Genetic Causes of Cerebral Small Vessel Diseases

Abstract

Cerebral small vessel disease (CSVD) includes various entities affecting the brain and, often, systemic small arteries, arterioles, venules, and capillaries. The underlying causes of CSVD are different, and some of them are genetic. Monogenic CSVD are responsible for 1-5% of all strokes and for several other disturbances. Despite many genes being involved, the phenotypes of monogenic CSVD partly overlap. Given that the genetic testing for different diseases can be challenging and time-consuming, the practicing neurologist should be adequately informed of the genetic background of CSVD and should be able to select patients to undergo genetic assessment as well as the genes to be analyzed. The purpose of this review is to summarize clinical, neurological and non-neurological, and neuroimaging features of monogenic CSVD, and to provide a flowchart to be used in clinical practice to guide neurologists in this field. The proposed flowchart and the relative tables can be applied to three different settings, depending on the presentation: 1) ischemic stroke and/or transient ischemic attack; 2) cerebral hemorrhage; 3) other neurological, non-neurological and/or neuroimaging features of monogenic CSVD, in absence of stroke syndromes due to infarction or hemorrhage.

Uncommon Causes of Nontraumatic Intracerebral Hemorrhage

“…Rare Causes of Intracerebral Hemorrhage lacunes, or microbleeds. 28 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy due to mutations in the NOTCH3 gene is the most common monogenic form of cerebral small vessel disease and may be responsible for ICH mainly in Asian patients. 29 WMHs of the temporal lobes and superior frontal gyri are often seen, 30 but are not specific (Figure S3).…”

“…In cerebral small vessel disease, stroke is exceptionally the first manifestation, so a monogenic cerebral small vessel disease is unlikely in adult patients with ICH in the absence of at least moderate white matter abnormalities, lacunes, or microbleeds. 28 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy due to mutations in the NOTCH3 gene is the most common monogenic form of cerebral small vessel disease and may be responsible for ICH mainly in Asian patients. 29 WMHs of the temporal lobes and superior frontal gyri are often seen, 30 but are not specific (Figure S3).…”

The Diagnostic Landscape of Adult Neurogenetic Disorders

“…A number of other genetic syndromes of cerebral small vessel disease with variable anatomic distributions of pathological cerebrovascular (ischemic and hemorrhagic) findings on imaging exist, including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), cathepsin-A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), COL4A1-related disease, pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), Fabry disease, HTRA1 heterozygotes, pseudoxanthoma elasticum, hereditary cerebral hemorrhage with amyloidosis (HCHWA), and retinal vasculopathy with cerebral leukodystrophy and systemic manifestations (RVFL-S), among others. Clinical clues to monogenic stroke syndromes include recurrent stroke, age at onset younger than 50 years old, lack of stroke risk factors, positive family history, and characteristic neuroimaging findings, most commonly symmetrical and progressive periventricular and subcortical white matter hyperintensities [69]. Other neurological features such as cognitive impairment, migraines, and mood disturbances may accompany cerebrovascular disease in these disorders, and systemic findings such as skin abnormalities, cardiac disease, diabetes, and kidney disease may help indicate specific disease categories.…”

Rare neurovascular genetic and imaging markers across neurodegenerative diseases

“…Similarly, HTRA1 encodes a protein involved with cell signaling, musculoskeletal development, vascular maturation, and protein degradation; however, when mutated it is associated with a phenotype similar to CADASIL, known as cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) 23 . Although the compendium of SVD‐associated genes continues to grow, these five largely remain a consensus of the most well‐established genes of interest 24 …”

“…23 Although the compendium of SVD-associated genes continues to grow, these five largely remain a consensus of the most well-established genes of interest. 24 The primary aim of this study was to examine the burden of MRIbased SVD markers (WMH, PVS, and lacunes) as a function of carrier status of non-synonymous, rare genetic variants of interest in a sample of patients with neurodegenerative diseases that are represented in the ONDRI study. In light of these previous findings in genetics and neuroimaging, we hypothesized that carrying rare genetic variation in SVD-associated genes described would contribute to greater burdens of SVD markers in both neurodegenerative disease and CVD patients.…”