Hereditary cerebral small vessel disease and stroke
Christian Baastrup Søndergaard1, Jørgen Erik Nielsen2, Christine Krarup Hansen1
1Department of Neurology, Copenhagen University Hospital, Bispebjerg, Denmark.
Insights
Hereditary cerebral small vessel diseases, often causing early stroke, require molecular genetic testing for diagnosis. This review guides clinicians on identifying these rare genetic disorders.
Area of Science:
- Neurology
- Genetics
- Vascular Medicine
Background:
- Cerebral small vessel disease (CSVD) has hereditary forms in ~5% of cases.
- Characterized by MRI findings like lacunar infarcts and white matter hyperintensities.
- Several monogenic disorders causing CSVD and stroke are known.
Purpose of the Study:
- To guide molecular genetic testing decisions in patients with CSVD and stroke.
- To review genetics, pathology, clinical features, imaging, and diagnosis of specific monogenic disorders.
- To highlight the importance of genetic counseling and diagnostic challenges.
Main Methods:
- Systematic review of monogenic hereditary CSVDs.
- Description of CADASIL, CARASIL, COL4A mutations, RVCL, Fabry disease, HCHWA, and FOXC1 mutations.
- Analysis of clinical presentation, neuroimaging, and diagnostic criteria.
Main Results:
- Monogenic CSVDs often present with early stroke, migraine, mood disturbances, dementia, and gait issues.
- Extra-cerebral manifestations (eye, kidney microangiopathy) can occur.
- Molecular genetic analysis is the definitive diagnostic standard.
Conclusions:
- Timely molecular genetic testing is crucial for diagnosing hereditary CSVDs.
- Early identification aids genetic counseling and potential targeted therapies (e.g., enzyme replacement in Fabry disease).
- Treatment options for most hereditary CSVDs remain limited.
Abstract:
Cerebral small vessel disease is considered hereditary in about 5% of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI. Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified. The purpose of this systematic review is to provide a guide for determining when to consider molecular genetic testing in patients presenting with small vessel disease and stroke. CADASIL, CARASIL, collagen type IV mutations (including PADMAL), retinal vasculopathy with cerebral leukodystrophy, Fabry disease, hereditary cerebral hemorrhage with amyloidosis, and forkhead box C1 mutations are described in terms of genetics, pathology, clinical manifestation, imaging, and diagnosis. These monogenic disorders are often characterized by early-age stroke, but also by migraine, mood disturbances, vascular dementia and often gait disturbances. Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys. Many present with clinically recognizable syndromes. Investigations include a thorough family medical history, medical history, neurological examination, neuroimaging, often supplemented by specific examinations e.g of the of vision, retinal changes, as well as kidney and heart function. However molecular genetic analysis is the final gold standard of diagnosis. There are increasing numbers of reports on new monogenic syndromes causing cerebral small vessel disease. Genetic counseling is important. Enzyme replacement therapy is possible in Fabry disease, but treatment options remain overall very limited.
