Table 2.
Monogenic disorders that include stroke in their phenotypic manifestation (modified from Falcone et al.).
| Disorder | Gene | Inheritance | Stroke Mechanism | Clinical Manifestation | Diagnostic Test |
|---|---|---|---|---|---|
| CADASIL | NOTCH3 | Autosomal dominant | SVD | Migraine with aura, recurrent strokes | Molecular genetic tests, skin biopsy |
| CARASIL | HTRA1 | Autosomal recessive | SVD | Recurrent strokes, vascular dementia, severe back pain, premature alopecia | Molecular genetic tests |
| Fabry’s disease | GAL | X-linked | Large-artery disease, SVD | Neuropathic, abdominal pain, angiokeratoma, renal and cardiac failure, | Molecular genetic tests, α galactosidase activity |
| MELAS | mtDNA | Maternal | Complex (microvascular and neuronal factors) | Seizures, headache, ataxia, hearing loss, muscle weakness | Muscle biopsy, mutational analysis of mtDNA |
| RVCL | TREX1 | Autosomal dominant | SVD | Visual loss, migraines, cognitive impairment, strokes | Molecular genetic tests |
| FOXC1-deletion related SVD | FOXC1 | De novo or inherited mutations, reciprocal translocations | SVD | Subcortical infarcts, ARS, hearing impairment, cerebellar malformations | Molecular genetic tests |
| COL4A1-A2 syndromes | COL4A1 and COL4A2 | Autosomal dominant | SVD | Lacunar infarcts, hemorrhages, including cerebral, developmental delay, seizures, migraine without aura, visual loss, nephropathy, myopathy arrhythmias | Molecular genetic tests |
| vEDS | COL3A1 | Autosomal dominant | Arterial dissection | Easy bruising, thin skin with visible veins, characteristic facial features, arterial, uterine or intestinal ruptures | Biochemical analysis, molecular genetic tests |
| Sickle-cell disease | H88 | Autosomal recessive | Large-artery disease, SVD, hemodynamic insufficiency | Pain crises, seizures, myelopathy, anemia, bacterial infection, pulmonary, abdominal and vaso-occlusive crises | Peripheral blood smear, electrophoresis, mutational analysis |
| Homocystinuria | CBS | Autosomal recessive | Large-artery disease, CE, SVD, arterial dissection | Mental retardation, atraumatic dislocation of lenses, Marfan-like skeletal deformations, premature atherosclerosis, thromboembolic | Urine analysis, homocysteine and methionine in plasma measurementsMolecular genetic tests |
| Marfan syndrome | FBN1 | Autosomal dominant | CE and arterial dissection | Pectus carinatum or excavatum, upper-to-lower segment ratio <0.86, or arm-span-to-height ratio >1.5; scoliosis >20%; ectopia lentis; dilation or dissection of the ascending aorta; lumbosacral dural ectasia | Clinical diagnosisMolecular genetic tests |
| Pseudoxanthoma elasticum | ABCC6 | Autosomal recessive | Large-artery disease and SVD | Increased elasticity and yellow-orange popular lesions of skin, ocular changes (angioid streaks), hypertension | Skin biopsy, molecular genetic tests |
| Disorder | Gene | Inheritance | Stroke mechanism | Clinical manifestation | Diagnostic test |
| CADASIL | NOTCH3 | Autosomal dominant | SVD | Migraine with aura, recurrent strokes | Molecular genetic tests, skin biopsy |
| CARASIL | HTRA1 | Autosomal recessive | SVD | Recurrent strokes, vascular dementia, severe back pain, premature alopecia | Molecular genetic tests |
| Fabry’s disease | GAL | X-linked | Large-artery disease, SVD | Neuropathic, abdominal pain, angiokeratoma, renal and cardiac failure, | Molecular genetic tests, α galactosidase activity |
| MELAS | mtDNA | Maternal | Complex (microvascular and neuronal factors) | Seizures, headache, ataxia, hearing loss, muscle weakness | Muscle biopsy, mutational analysis of mtDNA |
| RVCL | TREX1 | Autosomal dominant | SVD | Visual loss, migraines, cognitive impairment, strokes | Molecular genetic tests |
| FOXC1-deletion related SVD | FOXC1 | De novo or inherited mutations, reciprocal translocations | SVD | Subcortical infarcts, ARS, hearing impairment, cerebellar malformations | Molecular genetic tests |
| COL4A1-A2 syndromes | COL4A1 and COL4A2 | Autosomal dominant, de novo mutation | SVD | Hemorrhages, including cerebral, hemiparesis, developmental delay, seizures, lacunar infarcts, migraine without aura, visual loss, nephropathy, myopathy arrhythmias | Molecular genetic tests |
| vEDS | COL3A1 | Autosomal dominant | Arterial dissection | Easy bruising, thin skin with visible veins, characteristic facial features, arterial, uterine or intestinal ruptures | Biochemical analysis, molecular genetic tests |
| Sickle-cell disease | H88 | Autosomal recessive | Large-artery disease, SVD, hemodynamic insufficiency | Pain crises, seizures, myelopathy, anemia, bacterial infection, pulmonary, abdominal and vaso-occlusive crises | Peripheral blood smear, electrophoresis, mutational analysis |
| Homocystinuria | CBS | Autosomal recessive | Large-artery disease, CE, SVD, arterial dissection | Mental retardation, atraumatic dislocation of lenses, Marfan-like skeletal deformations, premature atherosclerosis, thromboembolic | Urine analysis, homocysteine and methionine in plasma measurements(molecular genetic tests) |
| Marfan’s syndrome | FBN1 | Autosomal dominant | CE and arterial dissection | Pectus carinatum or excavatum, upper-to-lower segment ratio <0.86, or arm-span-to-height ratio >1.5; scoliosis >20%; ectopia lentis; dilation or dissection of the ascending aorta; lumbosacral dural ectasia | Clinical diagnosis(molecular genetic tests) |
| Pseudoxanthoma elasticum | ABCC6 | Autosomal recessive | Large-artery disease and SVD | Increased elasticity and yellow-orange popular lesions of skin, ocular changes (angioid streaks), hypertension | Skin biopsy, molecular genetic tests |
CADASIL—cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CARASIL—cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. MELAS—mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. mtDNA—mitochondrial DNA; RVCL—retinal vasculopathy with cerebral leukodystrophy; vEDS—Vascular Ehlers-Danlos syndrome; SVD—small vessel disease; CE—cardioembolic.