Table 1.

Monogenic CSVD disorders

Syndrome	Gene	Mutation Prevalence	Disease Incidence	Clinical Syndrome	Imaging	Pathological Findings
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)	NOTCH3 Autosomal dominant	>230 mutations in 34 EGFR regions, >95% missense, mainly cysteine altering; cysteine-sparing mutations are less common Mutations lead to aggregation of NOTCH3 Extra-cellular domain (ECD)	Classical syndrome: 2–5 in 100,000 Mutations discovered 2.2 in 1,000	Transient ischemic attacks and strokes, neuropsychiatric symptoms, cognitive impairment, apathy, mood disturbance including depression, rarely psychosis; migraine with or without aura; seizures (5–10%)	Confluent WMH by fifth decade of life in anterior temporal lobes, external capsule, periventricular areas, centrum semiovale, superior frontal gyrus Lacunar infarcts, enlarged perivascular spaces, cerebral microhemorrhages Brain atrophy (late life)	• Deposition of granular osmiophilic material (GOM) adjacent to VSMCs caused by mutated NOTCH3 ECD, containing other proteins     • Arteriopathy, most severe in small penetrating cerebral and leptomeningeal arteries     • Widespread cortical neuronal apoptosis     • Arterial wall thickening and fibrosis, stenosis • Degeneration of VSMCs and pericytes     • Myelin degeneration     • Blood-brain barrier dysfunction
Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL)	HTRA1 Autosomal recessive (mainly)	Missense and nonsense mutations, and a few compound heterozygous individuals affecting protease activity of this serine protease	~5100 cases reported	Brain: ischemic strokes, cognitive decline and dementia by 30–40yo, gait disturbance, Spine: lumbago (low back pain), Hair: alopecia (hair loss) Heterozygous HTRA1 CSVD has milder presentation without extra-CNS symptoms, and some HTRA1 mutation carriers can be asymptomatic	Symmetrical WMH in periventricular and deep WM, occasionally in anterior temporal lobes and external capsules Notable hyperintense arc from pons to middle cerebellar peduncle in late disease stages. Lacunar infarcts in basal ganglia and thalamus, Cerebral microhemorrhages Herniated lumbar and cervical disks with degeneration Brain atrophy	• Loss of VSMCs     • Hyalinosis, fibrosis and thickening of blood vessel walls     • Thinning of cerebral arterioles ECM leading to enlargement, loss of vascular elasticity and collapse
Gould syndrome	COL4A1/2 (Collagen IV A1 and A2) Autosomal dominant	Missense mutations mainly in highly conserved glycine residues in the triple helical domain of the COL4A1 gene. Other mutations impairing translation; insertions also reported. Mutations in the 3’ untranslated region of COL4A1 cause Pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL).		Highly variable multi-system disease BBB dysfunction and recurrent subcortical hemorrhages. Disease affects brain, spinal cord, eye, muscles, and kidneys. Brain: cerebral SVD, cerebral aneurysms, stroke (hemorrhagic and ischemic). Eye: retinal arterial tortuosity, cataract, developmental microphthalmia, and Axenfeld–Rieger syndrome Other affected organs: kidney, anemia, muscular cramps, cardiac arrhythmias, and Raynaud’s PADMAL: dysarthria, ataxia, paresis, mood disturbance, gait abnormality, stroke and dementia.	White matter disease, lacunar infarcts, intracranial aneurysms of carotid siphon even in asymptomatic PADMAL: lacunar infarcts of BG, brain stem, pons, and periventricularly, pyramidal tract degeneration	• Intra and extracellular accumulation of defective collagen in vessel walls, small vessel fragility and barrier dysfunction     • Basement membrane instability     • PADMAL: proliferation of intima, increased elastic fibers, atrophy of tunica media of arterioles
Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S)	TREX1 (Three prime Repair EXonuclease 1) Autosomal dominant	C-terminal frameshift mutations, mis-localization, immune dysfunction	Exceedingly rare (<100 families known)	Brain capillary rarefaction, strokes, tumor-like lesions, proteinuria, hematuria, macular edema with perifoveal microangiopathic telangiectasias, migraines, psychiatric disturbances, possibly early death	Focal T2 hyperintense lesions (tumor like in appearance) in periventricular and deep WM Contrast-enhanced pseudotumors focal calcifications visible before symptoms Frontal lobes heavily affected; corpus callosum and infratentorial tissue spared	• Thicker and multilayered vascular basement membrane     • Vessels with fibrinoid vascular necrosis or thickened hyalinized walls
Fabry’s disease	GLA (α galactosidase A) X-linked recessive	Insufficient activity of αGAL (early and late onset depend on x-inactivation and other factors)	1 in 3,100–117,000	Neuropathy, angiokeratomas, hypohidrosis, corneal opacity, and hearing loss. Internal organs, such as the kidney, heart or brain, may also be affected, leading to progressive kidney damage, heart attacks, and strokes (type 1 or early onset); diffuse white matter lesion with severe intracerebral hemorrhage and epilepsy can occur. Type 2 or late onset spears kidney and other organs	Deep WM lesions, T1 hyperintensities in pulvinar (thalamus) are pathognomic infarcts in posterior circulation and vertebrobasilar dolichoectasia microbleeds, lacunar infarcts	• Accumulation of glycosphingolipids in ECs/VSMCs
Hereditary Cerebral Hemorrhage with Amyloidosis (HCHWA)	Dutch, Italian, Flemish, Iowa and Piedmont types: Aβ precursor protein (APP) Icelandic type: cystatin C (CST3)	CAA associated disease	Rare			Misfolded Aβ 42 amyloid deposition in arteries, arterioles, capillaries, and veins, and parenchyma, degeneration of VSMCs Icelandic: amyloid fibril deposition in cerebral arteries, lymphoid organs, skin, salivary glands, testes