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. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Careers. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. (2020). This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. About half of people with this condition 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). This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Phone: 203-263-9938 The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). How can gene variants affect health and development? During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. 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. Therapies are based on the specific symptoms in each individual. HHS Vulnerability Disclosure, Help Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. How can gene variants affect health and development? Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. 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. N Engl J Med. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Before Firstly, it segregates within the family with the phenotype. Figure 3. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Last updated: To use the sharing features on this page, please enable JavaScript. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Various muscles can be affected and muscle strength can become weakened. Fetal intracerebral hemorrhage and cataract: think COL4A1. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. It is passed through families in a autosomal dominant fashion. Eur J Paediatr Neurol. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Clin Neurol Neurosurg. 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. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. The signs and symptoms can manifest at almost any age from before birth to old age. Dev Med Child Neurol. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. Epub 2016 Apr 24. He would separate the two halves of her brain by 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. Gould Syndrome is an ultra rare genetic, multi-system disorder. The COL4A1 stroke syndrome. cuts under the microscope. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). 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. (2014) 34:757. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. (2006) 43:4905. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). 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. Fax: 203-263-9938, Washington, DC Office MeSH 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). Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, doi: 10.1056/NEJMoa053727, 7. Orphanet: HANAC syndrome Eur J Med Genet. Nat Methods. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. In the brain, intracerebral hemorrhage is the most frequent phenotype. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. What is the prognosis of a genetic condition? Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. (2015) 17:40524. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. doi: 10.1001/archneur.1983.04050080067013, 17. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for 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. Phone: 617-249-7300, Danbury, CT office Summary: Epub 2014 Jan 5. 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. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. 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. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Affected individuals may have no observable symptoms or only isolated migraines with aura. The .gov means its official. 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. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. (2002) 112:198202. doi: 10.1111/cge.12543. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies, https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, https://www.ncbi.nlm.nih.gov/pubmed/28254515, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, https://www.nature.com/articles/gim2014210, https://www.ncbi.nlm.nih.gov/pubmed/23225343, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, https://www.ncbi.nlm.nih.gov/pubmed/22868088, https://www.ncbi.nlm.nih.gov/pubmed/22574627, https://www.ncbi.nlm.nih.gov/pubmed/20558831, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, https://www.ncbi.nlm.nih.gov/pubmed/26610912, https://www.ncbi.nlm.nih.gov/books/NBK7046/, https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet, https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/, https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/, https://rarediseases.org/patient-assistance-programs/caregiver-respite/, Learn more about Patient Assistance Programs >, Arginine: Glycine Amidinotransferase Deficiency, https://rarediseases.org/non-member-patient/epilepsy-foundation/, Gould Syndrome Foundation (COL4a1/COL4A2), https://rarediseases.org/non-member-patient/gould-syndrome-foundation-col4a1-col4a2/, https://rarediseases.org/non-member-patient/national-kidney-foundation/, https://rarediseases.org/non-member-patient/nih-national-eye-institute/, NIH/National Institute of Neurological Disorders and Stroke, Aromatic L-Amino Acid Decarboxylase Deficiency, https://rarediseases.org/non-member-patient/nih-national-institute-of-neurological-disorders-and-stroke/, https://rarediseases.org/non-member-patient/the-arc/, Learn more about Patient Organization & Membership >, HANAC: hereditary angiopathy, nephropathy and cramps syndrome (OMIM #611773), POREN1: autosomal dominant type 1 porencephaly; porencephaly with infantile hemiplegia (OMIM #175780, RATOR: retinal arterial tortuosity (OMIM #180000), BSVD: brain small vessel disease with or without ocular anomalies (OMIM #607595), ICH: susceptibility to intracerebral hemorrhage (OMIM #614519). 10.1161/STROKEAHA.110.581918. Bennett RL, French KS, Resta RG, Doyle DL. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. How are genetic conditions treated or managed? All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). What are the different ways a genetic condition can be inherited? Curr Med Chem. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. Pathology. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. 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. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Maybe try a search? seizure activity. The COL4A2 test was negative. If either parent also carries the mutation, it is considered inherited. 1779 Massachusetts Avenue It is important to discuss these concepts with a genetic counselor and understand their implications. MedlinePlus also links to health information from non-government Web sites. 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 Curr Opin Neurol. COL4A1 Syndrome CADASIL Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Cephalic Disorders Fact Sheet. Front Aging Neurosci. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Neurologic phenotypes associated with COL4A1/2 mutations Other eye problems experienced by people with COL4A1-related brain small-vessel disease include clouding of the lens of the eye (cataract) and the presence of arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eye (arterial retinal tortuosity). Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle 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). 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). COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. 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. my mom suggested we call Boston Childrens Hospital. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. 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). (19). 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. Jeanne M, Gould DB. COL4A1-related brain small-vessel disease - MedlinePlus Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Stroke. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 2018;61:765-772. Neuropediatrics. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Understanding what it has taken to get her to this point, though, is close to unimaginable. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. Suite 500 Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. 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. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Facebook: https://www.facebook.com/Col4A1Foundation Please Note An official website of the United States government. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Childhood presentation of COL4A1 mutations. 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 brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. 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. She has regular physical, speech, and occupational therapy. doi: 10.1212/WNL.0b013e3181c3fd12, 9. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Copyright 2023 by Gould Syndrome Foundation -. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Arch Neurol. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. No microbleeds or cystic cavities were found. PMC Neurology. Hum Mol Genet. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. doi: 10.1056/NEJMoa1707914, 6. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. 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). for the triple helical CB3[IV] domain. Genet Med. 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. ACS Omega. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. Nearly half of these participants were diagnosed with infantile spasms. Accessibility Stroke. 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. It is ubiquitously expressed in many tissues and cell types. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. While there are other explanations, parental mosaicism should be considered. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Frontiers | p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. There are no standardized treatment protocols or guidelines for affected individuals. Finding the best care for Zeeva - Boston Children's Answers Please note that NORD provides this information for the benefit of the rare disease community. N Engl J Med. BMC Med Genet. (2011) 42:13. It looks like nothing was found at this location. Danbury, CT 06810 The information on this site should not be used as a substitute for professional medical care or advice. Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus (2008) 23:17. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. mutations: a novel genetic multisystem disease. Purpose of review: 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. doi: 10.1002/ana.23736, 4. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. 1779 Massachusetts Avenue 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. 2010 Aug;41(8):e513-8. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Quincy, MA 02169 Changing lives of those with rare disease. One patient (IV-3) was treated for spasticity and seizures with valproic acid.
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