Treatment In people with HANAC syndrome, angiopathy affects several parts of the body. 2010 IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). Internet. He was confident this would reduce or stop the Various muscles can be affected and muscle strength can become weakened. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. 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. Genet Med. Curr Opin Neurol. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. Matrix Biol. Hum Mol Genet. cuts under the microscope. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. In most cases, an affected person has one parent with the condition. 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. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. When this enzyme is elevated, it is a sign of muscle damage. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. government site. Neurology. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. What is the prognosis of a genetic condition? 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. 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. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole 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. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Front Aging Neurosci. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. doi: 10.1038/jp.2013.135, 29. Summary: doi: 10.1007/s10897-008-9169-9, 16. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: 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. Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature 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. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. How can gene variants affect health and development? January 31, 2019 Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. The site is secure. Epub 2010 Jun 17. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. (2010). 1779 Massachusetts Avenue COL4A1 Syndrome CADASIL 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). 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. Disease Overview. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). 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. J Perinatol. (2006) 354:148996. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. 2011 Cereb Circ Cogn Behav. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Phone: 202-588-5700. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. Recent findings: Am J Med Genet. Bennett RL, French KS, Resta RG, Doyle DL. When we didnt feel we had any options left for treatment, Danbury, CT 06810 (2014) 252:178994. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. Jeanne M, Gould DB. 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. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. Childhood presentation of COL4A1 mutations. doi: 10.1212/WNL.0b013e3181c3fd12, 9. COL4A1 mutations as a monogenic cause of cerebral Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Arch Ophthalmol. (2014) 83:122834. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. How can gene variants affect health and development? The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. He smiled, caught it, and asked Zeeva if he could throw it back. 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 As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. In most people, small vessel disease in the brain does not cause symptoms. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. 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. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). 2018;91:e2078-e2088. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Zeevas brain to treat a cyst in her brain caused by porencephaly. Neurology. BMC Med Genet. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). 1900 Crown Colony Drive Thats not to say Zeeva hasnt had to work hard since the surgery. Arch Neurol. 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 COL4A1 stroke syndrome. Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Your support helps to ensure everyones free access to NORDs rare disease reports. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Migraines can occur with or without aura. In addition to porencephaly there can be other forms of damage to the brain present at birth. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. 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. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . 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/. (2014) 11:3612. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. While there are other explanations, parental mosaicism should be considered. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. 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. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. (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). Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. He would separate the two halves of her brain by Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. 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. 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. Phone: 203-263-9938 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. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. N Engl J Med. doi: 10.1056/NEJMoa1707914, 6. Front. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). 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). Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Suite 310 Epub 2016 Apr 24. Epub 2014 Jan 5. In the human genome, there are 46 chromosomes. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. What does it mean if a disorder seems to run in my family? 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, . To better define pathology caused by Col4a1 mutations, we characterized myopathy in two different Col4a1 mutant mouse strainsCol4a1 ex41 and Col4a1 G394V.We selected these strains from an allelic series of Col4a1 mutant mice because they showed the most severe myopathy according to NPN quantification in quadriceps while having different effects on [1(IV)] 2 2(IV) secretion. 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. It is important to discuss these concepts with a genetic counselor and understand their implications. It looks like nothing was found at this location. Contact a health care provider if you have questions about your health. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. 2011 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%). Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. Prenatal clinical manifestations in individuals with COL4A1/2 variants. Genet Med. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. (2008) 23:17. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Gould Syndrome is a rare, genetic, multi-system disorder. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. doi: 10.1038/gim.2015.30, 21. Clinical Testing and Workup PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. 4 Both . (2009) 73:187382. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. 10.2174/092986710790936293. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. N Engl J Med. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. MeSH People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). Six alpha chains of type IV. Neurology. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. Affected individuals may have no observable symptoms or only isolated migraines with aura. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. Neurology. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. 1A-B). (No doctor had ever taken a call on their lunch break to speak with me). small vessel disease: a systematic review. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. The COL4A2 test was negative. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Individuals with HANAC syndrome also experience a variety of eye problems. 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. J Genet Couns. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. INTERNET 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. mutations: a novel genetic multisystem disease. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. These genes are the blueprints for two proteins that wind together like a long rope inside cells. Standardized (15) familiar pedigree is showed in Figure 1. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Axenfeld-Rieger anomaly and cataract can cause impaired vision. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Clipboard, Search History, and several other advanced features are temporarily unavailable. Curr Med Chem. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. 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). 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). The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Jeanne M, Gould DB. (2002) 112:198202. What is the prognosis of a genetic condition? COL4A1 is an essential component for basal membrane stability. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. 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. Progressive cerebral atrophies in three children with COL4A1 mutations. Careers. TTY: (866) 411-1010 Gould Syndrome is often 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. (2008) 17:42433. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. 2010 Aug;41(8):e513-8. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, It is not uncommon for an unaffected parent to have a severely affected child. The main symptom is single or repeated bleeding inside the skull (intracranial hemorrhaging) that can occur without cause (spontaneously), after trauma, or when taking drugs that slow blood clotting (anticoagulants).