Progress in the genetics of cerebrovascular disease: inherited subcortical arteriopathies.

W e have much to discover regarding the etiol-ogy of cerebral infarction, as the commonly recognized risk factors, such as hyperten-sion, diabetes, and atrial fibrillation, account for only a small proportion of stroke. Genetic factors are clearly important. Substantial genetic components underlie hypertension and diabetes. However, as contributors to the known risk factors for stroke, they are encompassed within that part of stroke risk that has already been identified. The importance of otherwise unspecified genetic factors in vascu-lar disease has been illustrated by coronary heart disease , in which having an affected first-degree relative may increase an individual's risk tenfold. 1 The evidence of a role for family history in cerebral infarction is less impressive, but present. 24 Even taken together, the many genetic conditions that predispose to stroke in a Mendelian (single-gene) fashion 5 explain few infarcts. Single-gene diseases that specifically and directly affect the cerebral circulation are seemingly limited, to date, to Dutch and Icelandic amyloid disease, 67 and these present primarily with intracerebral hemorrhage, not infarction. Bousser and Tournier-Lasserve 8 report the proceedings of an international workshop on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which has an auto-somal dominant pattern of inheritance. 9 " 16 The condition has now been localized to chromosome 19ql2 17 in two unrelated families, 1112 thus providing a marker for the condition. CADASIL presents clinically in the third to seventh decades, although some pedigrees have a consistently later age of onset 1314 than others. 10 It begins with recurrent stroke or, less commonly, transient ischemic attacks. Complete remission after the early episodes may be seen. 91016 After several years the pattern of progression may alter. Recurrent, discrete events may cease and be replaced by a steadily progressive pseudobulbar palsy and subcortical dementia. Cer-ebellar signs may occur. 910-16 Traditionally accepted vascular risk factors are conspicuously absent. Migraine-like headache and psychiatric complaints, particularly depression, are associated with the condition. Given the frequency of migraine in the general population, care must be taken when including migrainelike headache as part of this syndrome. The case series reported in the workshop proceedings 8 had a highly variable prevalence of migraine. Others (Verin) identify them with great frequency and still others (Chabriat, France) with an intermediate frequency. Depression is common in early dementia, and it may be no more unique to this illness than to other dementias. These questions need prospective , critical analysis …