However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. (2014) 252:178994. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Neurology. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. (2009) 73:187382. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. doi: 10.1056/NEJMoa053727, 7. How can gene variants affect health and development? The site is secure. MedlinePlus also links to health information from non-government Web sites. (E,F) IV-3Brain MRI showed left frontotemporal dilatation and diffusion tensor imaging (DTI) sequences demonstrated no left corticospinal tract (cranio-caudal fibers, indigo, with arrows). 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: 617-249-7300, Danbury, CT office No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. 1779 Massachusetts Avenue NORD strives to open new assistance programs as funding allows. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. Neurology. (2010). Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. Seattle, WA: University of Washington, Seattle; 1993-. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. 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. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. 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. It is important to discuss these concepts with a genetic counselor and understand their implications. Not only did Dr. Madsen, help heal Zeevas brain, but he was instrumental in supporting us as we founded the Gould Syndrome Foundation, a 501(c)(3) non-profit that promotes education, advocacy, and medical advancements in Gould Syndrome, COL4A1/COL4A2 diseases. What does it mean if a disorder seems to run in my family? Front Aging Neurosci. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Bone. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. We describe, here, the phenotype of a likely pathologic variant (p.Gly743Val) in exon 30 of the COL4A1 gene, responsible for an oculo-cerebral phenotype characterized by severe hypermetropia and highly penetrant porencephaly in absence of other systemic complications. National Taiwan University Hospital, Taiwan, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Carrera de Medicina, Universidad Cientfica del Sur, Peru, Federal University of Rio Grande do Sul, Brazil. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Bull Acad Natl Med. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. 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/. He smiled, caught it, and asked Zeeva if he could throw it back. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Phone: 202-588-5700. Migraines can occur with or without aura. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Eur J Paediatr Neurol. Neuropediatrics. Ophthalmological features associated with COL4A1 mutations. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Cereb Circ Cogn Behav. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Cavalin M, Mine M, Philbert M, et al. She, then, developed seizures which were controlled by valproic acid. If we dont have a program for you now, please continue to check back with us. functional hemispherectomy. doi: 10.1007/s00417-014-2800-6, 12. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. This condition causes mutations in genes that produce a specific type of collagen. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. FOIA In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. Epub 2010 Jun 17. doi: 10.1002/ajmg.10452, 18. HANAC syndrome is a rare condition, although the exact prevalence is unknown. Painful muscle cramps can occur and can develop before three years of age. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. The information on this site should not be used as a substitute for professional medical care or advice. It affects mainly young adults, children and more typically neonates. How are genetic conditions treated or managed? Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Curr Med Chem. 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. This is called genotype-phenotype correlation. PMC 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Further refinement of COL4A1 and COL4A2 related cortical malformations. 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. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. doi: 10.1056/NEJMoa071906, 14. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Before 1. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. 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. Bookshelf [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. This site needs JavaScript to work properly. 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. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Eur J Med Genet. 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). 11:827. doi: 10.3389/fneur.2020.00827. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Progressive cerebral atrophies in three children with COL4A1 mutations. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Bennett RL, French KS, Resta RG, Doyle DL. We provide education, advocacy, and resources for families and individuals affected. He would separate the two halves of her brain by Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Neurology. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel 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. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. Fetal intracerebral hemorrhage and cataract: think COL4A1. COL4A1 brain small-vessel disease is an autosomal dominant condition resulting from a mutation to the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen 1-6. Please note that NORD provides this information for the benefit of the rare disease community. ACS Omega. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Contact a health care provider if you have questions about your health. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. If either parent also carries the mutation, it is considered inherited. ClinVar; [VCV000389182.3]. Childhood presentation of COL4A1 mutations. How are genetic conditions treated or managed? Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. The signs and symptoms can manifest at almost any age from before birth to old age. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, In people with HANAC syndrome, angiopathy affects several parts of the body. Type IV collagen molecules attach to each other to form complex protein networks. Pathology. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Clin Neurol Neurosurg. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. (2010) 75:7479. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Am J Med Genet A. (2007) 357:268795. Individuals with HANAC syndrome also experience a variety of eye problems. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Would you like email updates of new search results? Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. 10.2174/092986710790936293. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. People with COL4A1-related brain small vessel disease 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). mutations: a novel genetic multisystem disease. (2020). 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. It is ubiquitously expressed in many tissues and cell types. 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. 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. COL4A1/A2-related disorders are dominant genetic disorders. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. In the brain, intracerebral hemorrhage is the most frequent phenotype. Summary: Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. People listened to us and to Zeeva in a very different and proactive way. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. 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. doi: 10.2214/ajr.149.2.351, 19. Neurology. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. The size and location of cerebral cavities contributes to clinical variability. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. 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. 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. Berg R, Aleck A, Kaplan A. Familial porencephaly. 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. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies, https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, https://www.ncbi.nlm.nih.gov/pubmed/28254515, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, https://www.nature.com/articles/gim2014210, https://www.ncbi.nlm.nih.gov/pubmed/23225343, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, https://www.ncbi.nlm.nih.gov/pubmed/22868088, https://www.ncbi.nlm.nih.gov/pubmed/22574627, https://www.ncbi.nlm.nih.gov/pubmed/20558831, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, https://www.ncbi.nlm.nih.gov/pubmed/26610912, https://www.ncbi.nlm.nih.gov/books/NBK7046/, https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet, https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/, https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/, https://rarediseases.org/patient-assistance-programs/caregiver-respite/, Learn more about Patient Assistance Programs >, Arginine: Glycine Amidinotransferase Deficiency, https://rarediseases.org/non-member-patient/epilepsy-foundation/, Gould Syndrome Foundation (COL4a1/COL4A2), https://rarediseases.org/non-member-patient/gould-syndrome-foundation-col4a1-col4a2/, https://rarediseases.org/non-member-patient/national-kidney-foundation/, https://rarediseases.org/non-member-patient/nih-national-eye-institute/, NIH/National Institute of Neurological Disorders and Stroke, Aromatic L-Amino Acid Decarboxylase Deficiency, https://rarediseases.org/non-member-patient/nih-national-institute-of-neurological-disorders-and-stroke/, https://rarediseases.org/non-member-patient/the-arc/, Learn more about Patient Organization & Membership >, HANAC: hereditary angiopathy, nephropathy and cramps syndrome (OMIM #611773), POREN1: autosomal dominant type 1 porencephaly; porencephaly with infantile hemiplegia (OMIM #175780, RATOR: retinal arterial tortuosity (OMIM #180000), BSVD: brain small vessel disease with or without ocular anomalies (OMIM #607595), ICH: susceptibility to intracerebral hemorrhage (OMIM #614519).