Edinburgh Imaging

27 Jun 22. Featured Paper

Systematic review of cerebral phenotypes associated with monogenic cerebral small‐vessel disease

Link to paper on Journal of the American Heart Association



Ed Whittaker, Sophie Thrippleton, Liza Y. W. Chong, Victoria G. Collins, Amy C. Ferguson, David E. Henshall, Emily Lancastle, Tim Wilkinson, Blair Wilson, Kirsty Wilson, Cathie Sudlow, Joanna Wardlaw and Kristiina Rannikmäe



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.





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Featured paper: Systematic review of cerebral phenotypes associated with monogenic cerebral small‐vessel disease

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