Last updated:
3/5/2025
Years published: 2019, 2023, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Douglas Gould, PhD, Professor, Director of Research, Denise B. Evans Endowed Chair in Ophthalmology, Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, and the Gould Syndrome Foundation, for assistance in the preparation of this report.
Summary
COL4A1/A2-related disorders are rare genetic disorders that affect many organs and systems of the body. They are typically characterized by abnormal blood vessels in the brain (cerebral vasculature defects), eye development defects (ocular dysgenesis), muscle disease (myopathy) and kidney abnormalities (renal pathology); however, the full spectrum of this syndrome is not yet completely characterized and there are many other aspects of the syndrome including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities that can be part of the spectrum of the disease. There are notable differences in the specific signs and symptoms (clinical heterogeneity) and different organs are affected to different degrees between patients, even among members of a family who carry the same gene variant.
The abnormal blood vessels in the brain are caused by COL4A1 and COL4A2 gene changes (variants). The health problems in affected people are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI).
COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance.
Treatment is directed to the specific symptoms that the affected person has.
Introduction
Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes of the cells. The two genes that code for these proteins are located tightly linked on chromosome 13.
The signs and symptoms can manifest at almost any age from birth to old age. Knowledge about COL4A1/A2-related disorders is incomplete due to the rarity of the condition, with a limited number of identified cases, the lack of large-scale clinical studies to establish clear patterns and the potential influence of other genetic or environmental factors that may modify the disease progression. There is a broad clinical spectrum with different organs being affected to varying degrees in different individuals.
Variants in COL4A1 or COL4A2 are estimated to cause approximately 20% cases of fetal intracerebral hemorrhage. Cerebral small vessel disease with hemorrhage is thought to be a milder form of porencephaly, sharing many symptoms except for the presence of brain cavities.
Some people do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood.
The primary symptom is intracranial hemorrhage, which may occur spontaneously (without a clear cause) or following a minor trauma or after taking anticoagulant medications (drugs that slow blood clotting).
There are many different conditions included in the spectrum of diseases caused by COL4A1 and COL4A2 variants.
Brain small vessel disease 1 with or without ocular anomalies (BSVD1) is a rare genetic disorder in which fluid-filled cysts and cavities develop on the surface of the brain. Affected people are more likely to have damage to their small blood vessels, including those in the brain. The age of onset, specific symptoms, disease progression and severity of BSVD1 vary greatly from one person to another, even among members of the same family. In some children, serious, life-threatening complications may occur in infancy; in others, there are only minor complications and intelligence is unaffected. Other affected people may not develop any symptoms until well into adulthood.
Symptoms that may occur in individuals with BDSV1 include:
Brain small vessel disease 2 (BSVD2), characterized by neurological problems including:
Other problems related with the cerebral vasculature that may occur in people with COL4A1 or COL4A2 variants are intracranial aneurysms (bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel), heart attack (myocardial infarction), arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, a stroke that happens when a blood clot blocks one of the small blood vessels deep in your brain, reduced white matter volume and vascular leukoencephalopathy as well as cerebral hemispheres that may be missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects).
Other conditions that are included in the spectrum of diseases caused by COL4A1 and COL4A2 variants include:
HANAC syndrome, an acronym for hereditary angiopathy, nephropathy, aneurysms and muscle cramps. Affected individuals may present with:
Pontine autosomal dominant microangiopathy with leukoencephalopathy, a rare neurologic disorder characterized by:
RATOR, retinal artery tortuosity (twisting) also known as familial isolated retinal arteriolar tortuosity which develops in adolescence and is progressive but usually resolves and that can be characterized by:
A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including:
COL4A1/A2-related disorders are caused by changes (variants) in the COL4A1 or COL4A2 genes. These genes are the blueprints for two proteins that wind together like a long rope inside cells. When these ‘ropes’ are secreted, they assemble into net-like structures outside the cells. When a disease-causing variant is present in one of these genes, the rope does not wind up properly and it stays inside the cell. This can lead to problems if:
The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways.
COL4A1/A2-related disorders inheritance is autosomal dominant. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
However, there are exceptions that depend on precisely when and where the variant arose. These exceptions are nuanced and should be discussed with a genetic counselor. For example, if the variant arises during the formation of the sperm or the egg, then all the cells that make up the child will carry the variant. If the variant arises after fertilization, then some cells will carry the variant and others will not – this is called mosaicism. Depending on the cell type that acquires the variant and when the variant arises, the individual may have many or few cells with the variant. It is not uncommon for an unaffected parent to have a severely affected child. While there are other explanations, parental mosaicism should be considered. Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that produce the COL4A1 protein normally and that can compensate for those cells that cannot.
When an individual has a gene variant but does not have symptoms, this is called incomplete or reduced penetrance. A similar term, “variable expressivity”, describes when affected individuals have widely varying signs and symptoms. Mosaicism can contribute to both reduced penetrance and variable expressivity, but other factors do as well. For example, an individual may have variants in other genes or have environmental factors (trauma, anticoagulant use, physical exertion etc.) that can affect symptoms.
The type of variant or its location in the gene can sometimes be associated with varying outcomes. This is called genotype-phenotype correlation. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders.
