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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 The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. 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. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. Neurology. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). People with HANAC syndrome develop kidney disease (nephropathy). While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Bookshelf Pathology. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. 2009 Jun 25 [Updated 2016 Jul 7]. doi: 10.1111/j.1469-8749.2011.04198.x, 26. (2015) 84:91826. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Further refinement of COL4A1 and COL4A2 related cortical malformations. 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. Figure 3. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The https:// ensures that you are connecting to the For instance, retinal arteriolar tortuosity relates to mutations in the amino-terminal one-third of the protein while mutations causing cataracts and ocular morphologic alterations are more likely to occur, closer to the carboxy terminus (22), like the variant we report. CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Neurology. It affects mainly young adults, children and more typically neonates. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. cuts under the microscope. Phone: 202-588-5700. for the triple helical CB3[IV] domain. 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. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Neurology. If we dont have a program for you now, please continue to check back with us. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. 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 Going from having seizures every day for six years to having no seizures is nothing short of a miracle. 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. What is the prognosis of a genetic condition? Clinical Testing and Workup Recent findings: Epub 2016 Apr 24. TTY: (866) 411-1010 The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). The information on this site should not be used as a substitute for professional medical care or advice. The surgery Migraines can occur with or without aura. In the human genome, there are 46 chromosomes. 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. He would separate the two halves of her brain by (2015) 17:40524. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. The risk is the same for males and females. Phone: 203-263-9938 Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. 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. doi: 10.1212/WNL.0b013e3181eee440, 28. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. In most people, small vessel disease in the brain does not cause symptoms. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. 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. 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). The retina is the light-sensitive membrane that lines the inside of the eyes. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. doi: 10.1212/WNL.0000000000000837, 20. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Summary: Please enable it to take advantage of the complete set of features! The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. 10.1161/STROKEAHA.110.581918. The p.Gly743Val variant is a conservative substitution that occurs in a position highly conserved across species (SIFT analysis: DeleteriousScore 0, median: 4.22, highly conserved nucleotide and amino acid, up to Tetraodon considering 11 species) and affects a crucial and abundant residue within the triple-helix-forming collagenous domain of the protein, which consist of long stretches of Gly-X-Y repeats. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Ophthalmological features associated with COL4A1 mutations. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. What does it mean if a disorder seems to run in my family? How can gene variants affect health and development? How are genetic conditions treated or managed? The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. 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). People listened to us and to Zeeva in a very different and proactive way. percent confident in Dr. Madsen and the epilepsy team. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Ann Zagaglia Selch C, Nisevic JR, et al. Type IV collagen molecules attach to each other to form complex protein networks. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. seizure activity. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. The COL4A2 test was negative. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. He also wanted to remove a shunt that was implanted in Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. There are 28 different types of collagen in your body and mutations in the genes that encode these proteins lead to multiple, highly diverse diseases. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. At least 50 individuals with this condition have been described in the scientific literature. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date. Fax: 203-263-9938, Washington, DC Office There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. How can gene variants affect health and development? Seattle, WA: University of Washington, Seattle; 1993-. doi: 10.1038/gim.2014.210, 3. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Standardized (15) familiar pedigree is showed in Figure 1. In addition to porencephaly there can be other forms of damage to the brain present at birth. Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina E. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. 1900 Crown Colony Drive Plaisier E, Ronco P. COL4A1-Related Disorders. Cavalin M, Mine M, Philbert M, et al. Contact a health care provider if you have questions about your health. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. What are the different ways a genetic condition can be inherited? Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Years published: 2019. INTERNET The COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. Maybe try a search? (2002) 112:198202. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. 2010 Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. NORD is a registered 501(c)(3) charity organization. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Nat Methods. small vessel disease: a systematic review. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). Early intervention is important in ensuring that children with reach their highest potential. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. No microbleeds or cystic cavities were found. The signs and symptoms can manifest at almost any age from before birth to old age. Washington, DC 20036 Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Suite 500 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. Affected individuals may have no observable symptoms or only isolated migraines with aura. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. These exceptions are nuanced and should be discussed with a genetic counselor.