COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Nearly half of these participants were diagnosed with infantile spasms. Probands' father had severe hypermetropia and bilateral cataracts. 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. Gould Syndrome is a rare, genetic, multi-system disorder. Neurology. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. seizure activity. (2014) 11:3612. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. 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. Mutations in the COL4A1 gene cause HANAC syndrome. Curr Opin Neurol. In people with HANAC syndrome, angiopathy affects several parts of the body. Am J Med Genet A. Front. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. The COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. January 31, 2019 Before (2015) 88:46873. I cannot describe the feeling of seeing your child healed. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. However, in people with HANAC syndrome, these aneurysms typically do not burst. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. The information on this site should not be used as a substitute for professional medical care or advice. 2009 Jun 25 [Updated 2016 Jul 7]. 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. 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. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. cuts under the microscope. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. 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. 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 . Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. doi: 10.1186/s12881-014-0097-2, 11. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. It affects mainly young adults, children and more typically neonates. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. 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). COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. The disorder causes many symptoms, not the least of which are strokes and epilepsy. J Neurol Sci. 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. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. 2011 1779 Massachusetts Avenue Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. (2013) 73:4857. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Please note that NORD provides this information for the benefit of the rare disease community. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. Neurology. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. GeneReviews. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. This is called genotype-phenotype correlation. 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). Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. doi: 10.1111/j.1469-8749.2011.04198.x, 26. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Danbury, CT 06810 Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. 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. the basement membranes surrounding the body's blood vessels, National Organization for Rare Disorders (NORD), BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES. It affects mainly young adults, children and more typically neonates. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. doi: 10.2214/ajr.149.2.351, 19. IV-3 was diagnosed with ventriculomegaly in utero. 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. Doctors and researchers to bring research and medical therapeutic options to those affected. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Cesarean delivery for pregnancies with fetus at risk for a COL4A1-related disorder is recommended to prevent brain vascular injury attributable to birth trauma during delivery (6). Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. (2015) 17:84353. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Cephalic Disorders Fact Sheet. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. U.S. Department of Health and Human Services, Autosomal dominant familial hematuria, retinal arteriolar tortuosity, contractures, Hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Phone: 617-249-7300, Danbury, CT office COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. 2018;61:765-772. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. (2002) 112:198202. MedlinePlus also links to health information from non-government Web sites. 2009 Jun 25 [updated 2016 Jul 7]. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. Years published: 2019. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Last updated: See our, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome, URL of this page: https://medlineplus.gov/genetics/condition/hereditary-angiopathy-with-nephropathy-aneurysms-and-muscle-cramps-syndrome/. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Curr Med Chem. Unable to load your collection due to an error, Unable to load your delegates due to an error. 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. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 sharing sensitive information, make sure youre on a federal Phone: 202-588-5700. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. His bedside manner was incredible. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. 8600 Rockville Pike Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). (2017) 377:111931. The signs and symptoms can manifest at almost any age from before birth to old age. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. Fax: 203-263-9938, Washington, DC Office Lanfranconi S, Markus HS. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. About half of people with this condition 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). Contact a health care provider if you have questions about your health. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). 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. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. How are genetic conditions treated or managed? Neurology. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. https://www.ncbi.nlm.nih.gov/pubmed/26610912. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Standardized (15) familiar pedigree is showed in Figure 1. Subsequently, it has been recognized that autosomal dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular disease, whose onset occurs from fetal life onward and whose severity may range from small-vessel disease to fatal intraparenchymal hemorrhage.,, While epilepsy is known to be a clinical feature of porencephaly, the In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. How can gene variants affect health and development? A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. 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. What does it mean if a disorder seems to run in my family? All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. 30. 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. He would separate the two halves of her brain by Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. At least six affected families have been described in the scientific literature. Changing lives of those with rare disease. mutations: a novel genetic multisystem disease. (2005) 308:116771. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. percent confident in Dr. Madsen and the epilepsy team. Matrix Biol. 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. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Neurology. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. 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. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . 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. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Science. In the human genome, there are 46 chromosomes. 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. Dev Med Child Neurol. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. (2008) 23:17. What does it mean if a disorder seems to run in my family? Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel. These genes are the blueprints for two proteins that wind together like a long rope inside cells. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. HANAC syndrome is a rare condition, although the exact prevalence is unknown. Understanding what it has taken to get her to this point, though, is close to unimaginable. doi: 10.1038/jp.2013.135, 29. 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.