basement membranes surrounding the body's blood vessels, Genetic Testing Registry: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, National Organization for Rare Disorders (NORD), ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. 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 This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. The degree of mosaicism is highly variable ranging from only a small percent of cells with the mutation to nearly all cells carrying the mutation and depends on the stage during development that the mutation occurred. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Careers. Arch Ophthalmol. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Maybe try a search? COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. 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. Autosomal Dominant Familial Porencephaly Type I. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. 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. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Clinical Testing and Workup Quincy, MA 02169 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. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Copyright 2023 by Gould Syndrome Foundation -. Eur J Paediatr Neurol. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Painful muscle cramps can occur and can develop before three years of age. cutting tissue called the corpus callosum, then make some additional delicate However, in people with HANAC syndrome, these aneurysms typically do not burst. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). came with risks and was the hardest decision we had ever faced, yet we felt 100 In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. PMC Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 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. 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/. Smoking, which also increases the risk of stroke, physical activities that can cause head trauma such as contact sports, and the use of anti-clotting (anticoagulant) medications, should be avoided. People with HANAC syndrome develop kidney disease (nephropathy). Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. eCollection 2022. U.S. Department of Health and Human Services, Autosomal dominant familial hematuria, retinal arteriolar tortuosity, contractures, Hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome. We provide education, advocacy, and resources for families and individuals affected. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). 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. 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. 2018;61:765-772. It looks like nothing was found at this location. 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. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. This condition causes mutations in genes that produce a specific type of collagen. Jeanne M, Gould DB. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: 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. Teaching families how to advocate for their loved ones and access medical information. Surgery may be necessary for individuals with severe cataracts. The p.Gly743Val variant is a conservative substitution that occurs in a position highly conserved across species (SIFT analysis: DeleteriousScore 0, median: 4.22, highly conserved nucleotide and amino acid, up to Tetraodon considering 11 species) and affects a crucial and abundant residue within the triple-helix-forming collagenous domain of the protein, which consist of long stretches of Gly-X-Y repeats. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. Other patients have been reported with cysts on the liver, irregular heartbeats (supraventricular arrhythmia), and Raynaud phenomenon, which is in which the fingers or toes become numb or have a prickly sensation in response to cold due to narrowing of blood vessels. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). ACS Omega. 55 Kenosia Avenue Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. 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 Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. NCI CPTC Antibody Characterization Program. (2017) 377:111931. 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. (18) and Staals et al. Neurology. Facebook: https://www.facebook.com/Col4A1Foundation Please Note PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. He was confident this would reduce or stop the Childhood presentation of COL4A1 mutations. 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. The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. (2010) 75:7479. Zeevas brain to treat a cyst in her brain caused by porencephaly. (2014) 15:16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. The .gov means its official. Phone: 203-263-9938 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). 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. His bedside manner was incredible. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. 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. Neuropediatrics. 8600 Rockville Pike Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. Cereb Circ Cogn Behav. 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). Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Matrix Biol. 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). Purpose of review: 1900 Crown Colony Drive The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. (No doctor had ever taken a call on their lunch break to speak with me). 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. 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. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. mutations: a novel genetic multisystem disease. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. (2008) 17:42433. mutations: a novel genetic multisystem disease. ClinVar; [VCV000389182.3]. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. The first time he came to meet us, Zeeva threw a sock at him. Axenfeld-Rieger anomaly and cataract can cause impaired vision. sharing sensitive information, make sure youre on a federal The severity of the condition varies greatly among affected individuals. What is the prognosis of a genetic condition? II-2 had a limp since childhood attributed to forceps delivery. Quincy, MA 02169 Thats not to say Zeeva hasnt had to work hard since the surgery. The number of genes implicated in epilepsy has grown rapidly in the past decade. Cephalic Disorders Fact Sheet. 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. To use the sharing features on this page, please enable JavaScript. Clipboard, Search History, and several other advanced features are temporarily unavailable. Bennett RL, French KS, Resta RG, Doyle DL. (2014) 252:178994. functional hemispherectomy. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Internet. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. 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. 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. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Suite 310 Ophthalmological features associated with COL4A1 mutations. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Am J Neuroradiol. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Fax: 203-263-9938, Washington, DC Office 2012;21:R97-R110. The information on this site should not be used as a substitute for professional medical care or advice. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family.