CADASIL IN A NORTH-AMERICAN FAMILY - CLINICAL, PATHOLOGICAL, AND RADIOLOGIC FINDINGS

Objective: To expand the reported phenotypic range of cerebral autosom al dominant arteriopathy with subcortical infarcts and leukoencephalop athy (CADASIL). Background: Despite numerous patient reports, our know ledge of the phenotypic range of CADASIL remains incomplete. Method: W e performed clinical, pathologic, and radiologic examinations on membe rs of a family with CADASIL. Results: The proband is a 61-year-old man with a history of migraine and depression who has experienced multipl e subcortical infarctions resulting in a stepwise decline. Neuropsycho logical testing documented a dementia syndrome with frontal lobe featu res and neurologic examination noted a left hemiparesis and a right-si ded palmomental reflex. Brain biopsy with light microscopy revealed a nonatherosclerotic small-vessel angiopathy with periodic acid-Schiff p ositive granular changes in the media and white matter gliosis, with u nremarkable cortex. Genetic testing confirmed a Notch3 mutation. The p roband's first cousin has a history of depression, one seizure possibl y resulting from an acute stroke, and a learning disorder. Neuropsycho logical testing demonstrated deficits in executive function and neurol ogic examination noted persistent extraneous adventitial movements, po or coordination, and primitive reflexes. Skin biopsy with electron mic roscopy demonstrated granular osmiophilic material within the basement membrane of vascular smooth muscle cells, which is considered to be p athognomonic of CADASIL. The proband's older son and younger son have histories of migraine and depression, respectively, and both also had learning disorders. MRI revealed diffuse white matter disease extendin g into the temporal lobes, and lacunar infarctions in these four nonhy pertensive patients. Other family members have experienced migraine, r ecurrent stroke, dementia, and depression. Conclusions: CADASIL is a g enetic basis for vascular dementia that may be manifest earlier in lif e than previously reported.