With input from doctors, researchers, and the US Food & Drug Administration, NORD has created IAMRARE to facilitate patient-powered natural history studies to shape rare disease research and treatments. (2010). Orphanet: HANAC syndrome Suite 500 Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. In addition to porencephaly there can be other forms of damage to the brain present at birth. 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, . Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. doi: For example, an individual may carry genetic variants elsewhere in their genome that confers protection or susceptibly to the mutation and environmental experiences (trauma, anticoagulant use, physical exertion etc.) 2010 NCI CPTC Antibody Characterization Program. MedlinePlus also links to health information from non-government Web sites. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 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). Rarely, new mutations in the gene occur in people with no history of the disorder in their family. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Lanfranconi S, Markus HS. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. The COL4A2 test was negative. 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. Clipboard, Search History, and several other advanced features are temporarily unavailable. People listened to us and to Zeeva in a very different and proactive way. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. 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. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. doi: 10.1111/j.1469-8749.2011.04198.x, 26. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). 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). The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. COL4A1 mutations as a monogenic cause of cerebral The main symptom is single or repeated bleeding inside the skull (intracranial hemorrhaging) that can occur without cause (spontaneously), after trauma, or when taking drugs that slow blood clotting (anticoagulants). The severity of the condition varies greatly among affected individuals. Migraines can occur with or without aura. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. Changing lives of those with rare disease. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Eur J Med Genet. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. (2017) 5758:2944. Ultrasound in utero from IV-6 (A). COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Type IV collagen networks play an important role in the basement membranes in virtually all tissues throughout the body, particularly the basement membranes surrounding the body's blood vessels (vasculature). One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. However, in people with HANAC syndrome, these aneurysms typically do not burst. doi: 10.1002/ajmg.10452, 18. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. (1987) 8:4216. Nearly half of these participants were diagnosed with infantile spasms. Col4a1 mutation generates vascular abnormalities correlated with COL4A1 mutations in patients with sporadic late-onset intracerebral 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. government site. 128:4839. Danbury, CT 06810 the basement membranes surrounding the body's blood vessels, National Organization for Rare Disorders (NORD), BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). His bedside manner was incredible. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. COL4A1 and COL4A2 are on Chr. 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. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Childhood presentation of COL4A1 mutations. Agenesis of the Corpus Callosum | National Institute of Neurological A diagnosis can be confirmed through molecular genetic testing. 4 Both . doi: 10.1016/j.ejpn.2009.04.010, 27. 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%). The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. N Engl J Med. 1. Cavalin M, Mine M, Philbert M, et al. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. . Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. The risk is the same for males and females. doi: 10.1038/gim.2015.30, 21. COL4A1 is an essential component for basal membrane stability. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. 2012;21:R97-R110. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. The https:// ensures that you are connecting to the These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. HANAC syndrome is caused by genetic changes in the COL4A1 gene. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. COL4A1/A2-related disorders are dominant genetic disorders. Collagen, type IV, alpha 1 - Wikipedia 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. Neurology. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Type IV collagen networks play an important role in the basement membranes in virtually all tissues throughout the body, particularly the basement membranes surrounding the body's blood vessels (vasculature). This group rarely survives beyond 2 years. Clin Neurol Neurosurg. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients even among members of a family who carry the same gene mutation. doi: 10.1055/s-0031-1275343, 24. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Nat Methods. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). (2010) 75:7479. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. He also wanted to remove a shunt that was implanted in BMC Med Genet. ClinVar; [VCV000389182.3]. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. IV-3 was diagnosed with ventriculomegaly in utero. percent confident in Dr. Madsen and the epilepsy team. At least six affected families have been described in the scientific literature. He would separate the two halves of her brain by 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. 2010;17(13):1317-24. doi: Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. eCollection 2022 Nov 8. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. Finding the best care for Zeeva - Boston Children's Answers 10.2174/092986710790936293. Autosomal Dominant Brain Small Vessel Disease. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. 1900 Crown Colony Drive (2014) 11:3612. Full ophthalmological evaluations including slit lamp and fundoscopy were realized and disclosed for bilateral hypermetropia in IV-3 [15 dioptre (D)], IV-6 (8.5 D), IV-5 (10 D), and III-3 (7 D). However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. doi: 10.1001/archneur.1983.04050080067013, 17. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. 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. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. sharing sensitive information, make sure youre on a federal Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. 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. doi: 10.1111/cge.12379, 13. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. mutations: a novel genetic multisystem disease. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. 55 Kenosia Avenue Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Doctors and researchers to bring research and medical therapeutic options to those affected. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. However, there are exceptions that depend on precisely when and where the mutation arose. Epub 2022 Apr 14. 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. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. How can gene variants affect health and development? Thats not to say Zeeva hasnt had to work hard since the surgery. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. These genes are the blueprints for two proteins that wind together like a long rope inside cells. Last updated: doi: 10.2214/ajr.149.2.351, 19. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. Congenital Cephalic Disorders Treatment eCollection 2022. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. 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. Bennett RL, French KS, Resta RG, Doyle DL. basement membranes surrounding the body's blood vessels, Genetic Testing Registry: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, National Organization for Rare Disorders (NORD), ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Pathology. Zeevas brain to treat a cyst in her brain caused by porencephaly. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. If either parent also carries the mutation, it is considered inherited. Neurology. Axenfeld-Rieger anomaly and cataract can cause impaired vision. (2005) 308:116771. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.