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. The COL4A1 and COL4A2 genes were screened in proband IV-6. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Careers. and transmitted securely. As a result, the skin around the affected area may turn white or blue for a brief period of time and the area may tingle or throb. Eur J Med Genet. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. September 2003. The COL4A2 test was negative. Gould Syndrome is a rare, genetic, multi-system disorder. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. doi: 10.1212/WNL.0000000000000837, 20. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. How can gene variants affect health and development? If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. Full ophthalmological evaluations including slit lamp and fundoscopy were realized and disclosed for bilateral hypermetropia in IV-3 [15 dioptre (D)], IV-6 (8.5 D), IV-5 (10 D), and III-3 (7 D). 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. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. Type IV collagen molecules attach to each other to form complex protein networks. Genet Med. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. 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. Quincy, MA 02169 For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Painful muscle cramps can occur and can develop before three years of age. Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation Gould Syndrome Foundation 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. It is passed through families in a autosomal dominant fashion. 2010 Aug;41(8):e513-8. Antiinflammatory therapy with canakinumab for atherosclerotic disease. The retina is the light-sensitive membrane that lines the inside of the eyes. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Accessibility Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. MedlinePlus also links to health information from non-government Web sites. Bone. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. 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). came with risks and was the hardest decision we had ever faced, yet we felt 100 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. Berg R, Aleck A, Kaplan A. Familial porencephaly. doi: 10.1038/gim.2014.210, 3. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. Migraines can occur with or without aura. Treatment 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 (2012) 54:56974. Further refinement of COL4A1 and COL4A2 related cortical malformations. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Danbury, CT 06810 More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. When this enzyme is elevated, it is a sign of muscle damage. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). Gould Syndrome is an ultra rare genetic, multi-system disorder. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. To use the sharing features on this page, please enable JavaScript. Phone: 203-263-9938 http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: J Perinatol. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Quincy, MA 02169 https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. 2012;21:R97-R110. He also wanted to remove a shunt that was implanted in Cysts can also form in one or both kidneys, and the cysts may grow larger over time. (2008) 17:42433. Federal government websites often end in .gov or .mil. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Surgery may be necessary for individuals with severe cataracts. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. 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. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). doi: 10.1212/WNL.0b013e3181c3fd12, 9. This group rarely survives beyond 2 years. 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. January 31, 2019 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. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. doi: 10.1056/NEJMoa053727, 7. PS: wrote thi paper and performed the review of the literature under the supervision of GN. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Ann 4 Both . This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Disclaimer. Am J Med Genet. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. 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. doi: 10.1007/s10897-008-9169-9, 16. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. When we didnt feel we had any options left for treatment, 10.1161/STROKEAHA.110.581918. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. 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). Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. N Engl J Med. seizure activity. 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).