Curr Med Chem. (2006) 354:148996. II-2 had a limp since childhood attributed to forceps delivery. The COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. government site. 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. Nat Methods. J Genet Couns. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Collagen type IV alpha 1 (COL4A1) silence hampers the invasion, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cells through blocking Hedgehog signaling pathway. Matrix Biol. Internet. 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. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Fax: 203-263-9938, Washington, DC Office The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. 2009 Jun 25 [Updated 2016 Jul 7]. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Washington, DC 20036 doi: 10.1111/j.1469-8749.2011.04198.x, 26. (2015) 88:46873. He was confident this would reduce or stop the 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). mutations: a novel genetic multisystem disease. See our, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome, URL of this page: https://medlineplus.gov/genetics/condition/hereditary-angiopathy-with-nephropathy-aneurysms-and-muscle-cramps-syndrome/. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Neurology. About half of people with this condition 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). It affects mainly young adults, children and more typically neonates. Unauthorized use of these marks is strictly prohibited. Front Aging Neurosci. Mutations in COL4A1 or COL4A2 cause Gould Syndrome and, because these two proteins are found in almost all tissues; nearly any organ can be affected. Stroke is a leading cause of death and serious long-term disability in developed nations. Children with the most severe brain malformations may have: Intellectual impairment Seizures Hydrocephalus Spasticity People who have a disorder of the corpus callosum typically have: 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 official website and that any information you provide is encrypted Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Ann Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. An official website of the United States government. Years published: 2019. doi: 10.1056/NEJMoa053727, 7. Dev Med Child Neurol. Keywords: COL4A1, Type IV collagen, familial porencephaly, ocular malformations, variable expressivity, Citation: Scoppettuolo P, Ligot N, Wermenbol V, Van Bogaert P and Naeije G (2020) p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Porencephaly and Severe Hypermetropia. Nearly half of these participants were diagnosed with infantile spasms. NCI CPTC Antibody Characterization Program. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. 10.2174/092986710790936293. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. seizure activity. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. In the human genome, there are 46 chromosomes. 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. Suite 310 This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. 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). ClinVar; [VCV000389182.3]. MedlinePlus also links to health information from non-government Web sites. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. MeSH 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. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). (2010) 14:1827. 1900 Crown Colony Drive Would you like email updates of new search results? 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. my mom suggested we call Boston Childrens Hospital. (2014) 252:178994. Some individuals develop cysts on the kidney. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. In affected individuals, stroke is usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke), although either type can occur. How can gene variants affect health and development? Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Childhood presentation of COL4A1 mutations. https://www.ncbi.nlm.nih.gov/pubmed/26610912. 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. can also contribute. To better define pathology caused by Col4a1 mutations, we characterized myopathy in two different Col4a1 mutant mouse strainsCol4a1 ex41 and Col4a1 G394V.We selected these strains from an allelic series of Col4a1 mutant mice because they showed the most severe myopathy according to NPN quantification in quadriceps while having different effects on [1(IV)] 2 2(IV) secretion. doi: 10.2214/ajr.149.2.351, 19. Epub 2014 Jan 5. Please enable it to take advantage of the complete set of features! Hereditary cerebral small vessel diseases: a review. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. The size and location of cerebral cavities contributes to clinical variability. What are the different ways a genetic condition can be inherited? 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Epub 2016 Apr 24. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. How are genetic conditions treated or managed? NORD is a registered 501(c)(3) charity organization. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. 2010;17(13):1317-24. doi: The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. (2017) 377:111931. 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. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Genetic counseling will be proposed when IV-3 and IV-6 intend to start a family as there is a 50% risk of mutation transmission to the next generation and potential obstetrical complications. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. Understanding what it has taken to get her to this point, though, is close to unimaginable. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. doi: 10.1136/jmg.2005.035584, 15. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. In a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects 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%). doi: 10.1126/science.1109418, 5. It is not uncommon for an unaffected parent to have a severely affected child. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. Neurology. doi: 10.1001/archneur.1983.04050080067013, 17. J Neurol Sci. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Treatment 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. Neurology. 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. Type IV collagen networks play an important role in the basement membranes in virtually all tissues throughout the body, particularly the basement membranes surrounding the body's blood vessels (vasculature). The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Dr. Madsen suggested Zeeva have an operation called a Painful muscle cramps can occur and can develop before three years of age. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Danbury, CT 06810 NORD strives to open new assistance programs as funding allows. 11:827. doi: 10.3389/fneur.2020.00827. 2018;91:e2078-e2088. Type IV collagen networks play an important role in the basement membranes in virtually all tissues throughout the body, particularly the basement membranes surrounding the body's blood vessels (vasculature). Individuals with HANAC syndrome also experience a variety of eye problems. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. 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. doi: 10.1111/cge.12379, 13. N Engl J Med. (2008) 23:17. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Recent findings: doi: 10.1056/NEJMoa1707914, 6. 2012;21:R97-R110. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) (2017) 5758:2944. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. Gould Syndrome is a rare, genetic, multi-system disorder. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Type IV collagen molecules attach to each other to form complex protein networks. However, in people with HANAC syndrome, these aneurysms typically do not burst. Curr Opin Neurol. The retina is the light-sensitive membrane that lines the inside of the eyes. 10.1161/STROKEAHA.110.581918. We provide education, advocacy, and resources for families and individuals affected. Bennett RL, French KS, Resta RG, Doyle DL. Suite 500 (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. He smiled, caught it, and asked Zeeva if he could throw it back. Before Phone: 202-588-5700. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). COL4A1 mutations are responsible for a wide range of abnormalities affecting mainly the brain and the retinal vasculature, the anterior and posterior ocular structures and the renal glomerules. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. cuts under the microscope. Suite 310 Clin Neurol Neurosurg. Gould Syndrome is an ultra rare genetic, multi-system disorder. Neurology. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. 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). Neurol. Genet Med. NORD is a registered 501(c)(3) charity organization. Neurology. All authors contributed to the article and approved the submitted version. Please note that NORD provides this information for the benefit of the rare disease community. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes.