosclerotic, non-amyloid systemic small vessel disease. Affected patients typically show migraine attacks, recurrent cerebral infarctions and a progressive cognitive decline eventually leading to subcortical vascular dementia. Psychiatric symptoms such as affective disorders appear in 40% of the mutation carriers. Seizures occur in about 10% Of the patients. At the age of 40 years, leukencephalopathy is present in all Mutation carriers, while a complete penetrance of clinical symptoms is usually observed LIP to the age of 60 years. CADASIL is caused by missense mutations in the NOTCH3 gene located on chromosome 19p13.1, We report on a German family with a very rare in-frame deletion in exon 5 of the NOTCH3 gene. In 2 of the 3 family members cerebral microhaemorrhages could be observed. One family member showed a late stroke onset with first cerebral ischaemic event at the age of 71 years. Characteristic and special features of the diagnostic evaluation and counselling of family members from three generations are discussed. The progression of leukencephalopathy with increasing age is demonstrated exemplarily by cerebral magnetic resonance imaging in 29-, 55- and 71-year-old mutation carriers.