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Longitudinal In Vivo Imaging of the Cerebrovasculature: Relevance to CNS Diseases
Published on: December 6, 2016
Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small-Vessel Disease
Ed Whittaker1, Sophie Thrippleton1, Liza Y W Chong1
1Medical School University of Edinburgh Edinburgh United Kingdom.
Insights
This study reveals distinct cerebral phenotypes across various monogenic causes of cerebral small-vessel disease (cSVD). Vascular changes on imaging are more frequent than clinical symptoms, highlighting the importance of genetic factors in cSVD.
Area of Science:
- Genetics
- Neurology
- Vascular Biology
Background:
- Cerebral small-vessel disease (cSVD) is a major contributor to stroke and vascular dementia.
- While often multifactorial, a subset of cSVD cases have a monogenic origin, with NOTCH3 being a well-known gene.
- Recent research has identified additional genes associated with monogenic cSVD, necessitating a comprehensive phenotype summary.
Purpose of the Study:
- To systematically review and summarize the cerebral phenotypes associated with recently identified monogenic cSVD genes.
- To compare the clinical and radiological manifestations across different cSVD-associated genes.
Main Methods:
- A systematic review was conducted, searching Medline/Embase for publications on carriers of pathogenic variants in COL4A1/2, TREX1, HTRA1, ADA2, or CTSA.
- Data on individual characteristics, clinical phenotypes, and neuroimaging findings were extracted and analyzed.
- Phenotype frequencies were summarized per gene and compared across genes.
Main Results:
- Data were extracted from 402 publications on individuals with variants in COL4A1/2, TREX1, HTRA1, ADA2, or CTSA.
- Clinical phenotypes varied significantly, with stroke prevalence ranging from 9% (TREX1) to 52% (HTRA1 heterozygotes), cognitive features from 0% (ADA2) to 64% (HTRA1 homozygotes), and psychiatric features from 0% (COL4A2, ADA2) to 57% (CTSA).
- Vascular radiological phenotypes were common (62%-100%), with white matter lesions being most frequent, except in ADA2 (ischemic) and COL4A2 (hemorrhagic) cases.
Conclusions:
- Distinct cerebral manifestation patterns exist among different monogenic cSVD genes.
- Vascular radiological changes are more prevalent than clinical neurological phenotypes and are present in most individuals with available neuroimaging.
- Further research, including population-based studies, is needed to refine understanding of monogenic cSVD for improved genetic testing, clinical management, and mechanistic insights.
Abstract:
Background Cerebral small-vessel disease (cSVD) is an important cause of stroke and vascular dementia. Most cases are multifactorial, but an emerging minority have a monogenic cause. While NOTCH3 is the best-known gene, several others have been reported. We aimed to summarize the cerebral phenotypes associated with these more recent cSVD genes. Methods and Results We performed a systematic review (PROSPERO [International Prospective Register of Systematic Reviews]: CRD42020196720), searching Medline/Embase (conception to July 2020) for any language publications describing COL4A1/2, TREX1, HTRA1, ADA2, or CTSA pathogenic variant carriers. We extracted data about individuals' characteristics and clinical and vascular radiological cerebral phenotypes. We summarized phenotype frequencies per gene, comparing patterns across genes. We screened 6485 publications including 402, and extracted data on 390 individuals with COL4A1, 123 with TREX1, 44 with HTRA1 homozygous, 41 with COL4A2, 346 with ADA2, 82 with HTRA1 heterozygous, and 14 with CTSA. Mean age ranged from 15 (ADA2) to 59 years (HTRA1 heterozygotes). Clinical phenotype frequencies varied widely: stroke, 9% (TREX1) to 52% (HTRA1 heterozygotes); cognitive features, 0% (ADA2) to 64% (HTRA1 homozygotes); and psychiatric features, 0% (COL4A2; ADA2) to 57% (CTSA). Among individuals with neuroimaging, vascular radiological phenotypes appeared common, ranging from 62% (ADA2) to 100% (HTRA1 homozygotes; CTSA). White matter lesions were the most common pathology, except in ADA2 and COL4A2 cases, where ischemic and hemorrhagic lesions dominated, respectively. Conclusions There appear to be differences in cerebral manifestations across cSVD genes. Vascular radiological changes were more common than clinical neurological phenotypes, and present in the majority of individuals with reported neuroimaging. However, these results may be affected by age and biases inherent to case reports. In the future, better characterization of associated phenotypes, as well as insights from population-based studies, should improve our understanding of monogenic cSVD to inform genetic testing, guide clinical management, and help unravel underlying disease mechanisms.
