CADASIL is one of the most frequent monogenic disorders of the cerebral small blood vessels caused by mutations in the NOTCH3 gene on chromosome 19q12.40 [4]. CADASIL has been reported worldwide in all ethnic groups with a prevalence approximately 2 per 100,000. In patients with ischemic stroke, CADASIL mutation was found in 0.5–4% of the patients. The main clinical features are recurrent stroke, migraine, psychiatric disturbance, and progressive cognitive deficit [5].

Ischemic stroke is the most frequent manifestation and affects 60% to 84% patients with CADASIL. The mean age at stroke onset is fifth decade and most of the patients show typical lacunar syndrome such as pure motor or pure sensory strokes, dysarthria or clumsy hand syndrome, and ataxic hemiparesis. Occlusive diseases of large cerebral arteries were present 20–30% of the patients, but symptomatic stenosis was rare. In general, hemorrhagic stroke has been described only sporadically in patients with CADASIL. However, recent studies from East Asia found that 25% of symptomatic patients with CADASIL had intracerebral hemorrhages (ICHs), and the presence of ICH was closely related to the number of cerebral microbleeds (CMBs). The patients with ICH had worse clinical outcome compared with those patients without ICH.

Recurrent stroke was reported in almost 70% of the patients who experienced an initial stroke. Eventually recurrent subcortical strokes result in vascular parkinsonism and pseudobulbar palsy in some patients. Although vascular risk factors have been found infrequently in patients with CADASIL in large clinical series, hypertension and smoking were associated with increased risk of stroke in CADASIL. Cognitive deficit is reported in approximately 60% patients, and majority of them develop dementia by age 65 years. Migraine is the most frequent early symptom that occurs in 22% to 77% patients. Migraine usually begins around age 20 years and will develop in 90% patients by age 40 years. Basilar migraine, hemiplegic migraine, or migraine with prolonged aura have been reported in patients with CADASIL. Psychiatric symptoms occur in 20% to 41% patients with CADASIL and mood disorders are most common. Other uncommon manifestations are epileptic seizures, acute reversible encephalopathy, and high risk of neurological complications following catheter angiography. As a pathognomonic finding, granular osmiophilic material can be observed in the walls of affected arterioles of the brain, and it can be also observed in skin and muscle, which is very useful for pathologic diagnosis. Brain magnetic resonance imaging (MRI) of patients with CADASIL frequently shows progressive white matter hyperintensity (WMH), multiple lacunar infarcts, and CMBs. The involvement of the anterior temporal lobe and external capsule is reported to be unique in comparison to that in the sporadic form of WMH (Fig. 22.1).

CARASIL is a single-gene disorder of cerebral small blood vessels with autosomal recessive inheritance. This disorder is caused by mutations in the HTRA1 gene encoding HtrA serine peptidase/protease 1 (HTRA1) [6]. Since the first report from a Japanese family in 1976, the disorder has been mainly reported in Japan. However, a small number of cases in patients from other ethnicities have also been reported recently. Compared with CADASIL, CARASIL seems to be much rarer because approximately only 50 patients have been reported so far.

The frequent clinical features are early-onset lacunar stroke, progressive cognitive deficit, gait disturbance, alopecia, and low back pain. Lacunar stroke, reported in approximately 50% patients, is the most frequent finding of CARASIL and is usually observed in the basal ganglia or brainstem. Cognitive decline is the second-most common symptom, and almost all patients will suffer from dementia when they reach 30 to 40 years of age. Alopecia can be found in almost 90% patients and it is the most frequent early manifestation of the disorder. Hair loss usually begins at adolescence and involves the entire scalp. Low back pain is present in approximately 80% patients and usually begins at 20 to 40 years of age. Migraine-like headache has not been reported with CARASIL. Brain MRI findings are similar to that in CADASIL patients. In cerebral small arteries, extensive degeneration of vascular smooth muscle cells and reduction in the mural extracellular matrix are found, but granular osmiophilic materials or amyloid deposition has not been observed.

Hereditary vascular retinopathy, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) were initially known as separate autosomal dominant disorders. The disorders present with various combinations of Raynaud phenomenon, migraine, cranial pseudotumor, and mild kidney or liver dysfunction in addition to vascular retinopathy as a common feature. Recently three disorders were localized to a same locus in chromosome 3p21, and these are now collectively called as autosomal dominant RVCL [7]. The disorder is caused by C-terminal heterozygous, frameshift mutations in TREX1 gene encoding a DNA-specific 3′ to 5′ exonuclease DNase III. Progressive visual loss usually starts at 20 to 30 years of age. Neurologic deficits present as stroke-like episodes following visual loss and consisted of multifocal cortical and subcortical dysfunction. Brain MRI can disclose multifocal WMH lesions even before neurological symptoms. The lesions can turn into contrast-enhancing lesions with edema, later at the time of focal neurologic deficit.

Mutations in a gene encoding type IV collagen α1 (COL4A1) were initially known to cause porencephaly and infantile hemiparesis; however, these mutations have been later found to cause cerebral SVD even in adulthood. In addition to infantile hemiparesis, lacunar stroke or ICH affects approximately 20% of patients with the mean age of onset of stroke at 36 years [8]. Typically, ICH was often recurrent and provoked by minor trauma, activity, or anticoagulant use. Asymptomatic intracranial aneurysm was also found frequently, while migraine was reported in 30% cases with a mean age of onset at 30 years.