Autosomal Dominant Familial Porencephaly Type I. Phone: 202-588-5700. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Firstly, it segregates within the family with the phenotype. J Neurol Sci. 2012;21:R97-R110. Therapies are based on the specific symptoms in each individual. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. 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. Autosomal Dominant Brain Small Vessel Disease. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. The number of genes implicated in epilepsy has grown rapidly in the past decade. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Epub 2022 Apr 14. doi: 10.1001/archophthalmol.2010.42, 10. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. doi: 10.2214/ajr.149.2.351, 19. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. (1982) 40:5679. Am J Med Genet A. Nearly half of these participants were diagnosed with infantile spasms. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. 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). (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. Genet Med. 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). Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. National Center for Biotechnology Information. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. doi: 10.1212/WNL.0b013e3181c3fd12, 9. 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. COL4A1 mutations as a monogenic cause of cerebral Ophthalmological features associated with COL4A1 mutations. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. doi: 10.1007/s00417-014-2800-6, 12. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. This page is currently unavailable. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Cavalin M, Mine M, Philbert M, et al. Ultrasound in utero from IV-6 (A). Suite 310 This group rarely survives beyond 2 years. cuts under the microscope. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant thus, Gould Syndrome is considered Autosomal Dominant. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. Seattle, WA: University of Washington, Seattle; 1993-. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. This site needs JavaScript to work properly. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. 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. functional hemispherectomy. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Stroke is a leading cause of death and serious long-term disability in developed nations. 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. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical relating to specific areas of the brain supplied by deep small arteries (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. Zeevas brain to treat a cyst in her brain caused by porencephaly. 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. Curr Opin Neurol. 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. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. At least six affected families have been described in the scientific literature. Changing lives of those with rare disease. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. 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. Maybe try a search? Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Affected individuals may have no observable symptoms or only isolated migraines with aura. 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. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Your support helps to ensure everyones free access to NORDs rare disease reports. (No doctor had ever taken a call on their lunch break to speak with me). Still other individuals may not develop any symptoms until well into adulthood. We provide education, advocacy, and resources for families and individuals affected. Curr Opin Neurol. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. 2009 Jun 25 [updated 2016 Jul 7]. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. A diagnosis can be confirmed through molecular genetic testing. It is passed through families in a autosomal dominant fashion. II-2 had a limp since childhood attributed to forceps delivery. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Pediatr Neurol. Various muscles can be affected and muscle strength can become weakened. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . IV-3 and IV-6 are closely followed by a neuropediatrician (VW). (2008) 23:17. Stroke. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. The disorder causes many symptoms, not the least of which are strokes and epilepsy. In the brain, intracerebral hemorrhage is the most frequent phenotype. IV-3 goes to a normal school, but special schooling is required for IV-6. To use the sharing features on this page, please enable JavaScript. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. 2010 Aug;41(8):e513-8. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. People listened to us and to Zeeva in a very different and proactive way. One patient (IV-3) was treated for spasticity and seizures with valproic acid. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. 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 COL4A1 Foundation, for assistance in the preparation of this report. How can gene variants affect health and development? Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. eCollection 2021. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. COL4A1 Syndrome CADASIL Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). The information on this site should not be used as a substitute for professional medical care or advice. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. It affects mainly young adults, children and more typically neonates. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. 8600 Rockville Pike Purpose of review: Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Careers. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. GeneReviews. At least 50 individuals with this condition have been described in the scientific literature. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. The site is secure. doi: 10.1212/WNL.0b013e3181eee440, 28. Copyright 2023 by Gould Syndrome Foundation -. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Type IV collagen molecules attach to each other to form complex protein networks. (2014) 11:3612. 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. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Recent findings: 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. eCollection 2022. 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. Before Neurology. (2015) 84:91826. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. doi: 10.1038/jp.2013.135, 29. doi: 10.1111/cge.12379, 13. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. 1. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. He would separate the two halves of her brain by The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. What does it mean if a disorder seems to run in my family? Washington, DC 20036 See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. doi: 10.1212/WNL.0000000000001309, 8. (2006) 354:148996. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Congenital Cephalic Disorders September 2003. Gould Syndrome is a rare, genetic, multi-system disorder. 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. 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. doi: 10.1056/NEJMoa071906, 14. Secondly, the p.Gly743Val variant is a missense mutation that shares features with other missense pathogenic mutations that occur in the COL4A1 gene exon 30: congenital porencephaly, epilepsy, and neuropsychological anomalies in p.Gly749Ser (23, 24), ophthalmologic defects and neuropsychological deficits in absence of systemic signs in variant p.Gly755Arg (2527), and antenatal fetal intracerebral hemorrhage, ocular anomalies associated to cerebral leukoencephalopathy in variant p.Gly773Arg (12, 28, 29). Here we report a family in which three siblings presented severe hypermetropia and porencephaly. Childhood presentation of COL4A1 mutations. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. Epub 2016 Apr 24. government site.