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Last updated: 11/1/2023
Years published: 2019, 2023
NORD gratefully acknowledges 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, multi-system disorders. 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, many other aspects of the syndrome including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients โ even among members of a family who carry the same gene variant.
Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene variants. The outcomes 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.
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. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene variants cause a highly variable, multisystem disorder. Mice with Col4a1 and Col4a2 gene variants have pathology in many organs and the presence and severity of pathology in each organ appears to depend on the location of the gene variant, genetic context and environmental interactions.
The signs and symptoms can manifest at almost any age from before birth to old age. Some individuals 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 variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique.
Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients.
Autosomal Dominant Familial Porencephaly Type I
The first reports of human COL4A1 gene variants were in patients with autosomal dominant porencephaly and a more recent study found that COL4A1 variants were found in ~16% of patients with porencephaly. Porencephaly refers to the formation of fluid-filled cysts or cavities within the brain. The size and location of cerebral cavities contributes to clinical variability. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur, and intelligence is unaffected. Still other individuals may not develop any symptoms until well into adulthood. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. Migraines can occur with or without aura. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of migraine headaches. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms.
Autosomal Dominant Brain Small Vessel Disease
COL4A1 or COL4A2 variants are estimated to underlie approximately 20% of cases of fetal intracerebral hemorrhage. In a retrospective study of 52 patients with COL4A1 variants, stroke occurred in 17.3% and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%) and small infarctions (13.5%). This study clearly demonstrates that COL4A1 and COL4A2 variants cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (except for the brain cavities). Affected individuals may have no observable symptoms or only isolated migraines with aura. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. The main symptom is single or repeated bleeding inside the skull (intracranial hemorrhaging) that can occur without cause (spontaneously), after trauma or when taking drugs that slow blood clotting (anticoagulants).
In addition to the effects of a clear COL4A1 or COL4A2 variant, large genetic studies reported associations of COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Recent studies using large databases and multi-ancestry meta-analyses reproducibly validate associations of the COL4A1/A2 gene location with cerebral small vessel disease, ischemic stroke and small vessel stroke, even after accounting for high blood pressure (hypertension). Notably, COL4A1 and COL4A2 (and to a lesser degree HTRA1) are the only genes that also cause monogenic cerebral small vessel disease.
Additional Signs and Symptoms
Many patients with COL4A1 and COL4A2 variants have additional signs and symptoms that do not include the cerebral vasculature. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms and muscle cramps. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye or only visible when tested (microscopic hematuria). Some individuals develop cysts on the kidney. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. In most people, small vessel disease in the brain does not cause symptoms. Painful muscle cramps can occur and can develop before three years of age. Various muscles can be affected, and muscle strength can become weakened. However, these findings can be observed independently or in combinations in many patients with COL4A1 and COL4A2 variants.
COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. In the back of the eye, affected individuals also have twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. The retina is the light-sensitive membrane that lines the inside of the eyes. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss.
A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium).
Other patients have been reported with cysts on the liver, irregular heartbeats (supraventricular arrhythmia) and Raynaud phenomenon, which is in which the fingers or toes become numb or have a prickly sensation in response to cold due to narrowing of blood vessels.
Congenital Cephalic Disorders
In addition to porencephaly there can be other forms of damage to the brain present at birth. Individuals with COL4A1 or COL4A2 variants can also develop clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects).
COL4A1/A2-related disorders are caused by changes (variants or mutations) 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 โropesโ 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 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks and 3) occasionally, the presence of the abnormal proteins outside the cells can interfere with the structure of the network.
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 are dominant genetic disorders. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene 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 โ 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 secrete COL4A1 normally and that can compensate for those cells that cannot.
When an individual tests positive for a variant but does not manifest the effects, it is referred to as having 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 carry genetic variants elsewhere in their genome that confers protection or susceptibility to the variant and environmental experiences (trauma, anticoagulant use, physical exertion etc.) can also contribute.
With genetic disorders, 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. Research in mice with Col4a1 mutations suggests that the position of the variant is very important. For example, the position of the variant along the length of the protein can influence the severity of cerebrovascular disease and variants in โfunctional subdomainsโ can influence the likelihood of tissue-specific involvement (for example, muscle). These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans.
COL4A1/A2-related disorders are believed to affect females and males in equal numbers. Over 400 families have been identified 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 is 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. Molecular genetic testing can detect variants in the COL4A1 and COL4A2 genes that cause these disorders but is available only as a diagnostic service at specialized laboratories.
Clinical Testing and Workup
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 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
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials will be critical to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COL4A1/A2-related disorders.
Consensus management guidelines have been recommended by the European Academy of Neurology. Genetic testing for COL4A1 or COL4A2 variants should be considered in individuals with porencephaly, peri- or post-natal intracerebral hemorrhage and leukoencephalopathy or white matter hyperintensities of unknown origin โ especially in patients with early age at onset or positive family history. Additional systemic features suggestive of COL4A1/A2-related disorders include congenital cataracts or ocular ASD, retinal vascular tortuosity, renal defects (hematuria, proteinuria, renal cysts) and hypotonia or muscle cramps. Individuals should undergo non-invasive multi-system workup (cerebral MRI, ophthalmologic evaluation and renal, hepatic, and cardiac echography). Pre-symptomatic testing of family members is recommended, and genetic counseling of family members should be available.
The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Pediatricians are often the first to detect patients with COL4A1/A2-related disorders. The care team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals to systematically and comprehensively plan treatment. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential.
Therapies are based on the specific symptoms in each individual. For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures and a shunt to treat hydrocephalus by draining excess fluid from the skull. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Surgery may be necessary for individuals with severe cataracts. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Endovascular therapy is a minimally invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel.
Early intervention is important in ensuring that children with COL4A1/A2-related disorders reach their highest potential. Services that may be beneficial for some affected individuals include medical, social and/or vocational services such as special remedial education.
As with all forms of cerebral small vessel disease, a healthy lifestyle should be encouraged, including smoking cessation, healthy diet and exercise, however intense physical activities, and activities that risk potential head trauma should be avoided. There are no evidence-based disease modifying interventions and current treatments focus on symptomatic management. Due to elevated risk of intracerebral hemorrhage, antiplatelets, anticoagulants, and intravenous thrombolysis should be avoided.
Furthermore, animal studies showed that Caesarean delivery may reduce risk of intracerebral hemorrhage and is recommended for people who are pregnant with a fetus known to have a COL4A1 and COL4A2 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, Hรฉron 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 Oct 31, 2023.
Col4a1 Gene Mutation โ Gould syndrome (Facebook) https://www.facebook.com/groups/1025583837503654 Accessed Oct 31, 2023.
Plaisier E, Ronco P. COL4A1-Related Disorders. 2009 Jun 25 [Updated 2016 Jul 7]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed Oct 31, 2023.
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