Genetic Disorders and Stroke

Recent studies estimated that 30-40% of the population is at risk for stroke caused by genetic variations.[1] The most common causes of stroke are still build-up of plaque, high blood pressure, atrial fibrillation, or excess cholesterol and fat buildup in the blood (hyperlipidemia).  Still, several well-known single-gene disorders increase the risk of stroke, especially in the those younger than age 50. 


For example, CADASIL and CARASIL are rare conditions that lead to the development of small vessel disease due to a mutation in the Notch 3 gene. Individuals with the Notch 3 mutation may have symptoms that include migraine headaches, memory dysfunction, and stroke at a young age.[2] The condition can be diagnosed with a skin biopsy.


Similarly, Fabry’s disease is a multi-organ disease linked to the x chromosome, which means it is passed down through the maternal line. It is likely to cause large and small vessel stroke due to a genetic defect in the GLA gene. This leads individuals with the condition to build up a particular type of fat known as globotriaosylceramide or Gb3 or GL-3. Enzyme replacement therapy is now available for this condition. 


The HBB mutation that causes sickle cell anemia can lead to ischemic and hemorrhagic strokes in both children and young adults.[3]


Defects in genes known to impact the lipoprotein enzyme (lipoprotein associated phospholipase A2) can cause elevated LDL (bad) cholesterol which increases the risk of stroke due to plaque build-up in the large vessels.[4]


Recent advancements in genomic technologies will speed up the discovery of more heritable types of stroke. This will enable new drug therapies targeting these gene defects to be developed.  Regardless of genetic risk for stroke, lifestyle modifications such as smoking cessation, eating a healthy diet, managing obesity, and regular physical exercise may delay the onset of stroke or reduce the negative effect of stroke in all individuals.[5]


Please talk to your treating providers if you have tested positive for known genetic disorders associated with stroke. They can help you identify appropriate preventive measures to reduce your specific risks.


[1] Dichgans, M, Pulit SL, Rosand J, Stroke genetics: discovery, biology, and clinical applications. Lancet Neurol 2019; 18:587-99.

[2] Zellner A, Scharrer E, Arzberger T, et al. CADASIL brain vessels show a HTRA1 loss-of-function profile. Acta Neuropathol 2018; 136:111-25.

[3] Switzer JA, Hess DC, Nichols FT, Adams RJ:  Pathophysiology and treatment of stroke in sickle-cell disease: present and future.  Lancet Neurol 2006; 5: 501-12.

[4] Hindy G, Engstrom G, Larsson SC, et al. Role of blood lipids in the development of ischemic stroke and its subtypes: a mendelian randomization study. Stroke 2018; 49: 820-27.

[5] Rutten-Jacobs LC, Larsson SC, Malik R, et al. Genetic risk, incident stroke, and the benefits of adhering to a healthy lifestyle: follow-up study of 306473 UK Biobank Participants.  BMJ 2018; 363: K4168.