COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. She has regular physical, speech, and occupational therapy. 2011 Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. 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). Epub 2010 Jun 17. Suite 500 For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). 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. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. 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). eCollection 2021. 2010;41:e513-518. seizure activity. Painful muscle cramps can occur and can develop before three years of age. PMC Would you like email updates of new search results? (2014) 11:3612. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). 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. 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. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. Neuropediatrics. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. There are no standardized treatment protocols or guidelines for affected individuals. It is passed through families in a autosomal dominant fashion. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Neurology. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. doi: 10.1212/01.WNL.0000123113.46672.68, 25. 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: 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. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. doi: 10.1038/gim.2015.30, 21. 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. 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. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. (2011) 42:13. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). Rarely, affected individuals will have a condition called Raynaud phenomenon in which the blood vessels in the fingers and toes temporarily narrow, restricting blood flow to the fingertips and the ends of the toes. Summary. It affects mainly young adults, children and more typically neonates. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. The number of genes implicated in epilepsy has grown rapidly in the past decade. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. COL4A1 is an essential component for basal membrane stability. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. (2015) 17:40524. Prenatal clinical manifestations in individuals with COL4A1/2 variants. Various muscles can be affected and muscle strength can become weakened. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. Danbury, CT 06810 Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Eur J Paediatr Neurol. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. 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). Clinically, COL4A1 mutations are responsible for different overlapping phenotypes including porencephaly (24), brain small vessel disease (2, 57) with or without ocular anomalies, HANAC (13) (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome, ophthalmological abnormalities (912), and non-syndromic autosomal dominant congenital cataracts (10). (2017) 377:111931. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. Thats not to say Zeeva hasnt had to work hard since the surgery. doi: 10.1038/jp.2013.135, 29. Bone. Clin Neurol Neurosurg. However, in people with HANAC syndrome, these aneurysms typically do not burst. 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). September 2003. Please enable it to take advantage of the complete set of features! Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. 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. Neurology. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. 2009 Jun 25 [updated 2016 Jul 7]. 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. Internet. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. 1779 Massachusetts Avenue Gould Syndrome is an ultra rare genetic, multi-system disorder. 55 Kenosia Avenue The COL4A2 test was negative. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. Phone: 203-263-9938 Clipboard, Search History, and several other advanced features are temporarily unavailable. COL4A1 and COL4A2 are on Chr. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. January 31, 2019 Here we report a family in which three siblings presented severe hypermetropia and porencephaly. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. Other eye problems experienced by people with COL4A1-related brain small-vessel disease include clouding of the lens of the eye (cataract) and the presence of arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eye (arterial retinal tortuosity). 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. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Quincy, MA 02169 Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Further refinement of COL4A1 and COL4A2 related cortical malformations. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. However, there are exceptions that depend on precisely when and where the mutation arose. BMC Med Genet. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. Berg R, Aleck A, Kaplan A. Familial porencephaly. doi: 10.1056/NEJMoa053727, 7. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Changing lives of those with rare disease. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. 1779 Massachusetts Avenue The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. In affected individuals, stroke is usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke), although either type can occur. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. (2013) 73:4857. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. NORD is a registered 501(c)(3) charity organization. doi: 10.1212/WNL.0000000000000837, 20. Am J Med Genet A. He would separate the two halves of her brain by Matrix Biol. He also wanted to remove a shunt that was implanted in Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. 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/. 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. Clinical Testing and Workup Phone: 203-263-9938 A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Any muscle may be affected, and cramps usually last from a few seconds to a few minutes, although in some cases they can last for several hours. 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. Front. 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. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. 2010;17(13):1317-24. doi: Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Acute urinary retention due to a novel collagen COL4A1 mutation. Bennett RL, French KS, Resta RG, Doyle DL. percent confident in Dr. Madsen and the epilepsy team. What are the different ways a genetic condition can be inherited? 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. Neurology. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. (2014) 34:757. (2015) 88:46873. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/.