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. These genes are the blueprints for two proteins that wind together like a long rope inside cells. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). doi: 10.1111/cge.12543. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. doi: 10.1126/science.1109418, 5. 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. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. 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. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. What does it mean if a disorder seems to run in my family? 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Gould Syndrome is an ultra rare genetic, multi-system disorder. Migraines can occur with or without aura. People with COL4A1-related brain small vessel disease 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). 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. NCI CPTC Antibody Characterization Program. What is the prognosis of a genetic condition? Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. 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). 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. doi: 10.1038/gim.2014.210, 3. doi: 10.1111/j.1469-8749.2011.04198.x, 26. It is ubiquitously expressed in many tissues and cell types. Fax: 203-263-9938, Washington, DC Office She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Neurology. functional hemispherectomy. (No doctor had ever taken a call on their lunch break to speak with me). (2005) 308:116771. 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: Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. 11:827. doi: 10.3389/fneur.2020.00827. COL4A1/A2-related disorders are dominant genetic disorders. 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. (2014) 11:3612. 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. 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. J Perinatol. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. 128:4839. (2018) 91:e207888. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. (2008) 17:42433. Ann Neurol. (2020). Neurology. It is passed through families in a autosomal dominant fashion. People with HANAC syndrome develop kidney disease (nephropathy). There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. doi: 10.1038/nmeth.2890, 22. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Autosomal Dominant Brain Small Vessel Disease. doi: 10.1186/s12881-014-0097-2, 11. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Arch Ophthalmol. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. 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. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. When this enzyme is elevated, it is a sign of muscle damage. Neurology. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Danbury, CT 06810 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. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. Danbury, CT 06810 IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Written informed consent was obtained from the patient and the patient's parents for publication of this case report. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. In most people, small vessel disease in the brain does not cause symptoms. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). Contact a health care provider if you have questions about your health. At least 50 individuals with this condition have been described in the scientific literature. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. 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. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. He also wanted to remove a shunt that was implanted in 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. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. cuts under the microscope. This condition causes mutations in genes that produce a specific type of collagen. Bookshelf Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. N Engl J Med. 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. Teaching families how to advocate for their loved ones and access medical information. One patient (IV-3) was treated for spasticity and seizures with valproic acid. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. How can gene variants affect health and development? 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. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Diseases Information Center National Center for Advancing Translational Sciences Browse by Disease About GARD Contact Us We recently launched the new GARD website and are still developing specific pages. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. 10.2174/092986710790936293. 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. The number of genes implicated in epilepsy has grown rapidly in the past decade. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Eur J Med Genet. 1900 Crown Colony Drive Fax: 203-263-9938, Washington, DC Office 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. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. The first time he came to meet us, Zeeva threw a sock at him. 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. (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). Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. 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). Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Neurology. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Phone: 203-263-9938 Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. How are genetic conditions treated or managed? I cannot describe the feeling of seeing your child healed. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. Antiinflammatory therapy with canakinumab for atherosclerotic disease. BMC Med Genet. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. An official website of the United States government. COL4A1 and COL4A2 are on Chr. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Phone: 202-588-5700. If either parent also carries the mutation, it is considered inherited. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. 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. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. What is the prognosis of a genetic condition? In the brain, intracerebral hemorrhage is the most frequent phenotype. National Center for Biotechnology Information. Washington, DC 20036 The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. 55 Kenosia Avenue Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Accessibility The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. (2014) 83:122834. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Axenfeld-Rieger anomaly and cataract can cause impaired vision. 8600 Rockville Pike (2010) 75:7479. 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 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 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 Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. Cereb Circ Cogn Behav. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. 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. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. The .gov means its official. II-2 had a limp since childhood attributed to forceps delivery. All authors contributed to the article and approved the submitted version. Painful muscle cramps can occur and can develop before three years of age. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. 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. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. (2014) 34:757. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. 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). Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. ClinVar; [VCV000389182.3]. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. National Taiwan University Hospital, Taiwan, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Carrera de Medicina, Universidad Cientfica del Sur, Peru, Federal University of Rio Grande do Sul, Brazil. Last updated: 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 . 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. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain.
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