N Engl J Med. 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/. Bull Acad Natl Med. 2010;17(13):1317-24. doi: doi: 10.1056/NEJMoa1707914, 6. 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. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. (2006) 43:4905. 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. Thats not to say Zeeva hasnt had to work hard since the surgery. For instance, retinal arteriolar tortuosity relates to mutations in the amino-terminal one-third of the protein while mutations causing cataracts and ocular morphologic alterations are more likely to occur, closer to the carboxy terminus (22), like the variant we report. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Unauthorized use of these marks is strictly prohibited. When we didnt feel we had any options left for treatment, 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, . Copyright 2023 by Gould Syndrome Foundation -. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, There are no standardized treatment protocols or guidelines for affected individuals. The risk is the same for males and females. doi: 10.1001/archneur.1983.04050080067013, 17. Phone: 203-263-9938 In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. She has regular physical, speech, and occupational therapy. Type IV collagen molecules attach to each other to form complex protein networks. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. 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. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. How can gene variants affect health and development? 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. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Gould Syndrome is a rare, genetic, multi-system disorder. Arch Ophthalmol. 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). Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 1900 Crown Colony Drive Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Berg R, Aleck A, Kaplan A. Familial porencephaly. Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). 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. 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. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Early intervention is important in ensuring that children with reach their highest potential. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. 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. official website and that any information you provide is encrypted The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. doi: 10.1016/j.ejpn.2009.04.010, 27. 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 COL4A1 mutations in patients with sporadic late-onset intracerebral 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. 2010;41:e513-518. IV-3 had a left hemisphere porencephalic cyst and the lack of evidence of a left corticospinal tract on tractography (Figures 3E,F), IV-5 had a porencephalic cyst on the right lateral ventricle (Figure 3C), and III-3 had leukoencephalopathy (Figure 3D). 2010 Aug;41(8):e513-8. September 2003. The .gov means its official. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. Bone. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Children with the most severe brain malformations may have: Intellectual impairment Seizures Hydrocephalus Spasticity People who have a disorder of the corpus callosum typically have: Plaisier E, Ronco P. COL4A1-Related Disorders. Nearly half of these participants were diagnosed with infantile spasms. Gould Syndrome is an ultra rare genetic, multi-system disorder. It is ubiquitously expressed in many tissues and cell types. Curr Opin Neurol. It looks like nothing was found at this location. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. (No doctor had ever taken a call on their lunch break to speak with me). doi: 10.1038/jp.2013.135, 29. Eur J Paediatr Neurol. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. 2012;21:R97-R110. Acute urinary retention due to a novel collagen COL4A1 mutation. Please note that NORD provides this information for the benefit of the rare disease community. Therapies are based on the specific symptoms in each individual. J Perinatol. Before Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. He smiled, caught it, and asked Zeeva if he could throw it back. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Resource(s) for Medical Professionals and Scientists on This Disease: eCollection 2022 Nov 8. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. 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. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. Dev Med Child Neurol. Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization It is important to discuss these concepts with a genetic counselor and understand their implications. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). COL4A1-related brain small-vessel disease - MedlinePlus Various muscles can be affected and muscle strength can become weakened. One patient (IV-3) was treated for spasticity and seizures with valproic acid. 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 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. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. 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. IV-3 goes to a normal school, but special schooling is required for IV-6. . Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. 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. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). 2008 May;192(5):971-84; discussion 984-6. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. What are the different ways a genetic condition can be inherited? This group rarely survives beyond 2 years. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. The surgery PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. doi: 10.1212/WNL.0000000000001309, 8. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. Maybe try a search? This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. FOIA Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. 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. 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. doi: 10.1136/jmg.2005.035584, 15. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. While there are other explanations, parental mosaicism should be considered. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Fax: 203-263-9938, Washington, DC Office Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Would you like email updates of new search results? J Neurol Sci. can also contribute. Neuropediatrics. 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). 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. 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. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. N Engl J Med. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. What is the prognosis of a genetic condition? Bookshelf Cavalin M, Mine M, Philbert M, et al. Accessibility The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). 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. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. 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. Still other individuals may not develop any symptoms until well into adulthood. The site is secure. (2008) 17:42433. All authors contributed to the article and approved the submitted version. doi: 10.1056/NEJMoa071906, 14. Autosomal Dominant Familial Porencephaly Type I. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). 2009 Jun 25 [updated 2016 Jul 7]. 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. If either parent also carries the mutation, it is considered inherited. Neurol. Ann 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. Painful muscle cramps can occur and can develop before three years of age. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Dev Med Child Neurol. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Front Aging Neurosci. Neurology. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: What are the different ways a genetic condition can be inherited? The information on this site should not be used as a substitute for professional medical care or advice. In people with HANAC syndrome, angiopathy affects several parts of the body. Nat Methods. Neurologic phenotypes associated with COL4A1/2 mutations This condition causes mutations in genes that produce a specific type of collagen. What is Gould Syndrome? - Gould Syndrome Foundation doi: 10.1055/s-0031-1275343, 24. 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 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). Genet Med. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. 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. The information on this site should not be used as a substitute for professional medical care or advice. Hereditary cerebral small vessel diseases: a review. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. 55 Kenosia Avenue The severity of the condition varies greatly among affected individuals. 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. Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Treatment trials will be critical to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COL4A1/A2-related disorders. doi: 10.1007/s10897-008-9169-9, 16. doi: 10.1126/science.1109418, 5. doi: 10.1111/cge.12379, 13. Seattle, WA: University of Washington, Seattle; 1993-. Suite 310 Pathology. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and