This observational and diagnostic study aims to better understand the clinical features and biological mechanisms associated with mutations in the COL4A1 and COL4A2 genes, which are known to cause a rare inherited small-vessel disease affecting the brain and other organs. These mutations can lead to a wide range of symptoms involving the brain, eyes, heart, blood vessels, kidneys, and muscles, and affected individuals within the same family may show very different clinical manifestations.
The study will systematically collect clinical and diagnostic information from individuals with confirmed COL4A1/COL4A2 mutations and their first-degree family members, including both affected and unaffected relatives. Family members who carry, or may carry, the mutation will be offered non-invasive eye and heart examinations to detect early or previously unrecognized organ involvement.
In addition, blood samples will be analyzed to study the activity of specific enzymes called matrix metalloproteinases (MMP2 and MMP9), which are thought to play a role in blood vessel damage in this condition. By linking genetic findings, clinical features, and laboratory data, the study seeks to clarify how these mutations cause disease and to identify early signs of organ involvement.
The overall goal of the study is to improve early diagnosis, guide the development of routine multi-organ screening strategies for affected individuals and families, and support future research toward targeted treatments.
Individuals (pediatric or adult) with a pathogenic or likely pathogenic mutation in the COL4A1 or COL4A2 genes and a clinical phenotype consistent with small vessel disease.
Adult first-degree family members (parents, siblings, or children) who are confirmed carriers or suspected carriers of the same COL4A1/COL4A2 mutation.
Adult first-degree family members who are non-carriers of the pathogenic mutation and who agree to provide a blood sample to be used as controls for laboratory analyses.
Ability to provide written informed consent; for minors, consent provided by a parent or legal guardian.
Refusal or inability to provide informed consent.
Individuals who do not meet the inclusion criteria above.
Any condition that, in the opinion of the investigators, would preclude participation in study procedures or reliable data collection.
Single group
Ophtalmological and cardiological screening
Diagnostic testParticipants who are confirmed or suspected carriers of a COL4A1 or COL4A2 pathogenic variant are offered non-invasive diagnostic ophthalmological and cardiological screening to assess potential organ involvement associated with the genetic condition. The ophthalmological screening includes anterior segment photography of both eyes and optical coherence tomography (OCT) to evaluate retinal structure, macular thickness, and retinal nerve fiber layer. The cardiological screening includes a resting electrocardiogram (ECG), ambulatory ECG monitoring, and transthoracic echocardiography to assess heart rhythm, conduction, and cardiac structure and function. These procedures are performed within routine clinical care settings and are used solely for observational and diagnostic purposes; no therapeutic intervention is administered as part of the study.
Prevalence and pattern of multi-organ involvement
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