COL4A1/A2-related disorders are thought to affect females and males in equal numbers. Over 400 families have been reported with these disorders in the medical literature and many more cases are known that are not in the published literature. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Given the variable expressivity of these variants, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. Interestingly, COL4A1 and COL4A2 variants appear to lead to generally similar outcomes although COL4A2 variants occur less frequently.
A diagnosis of COL4A1/A2-related disorders may be suspected based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. A diagnosis can be confirmed through molecular genetic testing. That detects variants in the COL4A1 and COL4A2 genes.
Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues including the brain. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques.
If individuals have muscle cramps, blood tests can reveal elevated levels of creatine kinase, which is a muscle enzyme. When this enzyme is elevated, it is a sign of muscle damage. This is not specific to COL4A1/A2-related disorders and is a sign of many different types of muscle disease. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected.
Treatment
Currently, no standardized treatment protocols exist for individuals affected by COL4A1/A2-related disorders. Since there are no disease-modifying interventions, current treatments focus on managing symptoms and reducing complications. Ongoing research and clinical trials will be critical in improving care for affected individuals.
The European Academy of Neurology has recommended consensus management guidelines. Genetic testing for COL4A1 or COL4A2 gene variants should be considered in individuals with:
A comprehensive multi-system evaluation should include cerebral MRI, ophthalmologic assessment, and renal, hepatic and cardiac imaging. Pre-symptomatic testing and genetic counseling are recommended for at-risk family members.
Managing COL4A1/A2-related disorders requires a team of specialists, often led by pediatricians who first detect the condition. The care team may include pediatric neurologists for the diagnosis and management the neurologic complications, ophthalmologists who treat eye-related manifestations such as cataracts and glaucoma, hematologists and cardiologists to address blood and heart-related concerns, nephrologists to manage kidney dysfunction and genetic professionals.
Treatment is tailored to each patient’s symptoms and may include:
Lifestyle recommendations:
Animal studies suggest that Cesarean delivery may reduce the risk of intracerebral hemorrhage and is recommended for pregnant individuals carrying a fetus with a COL4A1/A2 gene variant.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Coste T, Vincent-Delorme C, Stichelbout M, Devisme L, Gelot A, Deryabin I, Pelluard F, Aloui C, Leutenegger AL, Jouannic JM, Héron D, Gould DB, Tournier-Lasserve E. COL4A1/COL4A2 and inherited platelet disorder gene variants in fetuses showing intracranial hemorrhage. Prenat Diagn. 2022;42(5):601-610. doi:10.1002/pd.6113
Whittaker E, Thrippleton S, Chong LYW, et al. Systematic review of cerebral phenotypes associated with monogenic cerebral small-vessel disease. J Am Heart Assoc. 2022;11(12):e025629. doi:10.1161/JAHA.121.025629
Guey S, Lesnik Oberstein SAJ, Tournier-Lasserve E, Chabriat H. Hereditary cerebral small vessel diseases and stroke: a guide for diagnosis and management. Stroke. 2021;52(9):3025-3032. doi:10.1161/STROKEAHA.121.032620
Mancuso M, Arnold M, Bersano A, et al. Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology. Eur J Neurol. 2020;27(6):909-927. doi:10.1111/ene.14183
Zagaglia Selch C, Nisevic JR, et al. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Neurology. 2018;91:e2078-e2088. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/
Cavalin M, Mine M, Philbert M, et al. Further refinement of COL4A1 and COL4A2 related cortical malformations. Eur J Med Genet. 2018;61:765-772.
Jeanne M, Gould DB. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Matrix Biol. 2017;57-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/
Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. Clin Neurol Neurosurg. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515
Alavi MV, Mao M, Pawlikowski BT, et al. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/
Rannikmae K, Davies G, Thomson PA, et al. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurology. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/
Meuwissen ME, Halley DJ, Smit LS, et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Genet Med. 2015;17:843-853. https://www.nature.com/articles/gim2014210
Yoneda Y, Haginoya K, Kato M, et al. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Ann Neurol. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343
Kuo DS, Labelle-Dumais C, Gould DB. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Hum Mol Genet. 2012;21:R97-R110. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/
Federico A, Di Donato I, Bianchi S, et al. Hereditary cerebral small vessel diseases: a review. J Neurol Sci. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088
Shah S, Ellard S, Kneen R, et al. Childhood presentation of COL4A1 mutations. Dev Med Child Neurol. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627
Lanfranconi S, Markus HS. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke. 2010;41:e513-518. https://www.ncbi.nlm.nih.gov/pubmed/20558831
Alamowitch S, Plaisier E, Favrole P, et al. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Neurology. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/
Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. https://www.ncbi.nlm.nih.gov/pubmed/26610912
INTERNET
Gould Syndrome Family Support Group (Facebook) https://www.facebook.com/groups/col4a1 Accessed Feb 18, 2025.
Col4a1 Gene Mutation – Gould syndrome (Facebook) https://www.facebook.com/groups/1025583837503654 Accessed Feb 18, 2025.
Plaisier E, Ronco P. COL4A1-Related Disorders. 2009 Jun 25 [Updated 2016 Jul 7]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed Feb 18, 2025.
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