Monogenic causes of cerebral small vessel disease and stroke
Stéphanie Guey1, Hugues Chabriat1
1Translational Centre for Neurovascular Disorders, Hôpital Lariboisière AP-HP, Paris, France; Paris-Cité University, Inserm U1141 NeuroDiderot, Paris, France.
Insights
Cerebral small vessel diseases (cSVDs) cause 25% of strokes. Genetic testing is crucial for rare monogenic forms like CADASIL, but many genetic causes remain undiscovered.
Area of Science:
- Neurology
- Genetics
- Vascular Medicine
Background:
- Cerebral small vessel diseases (cSVDs) contribute significantly to stroke incidence and neurological disability.
- Monogenic disorders, particularly cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), represent a subset of cSVDs.
- Clinical presentation and imaging findings can overlap across different Mendelian cSVDs, necessitating comprehensive genetic evaluation.
Purpose of the Study:
- To highlight the genetic basis of cerebral small vessel diseases (cSVDs).
- To emphasize the importance of molecular screening in suspected cases of monogenic cSVDs.
- To discuss the current genetic testing strategies and identify gaps in knowledge regarding the genetic etiology of cSVDs.
Main Methods:
- Review of current literature on Mendelian forms of cSVDs.
- Analysis of genetic factors implicated in various cSVD subtypes.
- Discussion of diagnostic approaches including panel-targeted gene sequencing and exome sequencing.
Main Results:
- Over a dozen genes are implicated in Mendelian cSVDs, often presenting as autosomal dominant conditions.
- Specific genes are associated with ischemic stroke (e.g., CADASIL, HTRA1, PADMAL, CARASAL, LAMB1) or intracerebral hemorrhages (e.g., COL4A1/COL4A2, hereditary cerebral amyloid angiopathy).
- Genetic variants are identified in less than 15% of patients with suspected genetic cerebrovascular disease, indicating a need for further gene discovery.
Conclusions:
- Early detection of cSVDs with specific clinical and imaging red flags should prompt molecular screening.
- Simultaneous screening of known genes is the current standard for diagnosing Mendelian cSVDs.
- A significant proportion of genetic cerebrovascular diseases remain unexplained, underscoring the need to identify novel causative genes.
Abstract:
Cerebral small vessel disease (cSVDs) account for 25% of stroke and are a frequent cause of cognitive or motor disability in adults. In a small number of patients, cSVDs result from monogenic diseases, the most frequent being cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). An early disease onset, a suggestive family history, and a low vascular risk profile contrasting with a high load of cSVD imaging markers represent red flags that must trigger molecular screening. To date, a dozen of genes is involved in Mendelian cSVDs, most of them are responsible for autosomal dominant conditions of variable penetrance. Some of these mendelian cSVDs (CADASIL, HTRA1-related cSVD, pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), cathepsin-A related arteriopathy with strokes and leukoencephalopathy (CARASAL), and cSVD related to LAMB1 mutations) are causing ischemic stroke. Others (COL4A1/COL4A2-related angiopathy and hereditary cerebral amyloid angiopathy) preferentially lead to intracerebral hemorrhages. The clinical features of different Mendelian cSVDs can overlap. Therefore, the current approach is based on simultaneous screening of all genes involved in these conditions through a panel-targeted sequencing gene or exome sequencing. Nevertheless, a pathogenic variant is identified in less than 15% of patients with a suspected genetic cerebrovascular disease, suggesting that many additional genes remain to be identified.
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