The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). doi: 10.1016/j.ejpn.2009.04.010, 27. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. J Perinatol. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Years published: 2019. 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 structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. (2015) 17:84353. Zagaglia Selch C, Nisevic JR, et al. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Cephalic Disorders Fact Sheet. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. Epub 2014 Jan 5. doi: 10.1056/NEJMoa071906, 14. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. 128:4839. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. (2014) 11:3612. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. can also contribute. (2008) 17:42433. Nat Methods. COL4A1 is an essential component for basal membrane stability. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. 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. GeneReviews. 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. 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). It is passed through families in a autosomal dominant fashion. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. 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). (2017) 377:111931. So far, it appears as though mutations in COL4A1 and COL4A2 lead to identical disease, however, for reasons that are not yet understood, mutations in COL4A2 are much less frequent than those in COL4A1. PS: wrote thi paper and performed the review of the literature under the supervision of GN. 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. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. What does it mean if a disorder seems to run in my family? Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization Orphanet: HANAC syndrome Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. COL4A1 Mutations Cause Neuromuscular Disease with - ScienceDirect The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). Surgery may be necessary for individuals with severe cataracts. (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). The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Copyright 2023 by Gould Syndrome Foundation -. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. 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. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. 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. 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. How can gene variants affect health and development? No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Depending on the cell type that acquires the mutation and when the mutation arises, the individual may have many or few cells with the mutation. It affects mainly young adults, children and more typically neonates. 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. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). (2010) 75:7479. Pediatr Neurol. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Neurology. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. People listened to us and to Zeeva in a very different and proactive way. Phone: 203-263-9938 government site. Please enable it to take advantage of the complete set of features! COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Am J Neuroradiol. There are no standardized treatment protocols or guidelines for affected individuals. doi: 10.1007/s00417-014-2800-6, 12. 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. Standardized (15) familiar pedigree is showed in Figure 1. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Some individuals develop cysts on the kidney. Thats not to say Zeeva hasnt had to work hard since the surgery. doi: 10.1002/ana.23736, 4. N Engl J Med. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Hum Mol Genet. 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. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Fax: 203-263-9938, Washington, DC Office Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. 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. for the triple helical CB3[IV] domain. MedlinePlus also links to health information from non-government Web sites. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, 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. At least 50 individuals with this condition have been described in the scientific literature. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. However, there are exceptions that depend on precisely when and where the mutation arose. 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). Quincy, MA 02169 The .gov means its official. NORD is a registered 501(c)(3) charity organization. The site is secure. 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. 4 Both . An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. A diagnosis can be confirmed through molecular genetic testing. Resource(s) for Medical Professionals and Scientists on This Disease: Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Understanding what it has taken to get her to this point, though, is close to unimaginable. Progressive cerebral atrophies in three children with COL4A1 mutations.
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