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Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Neurology. Berg R, Aleck A, Kaplan A. Familial porencephaly. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. Neurologic phenotypes associated with COL4A1/2 mutations Col4a1 mutation generates vascular abnormalities correlated with 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). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. (2008) 17:42433. 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. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. 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. Neurology. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Genet Med. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. doi: 10.1212/WNL.0000000000001309, 8. Arch Ophthalmol. (18) and Staals et al. 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 signs and symptoms can manifest at almost any age from before birth to old age. Neuropediatrics. Neurology. 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). If either parent also carries the mutation, it is considered inherited. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. 2010 In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Fetal intracerebral hemorrhage and cataract: think COL4A1. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. (2006) 354:148996. 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. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. 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. 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). The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. Doctors and researchers to bring research and medical therapeutic options to those affected. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. 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. doi: 10.1007/s10897-008-9169-9, 16. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. MedlinePlus also links to health information from non-government Web sites. This page is currently unavailable. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. sharing sensitive information, make sure youre on a federal 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. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Teaching families how to advocate for their loved ones and access medical information. Before Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. It is not uncommon for an unaffected parent to have a severely affected child. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). How are genetic conditions treated or managed? 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. doi: 10.1111/j.1469-8749.2011.04198.x, 26. Jeanne M, Gould DB. In her first six years of life, Zeeva spent hundreds of nights in the hospital, had 13 operations and countless procedures, (from eye surgeries to Achilles heel, a shunt placed in her brain, and spine surgery). Changing lives of those with rare disease. No use, distribution or reproduction is permitted which does not comply with these terms. doi: 10.1002/ana.23736, 4. Science. https://www.ncbi.nlm.nih.gov/pubmed/26610912. Ophthalmological features associated with COL4A1 mutations. government site. Am J Neuroradiol. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. It is ubiquitously expressed in many tissues and cell types. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Treatment N Engl J Med. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. 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. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Childhood presentation of COL4A1 mutations. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Sue. doi: 10.1111/cge.12543. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. 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%). COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. 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. 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). 128:4839. II-2 had a limp since childhood attributed to forceps delivery. Standardized (15) familiar pedigree is showed in Figure 1. Suite 310 Frontiers | p.Gly743Val Mutation in COL4A1 Is Responsible for Familial (No doctor had ever taken a call on their lunch break to speak with me). However, there are exceptions that depend on precisely when and where the mutation arose. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. COL4A1 and COL4A2 are on Chr. Bookshelf eCollection 2021. 2010;41:e513-518. 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 Antiinflammatory therapy with canakinumab for atherosclerotic disease. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Washington, DC 20036 for the triple helical CB3[IV] domain. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. doi: 10.1038/nmeth.2890, 22. Neurol. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 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. (2014) 15:16. 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. (2011) 42:13. cutting tissue called the corpus callosum, then make some additional delicate Unable to load your collection due to an error, Unable to load your delegates due to an error. Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature In most people, small vessel disease in the brain does not cause symptoms. cuts under the microscope. 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. Bull Acad Natl Med. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. He was confident this would reduce or stop the Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. The pathogenic mechanisms of COL4A1 mutations are not fully elucidated and may vary according to the mutation type, the affected exon (mutations responsible for systemic HANAC syndrome cluster at exon 24 and 25), the position of the mutation within the triple-helix domain, and the mutation location. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. COL4A1 Syndrome CADASIL Zagaglia Selch C, Nisevic JR, et al. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Gould Syndrome is an ultra rare genetic, multi-system disorder. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 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. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. COL4A1 mutations in patients with sporadic late-onset intracerebral The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. 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. doi: 10.1016/j.matbio.2016.10.003, 23. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. Neurology. Neurology. Orphanet: HANAC syndrome The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. Neurology. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. (2014) 11:3612. (2017) 377:111931. 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. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) 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. Please note that NORD provides this information for the benefit of the rare disease community. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. In most cases, an affected person has one parent with the condition. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. 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. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. To use the sharing features on this page, please enable JavaScript. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. 2011 III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Cephalic Disorders Fact Sheet. 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 Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Neurol. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. What are the different ways a genetic condition can be inherited? Contact a health care provider if you have questions about your health. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. 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). Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. COL4A1/A2-Related Disorders - Symptoms, Causes, Treatment | NORD She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. The https:// ensures that you are connecting to the Resource(s) for Medical Professionals and Scientists on This Disease: 55 Kenosia Avenue 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. An official website of the United States government. The risk is the same for males and females. doi: 10.1212/WNL.0000000000000837, 20. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. 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). 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. Disclaimer. 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. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. PMC 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 expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. The COL4A2 test was negative. 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 Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Epub 2014 Jan 5. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Practical approach to the diagnosis of adult-onset - BMJ Would you like email updates of new search results? After a normal neonatal period, those affected develop a rapidly progressive course involving irritability, hyperaesthesia, visual and hearing loss, severe cognitive and motor deterioration, and seizures. NORD gratefully acknowledges Douglas Gould, PhD, Professor, Director of Research, Denise B. Evans Endowed Chair in Ophthalmology, Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, and the COL4A1 Foundation, for assistance in the preparation of this report. 2012;21:R97-R110. Federal government websites often end in .gov or .mil. Lanfranconi S, Markus HS. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Epub 2016 Apr 24. NORD is a registered 501(c)(3) charity organization. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. At the age of 12, IV-3 underwent cerebral palsy quality of life (CPQoL) questionnaires in which they expressed a satisfactory quality of life and a good relationship with other children. In the human genome, there are 46 chromosomes. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Please enable it to take advantage of the complete set of features! Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. doi: 10.2214/ajr.149.2.351, 19. How are genetic conditions treated or managed? Agenesis of the Corpus Callosum | National Institute of Neurological When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. 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. 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. Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDs mission. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age.