title: Hereditary cerebral small vessel disease and stroke.
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.
authors.affiliation: Department of Neurology, Copenhagen University Hospital, Bispebjerg, Denmark. Electronic address: csoend@gmail.com.
authors.forename: Christian Baastrup
authors.initials: CB
authors.lastname: Søndergaard
authors.affiliation: Department of Cellular and Molecular Medicine, Section of Neurogenetics, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jørgen Erik
authors.initials: JE
authors.lastname: Nielsen
authors.affiliation: Department of Neurology, Copenhagen University Hospital, Bispebjerg, Denmark.
authors.forename: Christine Krarup
authors.initials: CK
authors.lastname: Hansen
authors.affiliation: Department of Neurology, Copenhagen University Hospital, Bispebjerg, Denmark.
authors.forename: Hanne
authors.initials: H
authors.lastname: Christensen
mesh_terms: D000505:Alopecia / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000473:pathology*; D002544:Cerebral Infarction / Q000235:genetics / Q000473:pathology*; D059345:Cerebral Small Vessel Diseases / Q000235:genetics / Q000473:pathology*; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics / Q000473:pathology*; D013122:Spinal Diseases / Q000235:genetics / Q000473:pathology*; D020521:Stroke / Q000235:genetics / Q000473:pathology*
keywords: CADASIL; CARASIL; COL4A1; COL4A2; FOXC1; Fabry disease; Hereditary cerebral hemorrhage with amyloidosis; Hereditary cerebral small vessel disease; PADMAL; Retinal vasculopathy with cerebral leukodystrophy; stroke