From the Guidelines
Genetic factors, particularly CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) caused by mutations in the NOTCH3 gene, play a significant role in recurrent lacunar infarcts. The most recent and highest quality study 1 highlights the importance of CADASIL as a genetic cause of recurrent lacunar infarcts. Other genetic conditions that may contribute to recurrent lacunar strokes include:
- CARASIL (Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) due to HTRA1 gene mutations
- Fabry disease caused by GLA gene mutations
- MELAS syndrome from mitochondrial DNA mutations
- COL4A1/COL4A2 mutations affecting blood vessel integrity
- Genetic disorders of blood clotting such as Factor V Leiden and prothrombin gene mutations
- Genetic variants affecting homocysteine metabolism (MTHFR gene) and those associated with small vessel disease These genetic conditions can cause structural changes in small blood vessels, leading to vessel wall thickening, reduced blood flow, and ultimately, recurrent small strokes. Patients with unexplained recurrent lacunar infarcts, especially those with family history or early onset disease, should undergo genetic testing to identify these underlying causes, as specific management strategies may be available for certain genetic disorders 1. It is essential to prioritize the identification of genetic causes, as it can significantly impact morbidity, mortality, and quality of life for patients with recurrent lacunar infarcts.
From the Research
Genetic Causes of Recurrent Lacunar Infarcts
The genetic causes of recurrent lacunar (small vessel) infarcts are primarily associated with mutations in the NOTCH3 gene, which leads to Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) 2, 3, 4, 5, 6.
Key Features of CADASIL
- CADASIL is an adult-onset, dominantly inherited small-vessel disease of the brain 2
- It is characterized by recurrent subcortical infarctions, dementia, migraine with aura, and mood disturbance 2
- The disease is caused by missense mutations or small deletions in the NOTCH3 gene, leading to a gain or loss of cysteine residues in the extracellular domain of the Notch3 protein 4, 5
- These mutations result in the accumulation of granular osmiophilic material in arterial walls, leading to progressive wall thickening and fibrosis, and ultimately, lacunar infarcts 4, 5
Diagnosis and Clinical Manifestations
- CADASIL can be diagnosed based on clinical manifestations, imaging results, and genetic reports 6
- Clinical manifestations may include migraine with aura, transient ischemic attacks, strokes, and dementia 3, 4, 5
- Imaging results may show characteristic white matter hyperintensities and lacunar infarcts in the basal ganglia and fronto-temporal white matter 3, 4, 5
- Genetic testing can identify mutations in the NOTCH3 gene, confirming the diagnosis of CADASIL 2, 3, 6