She also showed severe hypermetropia. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. doi: 10.1007/s00417-014-2800-6, 12. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. The COL4A2 test was negative. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. 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). 55 Kenosia Avenue For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). (2017) 377:111931. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Ophthalmological features associated with COL4A1 mutations. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Quincy, MA 02169 Going from having seizures every day for six years to having no seizures is nothing short of a miracle. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. Bone. In affected individuals, stroke is usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke), although either type can occur. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: In the brain, intracerebral hemorrhage is the most frequent phenotype. 2009 Jun 25 [Updated 2016 Jul 7]. percent confident in Dr. Madsen and the epilepsy team. 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. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Stroke is a leading cause of death and serious long-term disability in developed nations. Unable to load your collection due to an error, Unable to load your delegates due to an error. doi: 10.1001/archneur.1983.04050080067013, 17. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Phone: 202-588-5700. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. Migraines can occur with or without aura. September 2003. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Clin Neurol Neurosurg. Eur J Paediatr Neurol. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. 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). Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. January 31, 2019 Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). Autosomal Dominant Brain Small Vessel Disease. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Ann When these ropes are secreted, they assemble into net-like structures outside the cells. (2005) 308:116771. The .gov means its official. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. 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. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Please enable it to take advantage of the complete set of features! It affects mainly young adults, children and more typically neonates. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. doi: 10.1111/cge.12543. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. It is important to discuss these concepts with a genetic counselor and understand their implications. Arch Ophthalmol. Type IV collagen molecules attach to each other to form complex protein networks. How can gene variants affect health and development? (2010) 14:1827. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. Genetic counseling will be proposed when IV-3 and IV-6 intend to start a family as there is a 50% risk of mutation transmission to the next generation and potential obstetrical complications. eCollection 2022 Nov 8. Accessibility IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. 1A-B). COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. 10.2174/092986710790936293. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant thus, Gould Syndrome is considered Autosomal Dominant. COL4A1 is an essential component for basal membrane stability and exon mutations of COL4A1 gene mutations are responsible for a broad spectrum of systemic manifestations characterized by small vessel involvement of variable severity, including neurological (1) [porencephaly (24), hemorrhage (2, 57) and aneurysms (8)], ophthalmological (912) (retinal artery tortuosity, Axenfeld Rieger anomalies, cataracts, and severe hypermetropia), renal (13) (renal cysts, and microscopic hematuria), and systemic (13) findings (cramps with a high creatine kinase level [CK], Raynaud's phenomenon, and arrhythmias). No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. 10.1161/STROKEAHA.110.581918. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. Dev Med Child Neurol. She has regular physical, speech, and occupational therapy. doi: 10.1212/WNL.0000000000000837, 20. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. What does it mean if a disorder seems to run in my 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. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. and transmitted securely. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Figure 3. doi: 10.1212/WNL.0000000000001309, 8. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. doi: 10.1212/01.WNL.0000123113.46672.68, 25. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. 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. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. How can gene variants affect health and development? Muscle cramps can be spontaneous or triggered by exercise. Neurology. Disease Overview. We are a registered 501(c)3 Nonprofit dedicated to providing hope and help to children and adults with Gould Syndrome; affecting COL4A1 and COL4A2 genes. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Neurol. 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. This group rarely survives beyond 2 years. Prenatal clinical manifestations in individuals with COL4A1/2 variants. doi: 10.1002/ana.23736, 4. About half of people with this condition 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). The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Phone: 617-249-7300, Danbury, CT office In the human genome, there are 46 chromosomes. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. 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. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). Genet Med. The information on this site should not be used as a substitute for professional medical care or advice. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. 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.
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