The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. mutations: a novel genetic multisystem disease. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. 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. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. 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. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. Front Aging Neurosci. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Neurology. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. To use the sharing features on this page, please enable JavaScript. 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. It affects mainly young adults, children and more typically neonates. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. 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. All authors contributed to the article and approved the submitted version. 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. 2010;17(13):1317-24. doi: Curr Opin Neurol. BMC Med Genet. Suite 310 In most cases, an affected person has one parent with the condition. doi: 10.1002/ajmg.10452, 18. doi: 10.1002/ana.23736, 4. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. small vessel disease: a systematic review. Clin Genet. 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 Ann Arch Ophthalmol. (2014) 15:16. Recent findings: Quincy, MA 02169 How are genetic conditions treated or managed? J Perinatol. eCollection 2021. functional hemispherectomy. Am J Med Genet A. (2004) 62:16135. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. Various muscles can be affected and muscle strength can become weakened. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). COL4A1/A2-related disorders are believed to affect females and males in equal numbers. (2005) 308:116771. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. The COL4A1 and COL4A2 genes were screened in proband IV-6. 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). The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. (2012) 54:56974. 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. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. 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. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: Genet Med. Some individuals develop cysts on the kidney. 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. doi: 10.1016/j.ejpn.2009.04.010, 27. NORD strives to open new assistance programs as funding allows. 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). She, then, developed seizures which were controlled by valproic acid. 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. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. doi: 10.1038/jp.2013.135, 29. Prenatal clinical manifestations in individuals with COL4A1/2 variants. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Before In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. 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). Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. A diagnosis can be confirmed through molecular genetic testing. Am J Neuroradiol. September 2003. Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina E. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. Pathology. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Migraines can occur with or without aura. An official website of the United States government. This site needs JavaScript to work properly. This group rarely survives beyond 2 years. doi: 10.1212/01.WNL.0000123113.46672.68, 25. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Would you like email updates of new search results? (2014) 252:178994. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. The information on this site should not be used as a substitute for professional medical care or advice. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. 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. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). 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. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. government site. The COL4A2 test was negative. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. (2002) 112:198202. ClinVar; [VCV000389182.3]. 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). (No doctor had ever taken a call on their lunch break to speak with me). The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. 10.2174/092986710790936293. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. The first time he came to meet us, Zeeva threw a sock at him. Treatment Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. 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. Seattle, WA: University of Washington, Seattle; 1993-. Antiinflammatory therapy with canakinumab for atherosclerotic disease. 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 people with HANAC syndrome, angiopathy affects several parts of the body. doi: 10.1038/gim.2015.30, 21. While there are other explanations, parental mosaicism should be considered. Summary: Epub 2016 Apr 24. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. When we didnt feel we had any options left for treatment, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Copyright 2023 by Gould Syndrome Foundation -. 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. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. It is passed through families in a autosomal dominant fashion. Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects). Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Early intervention is important in ensuring that children with reach their highest potential. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). However, in people with HANAC syndrome, these aneurysms typically do not burst. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Science. Last updated: It is important to discuss these concepts with a genetic counselor and understand their implications. 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. Genet Med. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. 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. 55 Kenosia Avenue Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. 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. Berg R, Aleck A, Kaplan A. Familial porencephaly. Quincy, MA 02169 The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Phone: 202-588-5700. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Axenfeld-Rieger anomaly is associated with various other eye abnormalities, including underdevelopment and eventual tearing of the colored part of the eye (iris), and a pupil that is not in the center of the eye. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Autosomal Dominant Familial Porencephaly Type I. 2011 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. 2010 Aug;41(8):e513-8. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Stroke. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Please note that NORD provides this information for the benefit of the rare disease community. With input from doctors, researchers, and the US Food & Drug Administration, NORD has created IAMRARE to facilitate patient-powered natural history studies to shape rare disease research and treatments. Neurology. Mutations in the COL4A1 gene cause HANAC syndrome. Years published: 2019. Dev Med Child Neurol. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Muscle cramps can be spontaneous or triggered by exercise. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Painful muscle cramps can occur and can develop before three years of age. 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. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation Gould Syndrome Foundation 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. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. came with risks and was the hardest decision we had ever faced, yet we felt 100 People listened to us and to Zeeva in a very different and proactive way. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. 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).
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