Disease
Gene
Inheritance
Mechanism
Clinical features
CADASIL
NOTCH3
AD
Small vessel
Migraine with aura, cognitive deficits
CARASIL
HTRA1
AR
Small vessel disease
Alopecia, cervical/lumbar spondylosis
Cerebral amyloid angiopathy
APP (Dutch type)
AD
Small and large vessel disease
ICH, dementia
CST3 (Icelandic type)
Icelandic type: stroke at early age (<30 years)
Cerebral cavernous malformations
KRIT1
AD
Leakage and rupture of dilated blood vessels
ICH, Retinal vascular malformations
CCM2
Ehlers-Danlos Type IV
COL3A
AD
Arterial dissection
Thin, translucent skin, easy bruising, characteristic facial features
Fabry disease
GAL
X-linked recessive
Small and large vessel disease
Angiokeratomas, neuropathy, acroparesthesias, corneal dystrophy, renal, cardiac failure
Hereditary Hemorrhagic Telangiectasia
Several
AD
AVM rupture, paradoxical embolism via pulmonary AVF
Ischemic > hemorrhagic stroke, pulmonary AVM, epistaxis, telangiectasia in lung, liver, GI tract, brain
HERNS/RVCL
TREX1
AD
Small vessel disease
Endotheliopathy, retinopathy, nephropathy, stroke, macular edema, migraines
Homocystinuria
CBS
AR
Small and large vessel disease, arterial dissection, cardiac embolism
Ectopia lentis, glaucoma, mental retardation
MTHFR
Marfan syndrome
FBN1
AD
Arterial dissection, embolism
Orthopedic abnormalities, aortic dissection, tall stature
MELAS
Mitochondrial DNA
Maternal
Several factors
Cataracts, sensorineural hearing loss, developmental delay, short stature, myopathy, seizures, cognitive delay
Menkes disease
ATP7A
X-linked
Small and large vessel disease
Growth failure, hypotonia, blue sclera, seizures, brittle hair
Moya Moya disease
RNF213
Familial type: AD
Small and large vessel disease
Recurrent TIA, ischemic stroke and ICH, epilepsy, Morning glory optic disk
Pseudoxanthoma elasticum
ABCC6
AR
Small and large vessel disease
Yellow/orange skin papules, ocular angioid streaks, atherosclerosis
Sickle cell disease
HBB
AR
Small and large vessel disease, vaso-occlusion
Pain crises, recurrent infections, anemia
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL )
Inheritance: autosomal dominant, small vessel arteriopathy caused by a mutation in NOTCH3 gene on chromosome 19p13.2-p13.1. Gene encodes transmembrane protein critical to vascular smooth muscle development and differentiation.
Clinical presentation: recurrent TIAs and subcortical lacunar strokes. Median age of onset is early 50s in men and women (but MRI changes precede strokes)
Recurrent strokes lead to cognitive decline and dementia, gait imbalance, depression, psychosis, pseudobulbar palsy, incontinence
Associated with migraine with aura in about 30 % of cases
Diagnosis: molecular genetic testing for NOTCH3 mutation
Skin biopsy to evaluate for granular osmophilic material in vascular basal lamina (highly specific)
Histology: small, medium vessel angiopathy that is negative for atherosclerosis or amyloid deposition
MRI: T2 hyperintensities in white matter of the anterior temporal poles (O’Sullivan sign) seen in 90 % of cases, as well as signal changes in external capsule and corpus callosum; diffuse brain atrophy; may see evidence of microbleeds on gradient echo (Fig. 10-1)
Cognitive testing recommended
Treatment: aggressive blood pressure, hyperlipidemia, DM control. No clear benefit of antiplatelet agents, but still used
Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL )
Inheritance: autosomal recessive, with mutation in high temperature requirement A serine peptidase 1 (HTRA1) gene on chromosome 10q
Clinical presentation: stroke onset typically in the third decade of life, and dementia in third to fifth decade
Associated with premature hair loss (teen age years), cervical or lumbar spondylosis, gait disturbance
Patients typically do not have typical cardiovascular risk factorsRelated posts:
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