Genetic stroke syndromes


Cerebral stroke is a major cause or morbity and moratility. In most cases, stroke is a result of multifactorial interactions and is not primarily genetic. However, in some cases, stroke is a clinical sign of an inherited monogenic disorder. Timely recognition of these genetic disorders is crucial for accurate diagnosis and prognosis, as effective therapies may be initiated.

Detailed clinical description

A stroke occurs when the blood supply to part of the brain (or the cerebellum: of all strokes, cerebellar strokes account for 1% – 4%.) is interrupted or reduced, preventing brain tissue from getting oxygen and nutrients. So, neuronal cells of the brain or cerebellum begin to die in minutes. There are two different types of stroke: (1) ischemic stroke, caused by an artery blocked by a clot; (2) hemorrhagic stroke, caused by a leaking or bursting of a blood vessel. Some people may have only a temporary disruption of blood flow, that leads to a so called transient ischemic attack (TIA). TIA symptoms and sings are reversible.

We won’t go further in the pure clinics of stroke in this post. We’ll focus instead on genetic stroke syndromes, i.e. those monogenic syndromes that manifest with stroke. Particularly, we’ll try to understand when a genetic conditions should be suspected in borderline cases, where atypicality or paucity of clinical signs may complicate the recognition of the underlying genetic condition.

Fabry disease

Fabry disease is a monogenic condition inherited in an X-linked recessive manner, so males are primarily affected (heterozygous females typically have milder symptoms at a later age of onset than males). The disease is caused by a pathogenic mutation in the GLA gene, coding for the the enzyme alpha-galactosidase A (α-Gal A). There a two forms of the disease: (1) in males with less than 1% of residual α-Gal A activity (classic form); (2) males with more than 1% α-Gal A residual activity.

The classic form usually has its onset in childhood or adolescence with acroparesthesia, angiokeratomas, anhidrosis/hypohidrosis/hyperhidrosis, characteristic corneal and lenticular opacities, and proteinuria. End-stage renal disease (ESRD) usually occurs in men in the third to fifth decade. In middle age, most males successfully treated for ESRD develop cardiac and/or cerebrovascular disease, which are a major cause of morbidity and mortality.

The non-classic form (males with more than 1% α-Gal A residual activity) is divided in three types: (a) the cardic variant; (b) the renal variant; (c) the  cerebrovascular variant presenting as stroke or TIA.

Sickle cell disease

Sickle cell disease (or sickle cell anemia) is a multisystem disease characterized by intermittent vaso-occlusive events and chronic hemolytic anemia, that lead to episodes of acute illness and progressive organ damage.  Tissue ischemia cause acute and chronic pain as well as organ damage to the bones, spleen, liver, brain, lungs, kidneys, and/or joints. The disease is autosomal recessive and is caused by mutations in the HBB gene. In sickle cell disease affected patients less than 20 tears old ischemic stroke is more common, whereas hemorragic stroke is more frequent in older patients. Strokes may begin early, at around 2-5 years of age, and recurrent strokes are frequent. Silent strokes are also possible.

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL)

CADASIL is a progressive disorder of the small arterial vessels of the brain. The typical clinical signs are mid-adult onset migraine, strokes, and white matter lesions, with resultant cognitive impairment in some patients. Subcortical brain infarction and TIA are common. Migraine with aura, mood disturbance, apathy are also typical. The disease is autosomal dominant and caused by mutations in the NOTCH3 gene. Family history of stroke events is a significant matter of suspicion for CADASIL, although the lack of family history does not exclude the possibily of CADASIL in a patient. Brain white matter hyperintensities are also an important sign when suspecting CADASIL. Notably, most NOTCH3 mutations are missense variants  that lead to the loss or gain of a cysteine residue.

Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CARASIL)

Stroke with onset in the third decade (typically with spastic gait, alopecia and spondylosis) and dementia with onset in the third through fifth decade, are characteristic of CARASIL. CARASIL is autosomal dominant and caused by mutations in the HTRA1 gene.

Retinal Vasculopathy with leukoencephalopathy and systemic manifestations (RVCLS)

RVCLS is autosomal dominant and caused by mutations in the TREX1 gene. RVCLS shows adult-onset with progressive vision loss, stroke, motor impairment, and cognitive decline. Psychiatric disturbances may also be evident (although they are less common). Some individuals have systemic vascular involvement evidenced by Raynaud phenomenon, micronodular cirrhosis, and glomerular dysfunction.  Age of onset is often between 35 and 50 years.

