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Beyond the Brain: Systematic Review of Extracerebral Phenotypes Associated With Monogenic Cerebral Small Vessel
Kristiina Rannikmäe1, David E Henshall1, Sophie Thrippleton2
1Centre for Medical Informatics, Usher Institute (K.R., D.E.H., T.W., K.W., C.S.), University of Edinburgh, United Kingdom.
Insights
Extracerebral phenotypes are frequent in monogenic cerebral small vessel disease (cSVD), often appearing more than stroke. This review highlights shared systemic involvement across multiple cSVD genes.
Area of Science:
- Neurology
- Genetics
- Systemic Diseases
Background:
- Monogenic causes account for a significant portion of cerebral small vessel disease (cSVD).
- Many genes implicated in monogenic cSVD are also linked to extracerebral conditions.
- Understanding these extracerebral manifestations is crucial for comprehensive diagnosis and management.
Purpose of the Study:
- To systematically review and assess the frequency of extracerebral phenotypes in individuals with monogenic cSVD.
- To identify shared extracerebral manifestations across different monogenic cSVD genes.
- To provide insights into the clinical spectrum of these genetic disorders.
Main Methods:
- A systematic literature review was conducted following PRISMA guidelines.
- Searched Medline/Embase for publications on pathogenic variants in key cSVD genes (COL4A1/2, TREX1, HTRA1, ADA2, CTSA).
- Extracted data on individual characteristics, extracerebral phenotypes, and stroke/TIA events.
Main Results:
- Included 96 (COL4A1), 32 (TREX1), 43 (HTRA1), 16 (COL4A2), 119 (ADA2), and 3 (CTSA) publications.
- Extracerebral phenotypes were prevalent, ranging from 14% to 100% across different genes.
- Ocular, renal, hepatic, muscle, and hematologic systems showed involvement in multiple monogenic cSVDs.
Conclusions:
- Extracerebral phenotypes are common and often shared among different monogenic cSVDs.
- Existing literature has biases; large-scale longitudinal studies are needed for unbiased data.
- Findings can aid patient selection for genetic testing, clinical management, and understanding cSVD mechanisms.
Background And Purpose:
An important minority of cerebral small vessel disease (cSVD) is monogenic. Many monogenic cSVD genes are recognized to be associated with extracerebral phenotypes. We assessed the frequency of these phenotypes in existing literature.
Methods:
We performed a systematic review following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), searching Medline/Embase for publications describing individuals with pathogenic variants in COL4A1/2, TREX1, HTRA1, ADA2, and CTSA genes (PROSPERO 74804). We included any publication reporting on ≥1 individual with a pathogenic variant and their clinically relevant phenotype. We extracted individuals' characteristics and information about associated extracerebral phenotypes and stroke/transient ischemic attack. We noted any novel extracerebral phenotypes and looked for shared phenotypes between monogenic cSVDs.
Results:
After screening 6048 publications, we included 96 COL4A1 (350 individuals), 32 TREX1 (115 individuals), 43 HTRA1 (38 homozygous/61 heterozygous individuals), 16 COL4A2 (37 individuals), 119 ADA2 (209 individuals), and 3 CTSA (14 individuals) publications. The majority of individuals originated from Europe/North America, except for HTRA1, where most were from Asia. Age varied widely, ADA2 individuals being youngest and heterozygous HTRA1/CTSA individuals oldest. Sex distribution appeared equal. Extracerebral phenotypes were common: 14% to 100% of individuals with a pathogenic variant manifested at least one extracerebral phenotype (14% COL4A2, 43% HTRA1 heterozygotes, 47% COL4A1, 57% TREX1, 91% ADA2, 94% HTRA1 homozygotes, and 100% CTSA individuals). Indeed, for 4 of 7 genes, an extracerebral phenotype was observed more frequently than stroke/transient ischemic attack. Ocular, renal, hepatic, muscle, and hematologic systems were each involved in more than one monogenic cSVD.
Conclusions:
Extracerebral phenotypes are common in monogenic cSVD with extracerebral system involvement shared between genes. However, inherent biases in the existing literature mean that further data from large-scale population-based longitudinal studies collecting health outcomes in a systematic unbiased way is warranted. The emerging knowledge will help to select patients for testing, inform clinical management, and provide further insights into the underlying mechanisms of cSVD.
