The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Phone: 202-588-5700. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. Pathology. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. 1779 Massachusetts Avenue Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. However, there are exceptions that depend on precisely when and where the mutation arose. 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. Summary. How can gene variants affect health and development? 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. 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. Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. 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. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Curr Med Chem. 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. Doctors and researchers to bring research and medical therapeutic options to those affected. Dev Med Child Neurol. Pediatr Neurol. The COL4A1 stroke syndrome. doi: 10.1038/jp.2013.135, 29. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Suite 500 PS: wrote thi paper and performed the review of the literature under the supervision of GN. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. 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. His bedside manner was incredible. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. (2006) 354:148996. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). Jeanne M, Gould DB. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. This condition causes mutations in genes that produce a specific type of collagen. 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. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. Acute urinary retention due to a novel collagen COL4A1 mutation. Gould Syndrome is an ultra rare genetic, multi-system disorder. Nat Methods. eCollection 2022 Nov 8. Eur J Med Genet. Clin Genet. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Epub 2010 Jun 17. NORD strives to open new assistance programs as funding allows. What is the prognosis of a genetic condition? Clipboard, Search History, and several other advanced features are temporarily unavailable. If either parent also carries the mutation, it is considered inherited. However, in people with HANAC syndrome, these aneurysms typically do not burst. Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina E. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. Neurology. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. 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. 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. 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). The risk is the same for males and females. Standardized (15) familiar pedigree is showed in Figure 1. These genes are the blueprints for two proteins that wind together like a long rope inside cells. Front. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. 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. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. (2004) 62:16135. Neurology. The first time he came to meet us, Zeeva threw a sock at him. Quincy, MA 02169 During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. 55 Kenosia Avenue 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). The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: 10.1161/STROKEAHA.110.581918. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. 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. She has regular physical, speech, and occupational therapy. Not only did Dr. Madsen, help heal Zeevas brain, but he was instrumental in supporting us as we founded the Gould Syndrome Foundation, a 501(c)(3) non-profit that promotes education, advocacy, and medical advancements in Gould Syndrome, COL4A1/COL4A2 diseases. 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. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. The COL4A1 and COL4A2 genes were screened in proband IV-6. doi: 10.1001/archophthalmol.2010.42, 10. 2011 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. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . No microbleeds or cystic cavities were found. 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. Neurology. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. 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/. doi: 10.1007/s00417-014-2800-6, 12. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. doi: 10.1056/NEJMoa1707914, 6. 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). J Neurol Sci. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. BMC Med Genet. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. (2005) 308:116771. Treatment It is not uncommon for an unaffected parent to have a severely affected child. Neurology. Phone: 203-263-9938 Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Before Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. All authors contributed to the article and approved the submitted version. People listened to us and to Zeeva in a very different and proactive way. Federal government websites often end in .gov or .mil. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. 2010;17(13):1317-24. doi: These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. mutations: a novel genetic multisystem disease. The site is secure. Quincy, MA 02169 Eur J Paediatr Neurol. (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). Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. 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. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. 1. J Genet Couns. 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. 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. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. seizure activity. How are genetic conditions treated or managed? Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. 4 Both . eCollection 2021. Zagaglia Selch C, Nisevic JR, et al. (2017) 377:111931. 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. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. 11:827. doi: 10.3389/fneur.2020.00827. He also wanted to remove a shunt that was implanted in In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. Contact a health care provider if you have questions about your health. Plaisier E, Ronco P. COL4A1-Related Disorders. doi: 10.2214/ajr.149.2.351, 19. 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. (2014) 34:757. Epub 2014 Jan 5. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Purpose of review: https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. 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. 1900 Crown Colony Drive What does it mean if a disorder seems to run in my family? The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. (1987) 8:4216. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding.
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