Mitochondrial Encephalopathy, Lactic Acidosis, and Strokelike Episodes (MELAS)

MELAS manifests mainly in the fourth decade with stroke-like episodes, encephalopathy with seizures and/or dementia, muscle weakness and exercise intolerance, recurrent headaches, recurrent vomiting, hearing impairment, peripheral neuropathy, learning disability, and short stature. The m.3243A>G mutation in the mitochondrial DNA (mtDNA) is the most frequent pathogenic variant, although other mutations in the mtDNA may be the cause.

Diagnostic criteria for MELAS: two schemes have been proposed, one by Hirano et al 1992 and one by Yatsuga et al 2012:

  1. Hirano et al 1992: a clinical diagnosis of MELAS can be made if the following three criteria are met: (1) stroke-like episodes before age 40 years, (2) encephalopathy characterized by seizures and/or dementia, (3) mitochondrial myopathy is evident by the presence of lactic acidosis and/or ragged-red fibers (RRFs) on muscle biopsy; AND at least two of the following: normal early psychomotor development, recurrent headaches, recurrent vomiting episodes.
  2. Yatsuga et al 2012: a clinical diagnosis of MELAS can be made in an individual with at least two category A and two category B criteria: Category A criteria: Headaches with vomiting, Seizures, Hemiplegia, Cortical blindness, Acute focal lesions on neuroimaging (see Suggestive Findings, Brain Imaging); Category B criteria: High plasma or cerebrospinal fluid (CSF) lactate, Mitochondrial abnormalities on muscle biopsy, a MELAS-related pathogenic variant.

Moyamoya disease

Moyamoya is a cerebral angiographic picture of bilateral intracranial carotid artery occlusion associated with telangiectatic vessels in the region of the basal ganglia. The Japanese word moyamoya means ‘something hazy like a puff of cigarette smoke, drifting in the air.’ Moyamoya disease is associated with recurrent TIA, ischemic stroke, and hemorrhagic stroke. Onset can be infancy (5-10 years), but also in adulthood (30-50 years). Epilepsy is common. So far, mutations have been identified in the RNF213, ACTA2, and GUCY1A3 genes, although other genes are to be identified. Juvenile patients with moyamoya disease initially present with transient motor disturbances resulting from transient brain ischemia, whereas adults present with intracranial hemorrhage.

Cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by the accumulation of cerebral amyloid-β (Aβ) in the tunica media and adventitia of leptomeningeal and cortical vessels of the brain. Familial forms of CAA exist. Mutations have been identified in the ITM2B, APP, and CST3 genes. The conditions is carachterized by the rupture of small cortical vessels, lobar hemorrhage, microbleeds, leukoencephalopathy, dementia (cognitive impairment may also be the presenting symptom), and the deposition of amyloid spells (this deposition is actually the cause of brain vessel fragility). This disorder can have severe morbidity and mortality if it is not identified and treated promptly. The disease can also be sporadic (i.e. non genetic). Sporadic CAA usually manifest after 60 years of age, whereas presenile CAA is usually familial.

COL4A1-related disorders

COL4A1 gene mutations cause a spectrum of vessel anomalies that include small-vessel brain disease of varying severity including:

  1. Porencephaly,  with infantile onset, variably associated with retinal arterial tortuosity, Axenfeld-Rieger anomaly, and cataract and, systemic findings, caused by kidney damage, muscle cramps, cerebral aneurysms, Raynaud phenomenon, cardiac arrhythmia, and hemolytic anemia. Diffuse periventricular leukoencephalopathy, lacunar infarcts, microhemorrhage, dilated perivascular spaces, and deep intracerebral hemorrhages may be seen on MRI.
  2. Brain small vessel disease with or without ocular anomalies: the increased fragility of blood vessels render them susceptible to hemorrhage, as early as in utero or by birth trauma, although the risk remains throughout life and some patients may present in adulthood.
  3. HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome, that usually leads to cerebral large vessel involvement (i.e. aneurysms), and systemic findings involving the kidney, muscle, and small vessels of the eye, whereas small-vessel brain disease remains asymptomatic.
  4. Isolated retinal artery tortuosity.
  5. Nonsyndromic autosomal dominant congenital cataract.

Ehlers-Danlos syndrome type 4 (vascular type)

Easy bruising, thin skin with visible veins, characteristic facial features (thin lips, lobeless ears, keratoconus, pinched, thin nose, periodontal disease, early loss of teeth), joint hypermobility mostly limited to the digits, and minimal or no skin hyperextensibility are typical of Ehlers-Danlos syndrome type 4 (EDS4, also known as the vascular type). Vascular dissection or rupture may be the presenting sign. Major complications may be diagnosed as early as 11 years of age, but the average age for the first major arterial or gastrointestinal complication may be around 30 years of age. Stroke and its neurologic sequelae (and even sudden death) may be the presenting sign in 70% of the cases. EDS4 is caused by mutation in the COL3A1 gene.

