Stroke. National Institute of Neurological Disorders and Stroke. By continuing to use this website, you agree to the Terms of Service & Privacy Policy, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Sue. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. Bull Acad Natl Med. Our data testing the effects of established mutations on collagen biosynthesis suggest that the intracellular retention of mutant COL4A1 proteins at the expense of their secretion appears to be a common effect of many COL4A1 mutations. The pathogenic mechanisms of COL4A1 mutations are not fully elucidated and may vary according to the mutation type, the affected exon (mutations responsible for systemic HANAC syndrome cluster at exon 24 and 25), the position of the mutation within the triple-helix domain, and the mutation location. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. When this enzyme is elevated, it is a sign of muscle damage. Unable to load your collection due to an error, Unable to load your delegates due to an error. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Phone: 617-249-7300, Danbury, CT office Jeanne M, Gould DB. 2010;17(13):1317-24. doi: These genes are the blueprints for two proteins that wind together like a long rope inside cells. Understanding what it has taken to get her to this point, though, is close to unimaginable. PMC COL4A1/A2-related disorders are dominant genetic disorders. No microbleeds or cystic cavities were found. The degree of mosaicism is highly variable ranging from only a small percent of cells with the mutation to nearly all cells carrying the mutation and depends on the stage during development that the mutation occurred. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Our review highlights that COL4A1 mutations can present for the first time in adult life with features of cerebral SVD, including subcortical hemorrhage and ischemic stroke, . Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Painful muscle cramps can occur and can develop before three years of age. Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation Gould Syndrome Foundation We are a registered 501 (c)3 Nonprofit dedicated to providing hope and help to children and adults with Gould Syndrome; affecting COL4A1 and COL4A2 genes. The information on this site should not be used as a substitute for professional medical care or advice. An official website of the United States government. MeSH IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. 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). The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. 2018;91:e2078-e2088. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Washington, DC 20036 Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Genet Med. This condition causes mutations in genes that produce a specific type of collagen. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. People with COL4A1-related brain small vessel disease also have leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI). Bone. Depending on the cell type that acquires the mutation and when the mutation arises, the individual may have many or few cells with the mutation. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. NORD is a registered 501(c)(3) charity organization. doi: 10.1056/NEJMoa1707914, 6. Other eye problems experienced by people with COL4A1-related brain small-vessel disease include clouding of the lens of the eye (cataract) and the presence of arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eye (arterial retinal tortuosity). Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. doi: 10.1038/gim.2014.210, 3. functional hemispherectomy. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. (2005) 308:116771. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. https://www.ncbi.nlm.nih.gov/pubmed/26610912. What is the prognosis of a genetic condition? Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role All authors contributed to the article and approved the submitted version. Gould Syndrome is an ultra rare genetic, multi-system disorder. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Diseases Information Center National Center for Advancing Translational Sciences Browse by Disease About GARD Contact Us We recently launched the new GARD website and are still developing specific pages. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). The first reports of human COL4A1 mutations were in patients with autosomal dominant porencephaly and a more recent study found that COL4A1 mutations were found in ~16% of patients with porencephaly. COL4A1 is an essential component for basal membrane stability and exon mutations of COL4A1 gene mutations are responsible for a broad spectrum of systemic manifestations characterized by small vessel involvement of variable severity, including neurological ( 1) [porencephaly ( 2 - 4 ), hemorrhage ( 2, 5 - 7) and aneurysms ( 8 )], ophthalmological (2009) 73:187382. Hereditary cerebral small vessel diseases: a review. (18) and Staals et al. doi: Clipboard, Search History, and several other advanced features are temporarily unavailable. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. 2011 Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. doi: 10.1056/NEJMoa071906, 14. doi: 10.1212/WNL.0000000000001309, 8. (2014) 11:3612. How can gene variants affect health and development? (2020). For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. Pediatr Neurol. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Probands' father had severe hypermetropia and bilateral cataracts. Neurology. 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 mutation. COL4A1 brain small-vessel disease is an autosomal dominant condition resulting from a mutation to the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen 1-6. