col4a1 syndrome life expectancy

Berg R, Aleck A, Kaplan A. Familial porencephaly. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. small vessel disease: a systematic review. doi: 10.1038/nmeth.2890, 22. 11:827. doi: 10.3389/fneur.2020.00827. Bookshelf (2020). What are the different ways a genetic condition can be inherited? 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. doi: 10.1186/s12881-014-0097-2, 11. https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, For information about clinical trials sponsored by private sources, contact: The COL4A1 stroke syndrome. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. A diagnosis can be confirmed through molecular genetic testing. 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. 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). 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. 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. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Ann Neurol. 1. 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). It is passed through families in a autosomal dominant fashion. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. cuts under the microscope. 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. 2011 Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Summary. Front Aging Neurosci. We provide education, advocacy, and resources for families and individuals affected. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Arch Ophthalmol. Am J Neuroradiol. Maybe try a search? For example, an individual may carry genetic variants elsewhere in their genome that confers protection or susceptibly to the mutation and environmental experiences (trauma, anticoagulant use, physical exertion etc.) Lenses corrected for hypermetropia. 2009 Jun 25 [Updated 2016 Jul 7]. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. 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. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium). 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. The first time he came to meet us, Zeeva threw a sock at him. No microbleeds or cystic cavities were found. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). 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. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 55 Kenosia Avenue Acute urinary retention due to a novel collagen COL4A1 mutation. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. 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. 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. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. NCI CPTC Antibody Characterization Program. She, then, developed seizures which were controlled by valproic acid. doi: 10.1212/WNL.0b013e3181c3fd12, 9. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. What does it mean if a disorder seems to run in my family? Jeanne M, Gould DB. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. doi: 10.2214/ajr.149.2.351, 19. Unauthorized use of these marks is strictly prohibited. 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). Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). COL4A1 is an essential component for basal membrane stability. 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. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Jeanne M, Gould DB. Epub 2014 Jan 5. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. (2017) 377:111931. In a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. 2009 Jun 25 [updated 2016 Jul 7]. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. (2004) 62:16135. Muscle cramps can be spontaneous or triggered by exercise. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Here, we report a patient with schizencephaly, detected by fetal ultrasonography and fetal magnetic resonance imaging, with a de novo novel mutation in COL4A1 (c.2645_2646delinsAA, p.Gly882Glu). HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. N Engl J Med. The retina is the light-sensitive membrane that lines the inside of the eyes. Gould Syndrome is an ultra rare genetic, multi-system disorder. Matrix Biol. Clin Neurol Neurosurg. Hum Mol Genet. Mutations in the COL4A1 gene cause HANAC syndrome. sharing sensitive information, make sure youre on a federal (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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. How are genetic conditions treated or managed? Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. 1779 Massachusetts Avenue Genet Med. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. This group rarely survives beyond 2 years. doi: 10.1056/NEJMoa071906, 14. (1982) 40:5679. 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. official website and that any information you provide is encrypted Ultrasound in utero from IV-6 (A). 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. It is important to discuss these concepts with a genetic counselor and understand their implications. J Genet Couns. 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. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. It affects mainly young adults, children and more typically neonates. (2010) 14:1827. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Eur J Paediatr Neurol. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. Gould Syndrome is an ultra rare genetic, multi-system disorder. Neurology. Neuropediatrics. Epub 2016 Apr 24. Neurology. People with HANAC syndrome develop kidney disease (nephropathy). Fax: 203-263-9938, Washington, DC Office Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Am J Med Genet A. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. 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. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. (2009) 73:187382. Stroke. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. 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. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. 1A-B). National Institute of Neurological Disorders and Stroke. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Cephalic Disorders Fact Sheet. 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. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. my mom suggested we call Boston Childrens Hospital. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. The surgery In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. 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). What does it mean if a disorder seems to run in my family? Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. How can gene variants affect health and development? Understanding what it has taken to get her to this point, though, is close to unimaginable. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. doi: 10.1111/j.1469-8749.2011.04198.x, 26. These exceptions are nuanced and should be discussed with a genetic counselor. 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: Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. The number of genes implicated in epilepsy has grown rapidly in the past decade. doi: 10.1016/j.matbio.2016.10.003, 23. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Last updated: 1900 Crown Colony Drive 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. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. (2014) 11:3612. Firstly, it segregates within the family with the phenotype. Genetic counseling will be proposed when IV-3 and IV-6 intend to start a family as there is a 50% risk of mutation transmission to the next generation and potential obstetrical complications. 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. MeSH 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). (2010). eCollection 2021. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. government site. COL4A1 and COL4A2 are on Chr. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 2018;61:765-772. Standardized (15) familiar pedigree is showed in Figure 1. Axenfeld-Rieger anomaly and cataract can cause impaired vision. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). Bennett RL, French KS, Resta RG, Doyle DL. All authors contributed to the article and approved the submitted version. An official website of the United States government. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. doi: 10.1007/s00417-014-2800-6, 12. Neurol. 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. 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). ClinVar; [VCV000389182.3]. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Federal government websites often end in .gov or .mil. 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.ncbi.nlm.nih.gov/pubmed/26610912. 2018;91:e2078-e2088. To use the sharing features on this page, please enable JavaScript. Danbury, CT 06810 At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Plaisier E, Ronco P. COL4A1-Related Disorders. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. January 31, 2019 COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. Curr Opin Neurol. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. doi: 10.1002/ana.23736, 4. 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. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. How are genetic conditions treated or managed? Type IV collagen molecules attach to each other to form complex protein networks. Washington, DC 20036 A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. 2010;41:e513-518. It looks like nothing was found at this location. BMC Med Genet. 55 Kenosia Avenue Disclaimer. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. Childhood presentation of COL4A1 mutations. Contact a health care provider if you have questions about your health.

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