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Monogenic causes of stroke: now and the future

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Abstract

Most stroke is multifactorial with multiple polygenic risk factors each conferring small increases in risk interacting with environmental risk factors, but it can also arise from mutations in a single gene. This review covers single-gene disorders which lead to stroke as a major phenotype, with a focus on those which cause cerebral small vessel disease (SVD), an area where there has been significant recent progress with findings that may inform us about the pathogenesis of SVD more broadly. We also discuss the impact that next generation sequencing technology (NGST) is likely to have on clinical practice in this area. The most common form of monogenic SVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, due to the mutations in the NOTCH3 gene. Several other inherited forms of SVD include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, collagen type IV α1 and α2 gene-related arteriopathy and FOXC1 deletion related arteriopathy. These monogenic forms of SVD, with overlapping clinical phenotypes, are beginning to provide insights into how the small arteries in the brain can be damaged and some of the mechanisms identified may also be relevant to more common sporadic SVD. Despite the discovery of these disorders, it is often challenging to clinically and radiologically distinguish between syndromes, while screening multiple genes for causative mutations that can be costly and time-consuming. The rapidly falling cost of NGST may allow quicker diagnosis of these rare causes of SVD, and can also identify previously unknown disease-causing variants.

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Acknowledgments

Rhea Tan is supported by the Agency for Science, Technology and Research Singapore. Hugh Markus is supported by an NIHR Senior Investigator award. His work is supported by the Cambridge Universities Trust NIHR Comprehensive Biomedical Research Centre.

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Authors and Affiliations

  1. Stroke Research Group, Clinical Neurosciences, University of Cambridge, Box 83, R3 Neurosciences, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK

    Rhea Y. Y. Tan & Hugh S. Markus

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  1. Rhea Y. Y. Tan
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  2. Hugh S. Markus
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Correspondence to Rhea Y. Y. Tan.

Box 1: Features that heighten clinical suspicion of a monogenic cause of SVD. Note many of these are indicators but not diagnostic. For example, CADASIL can occur in patients with risk factors which may indeed exacerbate the phenotype

Box 1: Features that heighten clinical suspicion of a monogenic cause of SVD. Note many of these are indicators but not diagnostic. For example, CADASIL can occur in patients with risk factors which may indeed exacerbate the phenotype

Clinical presentation

  • Onset of stroke at an early age.

  • Syndromic disease: history of other clinical features which fit with recognised monogenic stroke syndrome:

    • Other neurological history such as complicated migraines, seizures, early-onset cognitive impairment, psychiatric disturbances.

    • Non-neurological features such as skeletal, facial, ocular abnormalities.

Risk factors and other causes of white matter disease

  • The absence of identifiable risk factors such as diabetes, hypertension or smoking.

  • The absence of any other cause of stroke.

Family history

  • A family history of early-onset stroke or dementia, especially if this is occurring in a Mendelian pattern of inheritance.

Presence of atypical features of imaging, such as

  • Evidence of SVD beyond what is expected for age and risk factors.

  • Atypical distribution of white matter hyperintensities on T2/FLAIR MRI in anterior temporal poles and external capsule as seen in CADASIL.

  • Extensive microbleeds particularly in COL4A1/2 mutations.

  • Pseudotumours as seen in RVCL.

  • Vascular malformations such as aneurysms (COL4A1), dolichoectasia (Fabry Disease).

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Tan, R.Y.Y., Markus, H.S. Monogenic causes of stroke: now and the future. J Neurol 262, 2601–2616 (2015). https://doi.org/10.1007/s00415-015-7794-4

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