https://www.ncbi.nlm.nih.gov/pubmed/26610912. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. (2010). This is called genotype-phenotype correlation. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. 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 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. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. II-2 had a limp since childhood attributed to forceps delivery. (2007) 357:268795. NORD is a registered 501(c)(3) charity organization. (No doctor had ever taken a call on their lunch break to speak with me). They are typically 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 size and location of cerebral cavities contributes to clinical variability. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Neurology. This condition causes mutations in genes that produce a specific type of collagen. 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). Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. 2010;41:e513-518. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Neurology. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. 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. BMC Med Genet. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. 2008 May;192(5):971-84; discussion 984-6. N Engl J Med. Suite 310 (2015) 88:46873. 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. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. It affects mainly young adults, children and more typically neonates. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. 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. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Curr Med Chem. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. When these ropes are secreted, they assemble into net-like structures outside the cells. Please note that NORD provides this information for the benefit of the rare disease community. Bethesda, MD 20894, Web Policies These genes are the blueprints for two proteins that wind together like a long rope inside cells. Childhood presentation of COL4A1 mutations. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. 2011 came with risks and was the hardest decision we had ever faced, yet we felt 100 How can gene variants affect health and development? doi: 10.1055/s-0031-1275343, 24. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Mutations in the COL4A1 gene cause HANAC syndrome. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. The information on this site should not be used as a substitute for professional medical care or advice. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. 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. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. We provide education, advocacy, and resources for families and individuals affected. Jeanne M, Gould DB. Neurology. A diagnosis can be confirmed through molecular genetic testing. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. 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. Bookshelf Type IV collagen molecules attach to each other to form complex protein networks. For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Doctors and researchers to bring research and medical therapeutic options to those affected. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) doi: 10.1212/WNL.0b013e3181eee440, 28. 1A-B). Nat Methods. 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). Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Gould Syndrome is a rare, genetic, multi-system disorder. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. 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%). 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). Phone: 202-588-5700. 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). 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 1779 Massachusetts Avenue There are 28 different types of collagen in your body and mutations in the genes that encode these proteins lead to multiple, highly diverse diseases. (2012) 54:56974. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Facebook: https://www.facebook.com/Col4A1Foundation Please Note Before This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network. Please enable it to take advantage of the complete set of features! What does it mean if a disorder seems to run in my family? At least 50 individuals with this condition have been described in the scientific literature. Federal government websites often end in .gov or .mil. To use the sharing features on this page, please enable JavaScript. N Engl J Med. The COL4A2 test was negative. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, For information about clinical trials sponsored by private sources, contact: doi: 10.1212/WNL.0000000000000837, 20. Lenses corrected for hypermetropia. 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. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. When we didnt feel we had any options left for treatment, 128:4839. 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. Accessibility Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. 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. (2002) 112:198202. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Phone: 202-588-5700. eCollection 2022. Neurol. . 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. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. I dont think we will ever be able to truly articulate our appreciation for Dr. Madsen and Boston Childrens for all that they did for Zeeva and our family. Understanding what it has taken to get her to this point, though, is close to unimaginable. 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. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. 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, . The COL4A1 and COL4A2 genes were screened in proband IV-6.