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. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). 1779 Massachusetts Avenue Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. Lanfranconi S, Markus HS. 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 . Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. In the brain, intracerebral hemorrhage is the most frequent phenotype. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. doi: 10.1056/NEJMoa071906, 14. doi: 10.1016/j.matbio.2016.10.003, 23. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Suite 310 Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. 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. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. Neurology. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). PS: wrote thi paper and performed the review of the literature under the supervision of GN. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. The disorder causes many symptoms, not the least of which are strokes and epilepsy. N Engl J Med. 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. (18) and Staals et al. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. 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). Lenses corrected for hypermetropia. MeSH Type IV collagen molecules attach to each other to form complex protein networks. What does it mean if a disorder seems to run in my family? Prenatal clinical manifestations in individuals with COL4A1/2 variants. A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium). Arch Ophthalmol. Still other individuals may not develop any symptoms until well into adulthood. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. INTERNET Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. ClinVar; [VCV000389182.3]. Bookshelf This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. National Center for Biotechnology Information. These exceptions are nuanced and should be discussed with a genetic counselor. The information on this site should not be used as a substitute for professional medical care or advice. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Nearly half of these participants were diagnosed with infantile spasms. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Ultrasound in utero from IV-6 (A). 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. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Childhood presentation of COL4A1 mutations. (2008) 23:17. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. 1. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. The COL4A1 stroke syndrome. (2014) 252:178994. 2009 Jun 25 [updated 2016 Jul 7]. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. Gould Syndrome is a rare, genetic, multi-system disorder. doi: 10.1016/j.ejpn.2009.04.010, 27. 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. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. Stroke. Danbury, CT 06810 55 Kenosia Avenue Therapies are based on the specific symptoms in each individual. 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. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Epub 2010 Jun 17. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. 2018;61:765-772. 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. 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. It is not uncommon for an unaffected parent to have a severely affected child. In the brain, intracerebral hemorrhage is the most frequent phenotype. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual (called sporadic or de novo). 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. 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. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Cephalic Disorders Fact Sheet. Am J Med Genet A. In most cases, an affected person has one parent with the condition. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Suite 500 Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. Genet Med. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. The p.Gly743Val variant is a conservative substitution that occurs in a position highly conserved across species (SIFT analysis: DeleteriousScore 0, median: 4.22, highly conserved nucleotide and amino acid, up to Tetraodon considering 11 species) and affects a crucial and abundant residue within the triple-helix-forming collagenous domain of the protein, which consist of long stretches of Gly-X-Y repeats. 2010 Aug;41(8):e513-8. 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. (1987) 8:4216. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. 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. 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. We describe here the phenotype of a likely pathogenic gene variant, p.Gly743Val, which is responsible for a missense mutation in the COL4A1 gene exon 30 in a three generation family with severe hypermetropia and highly penetrant porencephaly in the absence of systemic manifestations. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Copyright 2023 by Gould Syndrome Foundation -. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. 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. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). While there are other explanations, parental mosaicism should be considered. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 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. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Affected individuals may have no observable symptoms or only isolated migraines with aura. Thats not to say Zeeva hasnt had to work hard since the surgery. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. 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. This page is currently unavailable. Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. Here, we report a patient with schizencephaly, detected by fetal ultrasonography and fetal magnetic resonance imaging, with a de novo novel mutation in COL4A1 (c.2645_2646delinsAA, p.Gly882Glu). doi: 10.1126/science.1109418, 5. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. (2002) 112:198202. 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 structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Fax: 203-263-9938, Washington, DC Office In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. 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. 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. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. So far, it appears as though mutations in COL4A1 and COL4A2 lead to identical disease, however, for reasons that are not yet understood, mutations in COL4A2 are much less frequent than those in COL4A1. 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. Phone: 203-263-9938 doi: 10.1136/jmg.2005.035584, 15. Danbury, CT 06810 Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. Zeevas brain to treat a cyst in her brain caused by porencephaly. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. (1982) 40:5679. 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. How can gene variants affect health and development? View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). He would separate the two halves of her brain by Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Painful muscle cramps can occur and can develop before three years of age. mutations: a novel genetic multisystem disease. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). Ophthalmological features associated with COL4A1 mutations. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. 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. The retina is the light-sensitive membrane that lines the inside of the eyes. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. 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. COL4A1 mutations as a monogenic cause of cerebral Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. 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. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. COL4A1 is an essential component for basal membrane stability. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. 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. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Clipboard, Search History, and several other advanced features are temporarily unavailable. She also showed severe hypermetropia. 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. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Science. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Phone: 617-249-7300, Danbury, CT office 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. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. One patient (IV-3) was treated for spasticity and seizures with valproic acid. 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. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Dev Med Child Neurol. Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. eCollection 2022. (2015) 17:40524. Ann Neurol. There are no standardized treatment protocols or guidelines for affected individuals. 1900 Crown Colony Drive (2010) 14:1827. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. 1900 Crown Colony Drive Contact a health care provider if you have questions about your health. doi: 10.1055/s-0031-1275343, 24. 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). 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. 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. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. Neurology. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Ann Neurol. small vessel disease: a systematic review.