A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). (2010). Curr Opin Neurol. He was confident this would reduce or stop the Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. When these ropes are secreted, they assemble into net-like structures outside the cells. Autosomal Dominant Familial Porencephaly Type I. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Phone: 203-263-9938 U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. Unauthorized use of these marks is strictly prohibited. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. (2011) 42:13. 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). Front. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. September 2003. Therapies are based on the specific symptoms in each individual. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. 1. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Some individuals develop cysts on the kidney. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Resource(s) for Medical Professionals and Scientists on This Disease: doi: 10.1055/s-0031-1275343, 24. Matrix Biol. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. 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. 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. Summary: 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. (2008) 23:17. Careers. Figure 3. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. This site needs JavaScript to work properly. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. A diagnosis can be confirmed through molecular genetic testing. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Contact a health care provider if you have questions about your health. 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. It is important to discuss these concepts with a genetic counselor and understand their implications. 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). 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. Further refinement of COL4A1 and COL4A2 related cortical malformations. The size and location of cerebral cavities contributes to clinical variability. 2018;91:e2078-e2088. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Clin Neurol Neurosurg. doi: 10.1001/archneur.1983.04050080067013, 17. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 1900 Crown Colony Drive the basement membranes surrounding the body's blood vessels, National Organization for Rare Disorders (NORD), BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. cuts under the microscope. The disorder causes many symptoms, not the least of which are strokes and epilepsy. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. 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. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. N Engl J Med. (19). Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: Phone: 202-588-5700. 55 Kenosia Avenue At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. small vessel disease: a systematic review. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. Genet Med. 2012;21:R97-R110. Understanding what it has taken to get her to this point, though, is close to unimaginable. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. (2008) 17:42433. Quincy, MA 02169 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. eCollection 2022. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. 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. FOIA 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. He smiled, caught it, and asked Zeeva if he could throw it back. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Phone: 203-263-9938 Plaisier E, Ronco P. COL4A1-Related Disorders. In most cases, an affected person has one parent with the condition. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Fetal intracerebral hemorrhage and cataract: think COL4A1. 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. (2014) 34:757. Years published: 2019. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. (2013) 73:4857. Prenatal clinical manifestations in individuals with COL4A1/2 variants. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). (2006) 43:4905. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. HHS Vulnerability Disclosure, Help He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). doi: 10.1001/archophthalmol.2010.42, 10. The COL4A1 and COL4A2 genes were screened in proband IV-6. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). 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).
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