Marfan syndrome

Marfan syndrome is a highly clinically variable disorder, which is caused by heterozygous mutations in the FBN1 gene. Ischemic stroke and arterial
dissection are possible in patients affected by this syndrome and represent a major concern. The diagnosis of Marfan syndrome is established in a proband when either of the following two criteria is satisfied

1. an FBN1 pathogenic variant + aortic root enlargement (Z-score ≥2.0) or ectopia lentis
2. Aortic root enlargement (Z-score ≥2.0) + ectopia lentis, or a defined combination of features throughout the body yielding a systemic score ≥7*

*Calculation of the systemic score

Feature Value
Wrist AND thumb sign 3
Wrist OR thumb sign 1
Pectus carinatum deformity 2
Pectus excavatum or chest asymmetry 1
Hindfoot deformity 2
Plain flat foot (pes planus) 1
Pneumothorax 2
Dural ectasia 2
Protrusio acetabulae 2
Reduced upper segment / lower segment AND increased arm span/height ratios 1
Scoliosis or thoracolumbar kyphosis 1
Reduced elbow extension 1
3 of 5 facial features 1
Skin striae 1
Myopia 1
Mitral valve prolapse 1

ADA2 Deficiency

Pathogenic mutations in the ADA2 gene cause an autosomal recessive spectrum of clinical features, sometimes distinguished in two different entities:

  • Sneddon syndrome, a noninflammatory arteriopathy characterized by onset of livedo reticularis in the second decade and onset of cerebrovascular disease in early adulthood.
  • VAIHS (𝑉asculitis, 𝐴utoinflammation, 𝐼mmunodeficiency, and 𝐻ematologic defects 𝑆yndrome), of which age at onset is usually in first decade, but can occur later). Most patients have features of a systemic vascular inflammatory disorder with skin ulceration and recurrent strokes, leading to neurologic dysfunction. Recurrent fever, elevated acute-phase proteins, myalgia/arthralgia, polyarteritis nodosa casused by the vasculitis, and/or livedo racemosa or reticularis. Renal and/or gastrointestinal involvement, hypertension, aneurysms,ischemic necrosis of the digits, and immunodeficiency are also possible.

It’s worth to mention that ADA2-related disorders shows high interfamilial and intrafamilial phenotypic variability (in age of onset, frequency and severity of manifestations) and that some individuals with biallelic ADA2 pathogenic variants may even remain asymptomatic until adulthood or may never develop clinical manifestations.

Hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (or Osler-Rendu-Weber disease) is an autosomal dominant vascular dysplasia leading to telangiectases and arteriovenous malformations of skin, mucosa, and viscera. Ischemic stroke is observed in different patients as a complication of this highly penetrant disorder, for which epistaxes is the presenting feature in most cases in young age, followed by malformations of blood vessels affecting lungs, brain, spinal cord, and liver. Mutations in the ENG, ACVRL1, and GDF2 genes cause different types of hereditary hemorrhagic telangiectasia.

Loeys-Dietz syndrome

Forms of Loeys-Dietz syndrome (characterized by aortic aneurysm with systemic involvement) resulting from mutations in the TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3, and SMAD2 genes, can be taken into account as rare genetic causes of stroke associated with connective tissue disorders, but they are actually often overlooked by stroke physicians.

Capillary malformation-arteriovenous malformation

Capillary malformation-arteriovenous malformation caused by mutations in the RASA1 gene is characterized by atypical capillary malformations and vascular malformations that can cause complications such as hemorrhage and stroke, in case vascular malformations are not treated. Mutations in the EPHB4 gene cause a vascular malformation similar to the RASA1-related disease.


Genetic testing strategy

A multigene panel based on whole exome sequencing or whole genome sequencing is ideal to recognize the genetic syndromes characterized by stroke.

Our panel for genetic stroke syndrome is the following:

Pan272 – Genetic stroke syndromes (ACTA2, ACVRL1, ADA2, APP, COL3A1, COL4A1, CST3, ENG, EPHB4, FBN1, GDF2, GLA, GUCY1A3, HBB, HTRA1, ITM2B, NOTCH3, RASA1, RNF213, SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2, TREX1, mtDNA)

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Kevin M. Barrett et al, Genetic Stroke Syndromes, Continuum (Minneap Minn). 2014 Apr; 20(2 Cerebrovascular Disease): 399–411. doi: 10.1212/01.CON.0000446109.20539.68

Kimon I. et al, Cerebellar Infarct, PMID: 29261863

Atul Mehta et al, Fabry Disease, Genereviews, PMID: 20301469 at large

Genereviews at large (

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