Summary: When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. doi: 10.1056/NEJMoa053727, 7. Thats not to say Zeeva hasnt had to work hard since the surgery. 11:827. doi: 10.3389/fneur.2020.00827. Ann Neurol. We describe here the phenotype of a likely pathogenic gene variant, p.Gly743Val, which is responsible for a missense mutation in the COL4A1 gene exon 30 in a three generation family with severe hypermetropia and highly penetrant porencephaly in the absence of systemic manifestations. (2014) 15:16. What does it mean to have a COL4A1 gene mutation: The COL4A1 gene provides instructions for making one component of type IV collagen, which is a flexible protein important in the structure of many. doi: 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. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Clinical spectrum of type IV collagen (COL4A1) mutations: a novel For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. 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. To use the sharing features on this page, please enable JavaScript. 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. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. Subsequently, it has been recognized that autosomal dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular disease, whose onset occurs from fetal life onward and whose severity may range from small-vessel disease to fatal intraparenchymal hemorrhage.,, While epilepsy is known to be a clinical feature of porencephaly, the The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. doi: 10.1038/jp.2013.135, 29. It is ubiquitously expressed in many tissues and cell types. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. In people with HANAC syndrome, angiopathy affects several parts of the body. 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). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Axenfeld-Rieger anomaly involves underdevelopment and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye. Please note that NORD provides this information for the benefit of the rare disease community. Practical approach to the diagnosis of adult-onset - BMJ 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. 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%). 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. 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. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Teaching families how to advocate for their loved ones and access medical information. Neurology. Molecular analysis in the father disclosed a heterozygous variant c.2228G>T (p.Gly743Val) in exon 30 of the COL4A1 gene that segregated with the phenotype. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. Antiinflammatory therapy with canakinumab for atherosclerotic disease. cutting tissue called the corpus callosum, then make some additional delicate He would separate the two halves of her brain by Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. 2010 Aug;41(8):e513-8. doi: 10.1056/NEJMoa071906, 14. Years published: 2019. Cavalin M, Mine M, Philbert M, et al. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. Please enable it to take advantage of the complete set of features! Unauthorized use of these marks is strictly prohibited. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Agenesis of the Corpus Callosum | National Institute of Neurological Matrix Biol. NORD is not a medical provider or health care facility and thus can neither diagnose any disease or disorder nor endorse or recommend any specific medical treatments. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. What does it mean if a disorder seems to run in my family? 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Still other individuals may not develop any symptoms until well into adulthood. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. How are genetic conditions treated or managed? This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. official website and that any information you provide is encrypted 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. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. The first time he came to meet us, Zeeva threw a sock at him. There are no standardized treatment protocols or guidelines for affected individuals. NORD is a registered 501(c)(3) charity organization. Washington, DC 20036 Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. 1779 Massachusetts Avenue doi: 10.1016/j.ejpn.2009.04.010, 27. 1900 Crown Colony Drive By continuing to use this website, you agree to the Terms of Service & Privacy Policy. eCollection 2022. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. (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). N Engl J Med. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Ultrasound in utero from IV-6 (A). Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Contact a health care provider if you have questions about your health. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. COL4A1 mutations as a monogenic cause of cerebral *Correspondence: Pasquale Scoppettuolo, [email protected], https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Stroke. The site is secure. 2009 Jun 25 [Updated 2016 Jul 7]. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. What are the different ways a genetic condition can be inherited? COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Am J Med Genet A. All individuals with this condition have arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eyes (arterial retinal tortuosity). 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). COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. 4 Both . Please note that NORD provides this information for the benefit of the rare disease community. 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: 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. (1982) 40:5679. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. percent confident in Dr. Madsen and the epilepsy team. doi: 10.1212/WNL.0b013e3181eee440, 28. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. (2015) 17:84353. 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. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. The retina is the light-sensitive membrane that lines the inside of the eyes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Neurology. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Neurology. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Seattle, WA: University of Washington, Seattle; 1993-. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Bookshelf 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). Ann Neurol. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Further refinement of COL4A1 and COL4A2 related cortical malformations. 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/. Genet Med. 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. The .gov means its official. The https:// ensures that you are connecting to the functional hemispherectomy. ClinVar; [VCV000389182.3]. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. 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. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Cesarean delivery for pregnancies with fetus at risk for a COL4A1-related disorder is recommended to prevent brain vascular injury attributable to birth trauma during delivery (6). This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. cuts under the microscope. Contact a health care provider if you have questions about your health. The blood vessels as well as thin sheet-like structures called basement membranes that separate and support cells are weakened and more susceptible to breakage. Neuropediatrics. doi: 10.1212/WNL.0000000000000837, 20. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. 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. Phone: 203-263-9938 COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. (2008) 23:17. National Center for Biotechnology Information. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. At least 50 individuals with this condition have been described in the scientific literature. 55 Kenosia Avenue In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. 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). BMC Med Genet. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Suite 500 Hum Mol Genet. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. NORD strives to open new assistance programs as funding allows. ACS Omega. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. J Neurol Sci. 2010;41:e513-518. COL4A1/A2-Related Disorders - Symptoms, Causes, Treatment | NORD It looks like nothing was found at this location. (2014) 83:122834. doi: 10.1212/WNL.0000000000001309, 8. 2018;61:765-772. 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, . Neurol. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. It is not uncommon for an unaffected parent to have a severely affected child. Science. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. doi: 10.1212/01.WNL.0000123113.46672.68, 25. COL4A1 Mutations Cause Neuromuscular Disease with - ScienceDirect Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. National Taiwan University Hospital, Taiwan, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Carrera de Medicina, Universidad Cientfica del Sur, Peru, Federal University of Rio Grande do Sul, Brazil. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. doi: 10.1038/gim.2014.210, 3. 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). 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. Disclaimer. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Orphanet: HANAC syndrome Jeanne M, Gould DB. For example, an individual may carry genetic variants elsewhere in their genome that confers protection or susceptibly to the mutation and environmental experiences (trauma, anticoagulant use, physical exertion etc.) Going from having seizures every day for six years to having no seizures is nothing short of a miracle. COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel - Stroke 1900 Crown Colony Drive 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. Various muscles can be affected and muscle strength can become weakened. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. COL4A1/A2-related disorders are dominant genetic disorders. The severity of the condition varies greatly among affected individuals. Axenfeld-Rieger anomaly is associated with various other eye abnormalities, including underdevelopment and eventual tearing of the colored part of the eye (iris), and a pupil that is not in the center of the eye. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. seizure activity. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. Lenses corrected for hypermetropia. His bedside manner was incredible. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. doi: 10.1111/cge.12543. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. Zeevas brain to treat a cyst in her brain caused by porencephaly. (2002) 112:198202. Fetal intracerebral hemorrhage and cataract: think COL4A1. 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-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Federal government websites often end in .gov or .mil. Muscle cramps can be spontaneous or triggered by exercise. All authors contributed to the article and approved the submitted version. 1. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. How can gene variants affect health and development? Maybe try a search? 30. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. and transmitted securely. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Therapies are based on the specific symptoms in each individual. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Neurology. The risk is the same for males and females. https://www.ncbi.nlm.nih.gov/pubmed/26610912. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. 2018;91:e2078-e2088. Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. doi: 10.2214/ajr.149.2.351, 19. In the human genome, there are 46 chromosomes. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Quincy, MA 02169 Arch Neurol. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, 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. At least six affected families have been described in the scientific literature. Standardized (15) familiar pedigree is showed in Figure 1. (2005) 308:116771. Some individuals develop cysts on the kidney. Surgery may be necessary for individuals with severe cataracts. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. How are genetic conditions treated or managed? Copyright 2023 by Gould Syndrome Foundation -. Early intervention is important in ensuring that children with reach their highest potential. 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. While there are other explanations, parental mosaicism should be considered. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1