J Genet Couns. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Painful muscle cramps can occur and can develop before three years of age. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. 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. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. In most cases, an affected person has one parent with the condition. Col4a1 mutation generates vascular abnormalities correlated with Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. NORD is a registered 501(c)(3) charity organization. IV-3 goes to a normal school, but special schooling is required for IV-6. (2014) 252:178994. J Med Genet. Neurology. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. COL4A1/A2-related disorders are dominant genetic disorders. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role Clinical spectrum of type IV collagen (COL4A1) mutations: a novel To use the sharing features on this page, please enable JavaScript. Resource(s) for Medical Professionals and Scientists on This Disease: Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). After a normal neonatal period, those affected develop a rapidly progressive course involving irritability, hyperaesthesia, visual and hearing loss, severe cognitive and motor deterioration, and seizures. Suite 500 Zeevas brain to treat a cyst in her brain caused by porencephaly. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. He smiled, caught it, and asked Zeeva if he could throw it back. These genes are the blueprints for two proteins that wind together like a long rope inside cells. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. 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. Other eye problems experienced by people with COL4A1-related brain small-vessel disease include clouding of the lens of the eye (cataract) and the presence of arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eye (arterial retinal tortuosity). The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. The disorder causes many symptoms, not the least of which are strokes and epilepsy. This page is currently unavailable. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. doi: 10.1212/WNL.0b013e3181c3fd12, 9. Antiinflammatory therapy with canakinumab for atherosclerotic disease. This site needs JavaScript to work properly. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. September 2003. 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. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. The signs and symptoms can manifest at almost any age from before birth to old age. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. Muscle cramps can be spontaneous or triggered by exercise. Neurology. eCollection 2021. Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature Dev Med Child Neurol. 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. PS: wrote thi paper and performed the review of the literature under the supervision of GN. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. No microbleeds or cystic cavities were found. Disease Overview. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. doi: 10.1111/cge.12379, 13. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. 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). 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. 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. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. Disclaimer. Pathology. Hereditary cerebral small vessel diseases: a review. Gould Syndrome is an ultra rare genetic, multi-system disorder. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. II-2 had a limp since childhood attributed to forceps delivery. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Childhood presentation of COL4A1 mutations. Therapies are based on the specific symptoms in each individual. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. Epub 2022 Apr 14. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. 1. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. COL4A1-related brain small-vessel disease - MedlinePlus COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. doi: 10.1212/01.WNL.0000123113.46672.68, 25. (1982) 40:5679. (2010). 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. 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. In her first six years of life, Zeeva spent hundreds of nights in the hospital, had 13 operations and countless procedures, (from eye surgeries to Achilles heel, a shunt placed in her brain, and spine surgery). COL4A1 and COL4A2 are on Chr. (2004) 62:16135. Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. All authors contributed to the article and approved the submitted version. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Cesarean delivery for pregnancies with fetus at risk for a COL4A1-related disorder is recommended to prevent brain vascular injury attributable to birth trauma during delivery (6). Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. 30. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Eur J Med Genet. CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical relating to specific areas of the brain supplied by deep small arteries (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. National Taiwan University Hospital, Taiwan, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Carrera de Medicina, Universidad Cientfica del Sur, Peru, Federal University of Rio Grande do Sul, Brazil. NORD strives to open new assistance programs as funding allows. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. 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. People with HANAC syndrome develop kidney disease (nephropathy). Ann Neurol. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. COL4A1 mutations in patients with sporadic late-onset intracerebral Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). Facebook: https://www.facebook.com/Col4A1Foundation Please Note Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 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. Last updated: Still other individuals may not develop any symptoms until well into adulthood. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. What is the prognosis of a genetic condition? 1779 Massachusetts Avenue Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Fax: 203-263-9938, Washington, DC Office Stroke is a leading cause of death and serious long-term disability in developed nations. 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. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. Neurology. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. COL4A1 brain small-vessel disease is an autosomal dominant condition resulting from a mutation to the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen 1-6. What are the different ways a genetic condition can be inherited? He also wanted to remove a shunt that was implanted in What is Gould Syndrome? - Gould Syndrome Foundation 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. TTY: (866) 411-1010 Ultrasound in utero from IV-6 (A). This condition causes mutations in genes that produce a specific type of collagen. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Plaisier E, Ronco P. COL4A1-Related Disorders. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for 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. doi: 10.1136/jmg.2005.035584, 15. What are the different ways a genetic condition can be inherited? Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. (2015) 17:40524. 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). The information on this site should not be used as a substitute for professional medical care or advice. (No doctor had ever taken a call on their lunch break to speak with me). When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Nearly half of these participants were diagnosed with infantile spasms. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. my mom suggested we call Boston Childrens Hospital. The surgery (1987) 8:4216. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. The number of genes implicated in epilepsy has grown rapidly in the past decade. I cannot describe the feeling of seeing your child healed. Seattle, WA: University of Washington, Seattle; 1993-. 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. Am J Neuroradiol. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. Lanfranconi S, Markus HS. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. Clin Neurol Neurosurg. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Six alpha chains of type IV. 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%). N Engl J Med. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Ann Recent findings: 1A-B). The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Epub 2010 Jun 17. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. doi: 10.1002/ajmg.10452, 18. Our review highlights that COL4A1 mutations can present for the first time in adult life with features of cerebral SVD, including subcortical hemorrhage and ischemic stroke, . In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. Unable to load your collection due to an error, Unable to load your delegates due to an error. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. When we didnt feel we had any options left for treatment, Bull Acad Natl Med. Probands' father had severe hypermetropia and bilateral cataracts. eCollection 2022. 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. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. The risk is the same for males and females. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. 2010;17(13):1317-24. doi: When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. In the brain, intracerebral hemorrhage is the most frequent phenotype. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. (2015) 17:84353. sharing sensitive information, make sure youre on a federal (2007) 357:268795. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). Figure 3. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. 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. Graefe's Arch Clin Exp Ophthalmol. doi: 10.1126/science.1109418, 5. Migraines can occur with or without aura. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease.