Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. It affects mainly young adults, children and more typically neonates. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual (called sporadic or de novo). Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. 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). Eur J Paediatr Neurol. 2008 May;192(5):971-84; discussion 984-6. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. 2018;61:765-772. Front Aging Neurosci. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Gould Syndrome is a rare, genetic, multi-system disorder. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. 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. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. 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. These genes are the blueprints for two proteins that wind together like a long rope inside cells. 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. functional hemispherectomy. 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. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. Neurology. 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 More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. 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. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Genet Med. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. doi: 10.1212/WNL.0b013e3181eee440, 28. Surgery may be necessary for individuals with severe cataracts. eCollection 2022. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. 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. PS: wrote thi paper and performed the review of the literature under the supervision of GN. Gould Syndrome is an ultra rare genetic, multi-system 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. Plaisier E, Ronco P. COL4A1-Related Disorders. Bethesda, MD 20894, Web Policies NORD is a registered 501(c)(3) charity organization. NORD gratefully acknowledges Douglas Gould, PhD, Professor, Director of Research, Denise B. Evans Endowed Chair in Ophthalmology, Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, and the COL4A1 Foundation, for assistance in the preparation of this report. 2010;41:e513-518. Firstly, it segregates within the family with the phenotype. doi: 10.1056/NEJMoa053727, 7. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . 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. Copyright 2023 by Gould Syndrome Foundation -. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Am J Med Genet A. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. 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. The COL4A2 test was negative. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. (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). Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. 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. Phone: 617-249-7300, Danbury, CT office Clin Genet. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. Neurology. INTERNET COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Disease Overview. He also wanted to remove a shunt that was implanted in 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. Cavalin M, Mine M, Philbert M, et al. Suite 500 Clinical Testing and Workup Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Curr Opin Neurol. Ophthalmological features associated with COL4A1 mutations. (2014) 83:122834. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. doi: 10.1055/s-0031-1275343, 24. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. If either parent also carries the mutation, it is considered inherited. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Stroke is a leading cause of death and serious long-term disability in developed nations. 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. In the human genome, there are 46 chromosomes. ClinVar; [VCV000389182.3]. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. 128:4839. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. 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. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Gould Syndrome is an ultra rare genetic, multi-system disorder. (2015) 88:46873. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). 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.
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