col4a1 syndrome life expectancy

Finding the best care for Zeeva - Boston Children's Answers 2010;41:e513-518. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. This page is currently unavailable. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. 128:4839. With input from doctors, researchers, and the US Food & Drug Administration, NORD has created IAMRARE to facilitate patient-powered natural history studies to shape rare disease research and treatments. 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). 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. basement membranes surrounding the body's blood vessels, Genetic Testing Registry: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, National Organization for Rare Disorders (NORD), ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS. 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. eCollection 2022 Nov 8. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Phone: 203-263-9938 U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. IV-3 goes to a normal school, but special schooling is required for IV-6. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. 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. Epub 2014 Jan 5. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 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. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. Bennett RL, French KS, Resta RG, Doyle DL. For instance, retinal arteriolar tortuosity relates to mutations in the amino-terminal one-third of the protein while mutations causing cataracts and ocular morphologic alterations are more likely to occur, closer to the carboxy terminus (22), like the variant we report. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). (2005) 308:116771. doi: 10.1002/ana.23736, 4. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). mutations: a novel genetic multisystem disease. J Med Genet. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Teaching families how to advocate for their loved ones and access medical information. doi: 10.1212/WNL.0000000000001309, 8. doi: 10.1016/j.ejpn.2009.04.010, 27. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 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. Quincy, MA 02169 Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. These genes are the blueprints for two proteins that wind together like a long rope inside cells. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. It looks like nothing was found at this location. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. Neurol. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 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. Gould Syndrome is an ultra rare genetic, multi-system disorder. (2017) 377:111931. 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. (1982) 40:5679. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. The surgery Hereditary cerebral small vessel diseases: a review. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Phone: 203-263-9938 Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. In the human genome, there are 46 chromosomes. What is Gould Syndrome? - Gould Syndrome Foundation Am J Med Genet A. There are no standardized treatment protocols or guidelines for affected individuals. Please note that NORD provides this information for the benefit of the rare disease community. 2009 Jun 25 [updated 2016 Jul 7]. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Cereb Circ Cogn Behav. Changing lives of those with rare disease. my mom suggested we call Boston Childrens Hospital. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. If either parent also carries the mutation, it is considered inherited. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. 2010 Aug;41(8):e513-8. Front. 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. 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. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Danbury, CT 06810 Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. doi: 10.1055/s-0031-1275343, 24. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Nat Methods. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and doi: 10.1212/WNL.0b013e3181c3fd12, 9. ClinVar; [VCV000389182.3]. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. 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. Unable to load your collection due to an error, Unable to load your delegates due to an error. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES 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 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. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Arch Ophthalmol. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Your support helps to ensure everyones free access to NORDs rare disease reports. Summary. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. (2015) 84:91826. It is important to discuss these concepts with a genetic counselor and understand their implications. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: 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. How can gene variants affect health and development? 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 (24), hemorrhage (2, 57) and aneurysms (8)], ophthalmological (912) (retinal artery tortuosity, Axenfeld Rieger anomalies, cataracts, and severe hypermetropia), renal (13) (renal cysts, and microscopic hematuria), and systemic (13) findings (cramps with a high creatine kinase level [CK], Raynaud's phenomenon, and arrhythmias). Gould Syndrome is often characterized by abnormal blood vessels in the brain (cerebral vasculature defects), eye development defects (ocular dysgenesis), muscle disease (myopathy), and kidney abnormalities (renal pathology); however, many other aspects of the syndrome including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Individuals with HANAC syndrome also experience a variety of eye problems. Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization 1. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Firstly, it segregates within the family with the phenotype. (2020). A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. It is passed through families in a autosomal dominant fashion. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. Berg R, Aleck A, Kaplan A. Familial porencephaly. In most people, small vessel disease in the brain does not cause symptoms. How can gene variants affect health and development? 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. People listened to us and to Zeeva in a very different and proactive way. doi: 10.1038/jp.2013.135, 29. doi: 10.1056/NEJMoa1707914, 6. Cephalic Disorders Fact Sheet. N Engl J Med. Treatment 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. Pathology. Would you like email updates of new search results? Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). (2014) 34:757. Neurology. The https:// ensures that you are connecting to the 8600 Rockville Pike 2018;91:e2078-e2088. This condition causes mutations in genes that produce a specific type of collagen. COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel - Stroke Maybe try a search? 1A-B). Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). 11:827. doi: 10.3389/fneur.2020.00827. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Fax: 203-263-9938, Washington, DC Office eCollection 2021. (2010) 14:1827. doi: 10.2214/ajr.149.2.351, 19. 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, . Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. When this enzyme is elevated, it is a sign of muscle damage. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). What are the different ways a genetic condition can be inherited? 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. Curr Opin Neurol. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. She has regular physical, speech, and occupational therapy. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Genet Med. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Am J Neuroradiol. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Lanfranconi S, Markus HS. Mutations in the COL4A1 gene cause HANAC syndrome. One patient (IV-3) was treated for spasticity and seizures with valproic acid. 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. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. 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%). Plaisier E, Ronco P. COL4A1-Related Disorders. Affected individuals may have no observable symptoms or only isolated migraines with aura. Ultrasound in utero from IV-6 (A). 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. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Neurology. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Hum Mol Genet. 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