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. The 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 may need to systematically and comprehensively plan treatment. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Accessibility The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. doi: 10.1111/cge.12543. She also showed severe hypermetropia. COL4A1 -Related Disorders - PubMed NCI CPTC Antibody Characterization Program. COL4A1 mutations as a monogenic cause of cerebral Smoking, which also increases the risk of stroke, physical activities that can cause head trauma such as contact sports, and the use of anti-clotting (anticoagulant) medications, should be avoided. Bookshelf What are the different ways a genetic condition can be inherited? 30. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. (2008) 17:42433. 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. FOIA As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. We are a registered 501(c)3 Nonprofit dedicated to providing hope and help to children and adults with Gould Syndrome; affecting COL4A1 and COL4A2 genes. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Any muscle may be affected, and cramps usually last from a few seconds to a few minutes, although in some cases they can last for several hours. seizure activity. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. (2013) 73:4857. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. Suite 500 doi: 10.1055/s-0031-1275343, 24. People listened to us and to Zeeva in a very different and proactive way. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Arch Ophthalmol. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. (2017) 377:111931. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Front. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. At least 50 individuals with this condition have been described in the scientific literature. doi: 10.1186/s12881-014-0097-2, 11. MedlinePlus also links to health information from non-government Web sites. Maybe try a search? She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Quincy, MA 02169 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. In the brain, intracerebral hemorrhage is the most frequent phenotype. Clin Neurol Neurosurg. MedlinePlus also links to health information from non-government Web sites. cutting tissue called the corpus callosum, then make some additional delicate and transmitted securely. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). (E,F) IV-3Brain MRI showed left frontotemporal dilatation and diffusion tensor imaging (DTI) sequences demonstrated no left corticospinal tract (cranio-caudal fibers, indigo, with arrows). COL4A1-related brain small-vessel disease - MedlinePlus Summary: All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Type IV collagen molecules attach to each other to form complex protein networks. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). If we dont have a program for you now, please continue to check back with us. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. The size and location of cerebral cavities contributes to clinical variability. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Matrix Biol. Fax: 203-263-9938, Washington, DC Office (2018) 91:e207888. The retina is the light-sensitive membrane that lines the inside of the eyes. This group rarely survives beyond 2 years. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Autosomal Dominant Brain Small Vessel Disease. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. eCollection 2022. my mom suggested we call Boston Childrens Hospital. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. Recent findings: The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. (2017) 5758:2944. Last updated: A diagnosis can be confirmed through molecular genetic testing. (2004) 62:16135. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. There are no standardized treatment protocols or guidelines for affected individuals. Various muscles can be affected and muscle strength can become weakened. Ann Neurol. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. This site needs JavaScript to work properly. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. Front Aging Neurosci. Patients must rely on the personal and individualized medical advice of their qualified health care professionals before seeking any information related to their particular diagnosis, cure or treatment of a condition or disorder. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. COL4A1 brain small-vessel disease - Radiopaedia Clinical Testing and Workup In her first six years of life, Zeeva spent hundreds of nights in the hospital, had 13 operations and countless procedures, (from eye surgeries to Achilles heel, a shunt placed in her brain, and spine surgery). Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). IV-3 and IV-6 are closely followed by a neuropediatrician (VW). It is important to discuss these concepts with a genetic counselor and understand their implications. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. 1. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. When these ropes are secreted, they assemble into net-like structures outside the cells. How can gene variants affect health and development? IV-3 was diagnosed with ventriculomegaly in utero. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Bennett RL, French KS, Resta RG, Doyle DL. Eur J Med Genet. ACS Omega. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. 2009 Jun 25 [Updated 2016 Jul 7]. What is Gould Syndrome? - Gould Syndrome Foundation This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders.