government site. People with HANAC syndrome develop kidney disease (nephropathy). doi: 10.1136/jmg.2005.035584, 15. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. ClinVar; [VCV000389182.3]. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. 2010 Aug;41(8):e513-8. PS: wrote thi paper and performed the review of the literature under the supervision of GN. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 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. Figure 3. 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. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. doi: 10.1212/WNL.0000000000000837, 20. 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. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Years published: 2019. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). Graefe's Arch Clin Exp Ophthalmol. 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. (2011) 42:13. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Childhood presentation of COL4A1 mutations. Lenses corrected for hypermetropia. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. 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). 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. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Autosomal Dominant Brain Small Vessel Disease. 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. Congenital Cephalic Disorders 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. (2017) 377:111931. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Ann Here we report a family in which three siblings presented severe hypermetropia and porencephaly. Therapies are based on the specific symptoms in each individual. What are the different ways a genetic condition can be inherited? COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Eur J Paediatr Neurol. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. Bull Acad Natl Med. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. Neuropediatrics. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Neurol. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. All authors contributed to the article and approved the submitted version. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. sharing sensitive information, make sure youre on a federal Epub 2022 Apr 14. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). 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. Neurology. Neurol. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. 2012;21:R97-R110. 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. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. 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. Type IV collagen networks play an important role in the basement membranes in virtually all tissues throughout the body, particularly the basement membranes surrounding the body's blood vessels (vasculature). Thats not to say Zeeva hasnt had to work hard since the surgery. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. (2014) 83:122834. (2015) 17:40524. For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures, and a shunt to treat hydrocephalus by draining excess fluid from the skull. 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. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Sue. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Clin Neurol Neurosurg. National Center for Biotechnology Information. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). can also contribute. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. 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). This group rarely survives beyond 2 years. 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. Resource(s) for Medical Professionals and Scientists on This Disease: 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. Internet. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, 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. Stroke is a leading cause of death and serious long-term disability in developed nations. Prenatal clinical manifestations in individuals with COL4A1/2 variants. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Neurology. In most cases, an affected person has one parent with the condition. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Am J Med Genet A. I cannot describe the feeling of seeing your child healed. The severity of the condition varies greatly among affected individuals. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. January 31, 2019 N Engl J Med. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Type IV collagen molecules attach to each other to form complex protein networks. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. To use the sharing features on this page, please enable JavaScript. (2009) 73:187382. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. What does it mean if a disorder seems to run in my family? Pediatr Neurol. Bone. The COL4A1 stroke syndrome. 1900 Crown Colony Drive The information on this site should not be used as a substitute for professional medical care or advice. 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. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Neurology. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Matrix Biol. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. Phone: 617-249-7300, Danbury, CT office 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. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Firstly, it segregates within the family with the phenotype. J Perinatol. Before Type IV collagen molecules attach to each other to form complex protein networks. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. The surgery Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel. doi: 10.1212/WNL.0000000000001309, 8. Neurology. Genet Med. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 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. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. What are the different ways a genetic condition can be inherited? How are genetic conditions treated or managed? This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. This site needs JavaScript to work properly. 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. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Summary. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Individuals with HANAC syndrome also experience a variety of eye problems. (2010) 75:7479. When this enzyme is elevated, it is a sign of muscle damage. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Progressive cerebral atrophies in three children with COL4A1 mutations. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Copyright 2023 by Gould Syndrome Foundation -. (2014) 11:3612. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Clipboard, Search History, and several other advanced features are temporarily unavailable. 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. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Treatment 2018;61:765-772. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Neurology. doi: 10.1111/j.1469-8749.2011.04198.x, 26. (2010). 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. 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). doi: 10.1038/gim.2014.210, 3. Early intervention is important in ensuring that children with reach their highest potential. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Please note that NORD provides this information for the benefit of the rare disease community. 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. I dont think we will ever be able to truly articulate our appreciation for Dr. Madsen and Boston Childrens for all that they did for Zeeva and our family. BMC Med Genet. 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). To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Would you like email updates of new search results? Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. 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. Summary: 10.2174/092986710790936293. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Further refinement of COL4A1 and COL4A2 related cortical malformations. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. official website and that any information you provide is encrypted Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. (19). View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Science. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. There are 28 different types of collagen in your body and mutations in the genes that encode these proteins lead to multiple, highly diverse diseases. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. doi: 10.1007/s00417-014-2800-6, 12. 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. She has regular physical, speech, and occupational therapy. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. (2015) 84:91826. Contact a health care provider if you have questions about your health. While there are other explanations, parental mosaicism should be considered. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). Secondly, the p.Gly743Val variant is a missense mutation that shares features with other missense pathogenic mutations that occur in the COL4A1 gene exon 30: congenital porencephaly, epilepsy, and neuropsychological anomalies in p.Gly749Ser (23, 24), ophthalmologic defects and neuropsychological deficits in absence of systemic signs in variant p.Gly755Arg (2527), and antenatal fetal intracerebral hemorrhage, ocular anomalies associated to cerebral leukoencephalopathy in variant p.Gly773Arg (12, 28, 29). What is the prognosis of a genetic condition? MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. She, then, developed seizures which were controlled by valproic acid. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). (1982) 40:5679. 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. These genes are the blueprints for two proteins that wind together like a long rope inside cells. 11:827. doi: 10.3389/fneur.2020.00827. (2007) 357:268795. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 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. 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. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. 1. . No microbleeds or cystic cavities were found. Stroke. doi: 10.2214/ajr.149.2.351, 19. Please enable it to take advantage of the complete set of features! 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. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. How are genetic conditions treated or managed? Epub 2016 Apr 24. 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. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. The size and location of cerebral cavities contributes to clinical variability. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. 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.

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