Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small‐Vessel Disease
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-06-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.121.025629 |
| _version_ | 1797301681641226240 |
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| author | 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 Kristiina Rannikmäe |
| author_facet | 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 Kristiina Rannikmäe |
| author_sort | Ed Whittaker |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T23:26:04Z |
| format | Article |
| id | doaj.art-c3b08e334d8841109cc35176e9197dee |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-07T23:26:04Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-c3b08e334d8841109cc35176e9197dee2024-02-21T04:31:45ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-06-01111210.1161/JAHA.121.025629Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small‐Vessel DiseaseEd Whittaker0Sophie Thrippleton1Liza Y. W. Chong2Victoria G. Collins3Amy C. Ferguson4David E. Henshall5Emily Lancastle6Tim Wilkinson7Blair Wilson8Kirsty Wilson9Cathie Sudlow10Joanna Wardlaw11Kristiina Rannikmäe12Medical School University of Edinburgh Edinburgh United KingdomMedical School University of Edinburgh Edinburgh United KingdomMedical School University of Edinburgh Edinburgh United KingdomMedical School University of Edinburgh Edinburgh United KingdomCentre for Medical Informatics Usher Institute University of Edinburgh Edinburgh United KingdomCentre for Medical Informatics Usher Institute University of Edinburgh Edinburgh United KingdomMedical School University of Edinburgh Edinburgh United KingdomCentre for Medical Informatics Usher Institute University of Edinburgh Edinburgh United KingdomNHS Greater Glasgow and Clyde Glasgow United KingdomNHS Lothian Edinburgh United KingdomCentre for Medical Informatics Usher Institute University of Edinburgh Edinburgh United KingdomCentre for Clinical Brain Sciences University of Edinburgh Edinburgh United KingdomCentre for Medical Informatics Usher Institute University of Edinburgh Edinburgh United KingdomBackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.121.025629Mendelianradiological featuressmall‐vessel diseasestrokesystematic review |
| spellingShingle | 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 Kristiina Rannikmäe Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small‐Vessel Disease Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease Mendelian radiological features small‐vessel disease stroke systematic review |
| title | Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small‐Vessel Disease |
| title_full | Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small‐Vessel Disease |
| title_fullStr | Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small‐Vessel Disease |
| title_full_unstemmed | Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small‐Vessel Disease |
| title_short | Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small‐Vessel Disease |
| title_sort | systematic review of cerebral phenotypes associated with monogenic cerebral small vessel disease |
| topic | Mendelian radiological features small‐vessel disease stroke systematic review |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.121.025629 |
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