III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Am J Neuroradiol. 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. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. This site needs JavaScript to work properly. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. TTY: (866) 411-1010 Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Arch Ophthalmol. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. J Perinatol. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. N Engl J Med. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Jeanne M, Gould DB. Epub 2022 Apr 14. FOIA Internet. 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 are caused by dominant mutations in the COL4A1 or COL4A2 genes. Hum Mol Genet. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Further refinement of COL4A1 and COL4A2 related cortical malformations. To use the sharing features on this page, please enable JavaScript. Neurology. (2018) 91:e207888. The https:// ensures that you are connecting to the It affects mainly young adults, children and more typically neonates. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. 1779 Massachusetts Avenue I cannot describe the feeling of seeing your child healed. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). COL4A1 Syndrome CADASIL Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. 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, . Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Resource(s) for Medical Professionals and Scientists on This Disease: Matrix Biol. (2010) 14:1827. Six alpha chains of type IV. A diagnosis can be confirmed through molecular genetic testing. doi: Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 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. 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). She has regular physical, speech, and occupational therapy. Copyright 2023 by Gould Syndrome Foundation -. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, In most people, small vessel disease in the brain does not cause symptoms. 2018;91:e2078-e2088. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. 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. 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. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. HANAC syndrome is caused by genetic changes in the COL4A1 gene. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Not only did Dr. Madsen, help heal Zeevas brain, but he was instrumental in supporting us as we founded the Gould Syndrome Foundation, a 501(c)(3) non-profit that promotes education, advocacy, and medical advancements in Gould Syndrome, COL4A1/COL4A2 diseases. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. (1987) 8:4216. 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. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. It is passed through families in a autosomal dominant fashion. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. Accessibility The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. Molecular analysis in the father disclosed a heterozygous variant c.2228G>T (p.Gly743Val) in exon 30 of the COL4A1 gene that segregated with the phenotype. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. (18) and Staals et al. Congenital Cephalic Disorders In addition to porencephaly there can be other forms of damage to the brain present at birth. (2006) 43:4905. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. 1A-B). Ann Neurol. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. 2010;17(13):1317-24. doi: Neurology. Ann Neurol. Would you like email updates of new search results? Please enable it to take advantage of the complete set of features! Before Careers. Unable to load your collection due to an error, Unable to load your delegates due to an error. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Purpose of review: Nat Methods. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. 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. https://www.ncbi.nlm.nih.gov/pubmed/26610912. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. His bedside manner was incredible. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. Keywords: COL4A1, Type IV collagen, familial porencephaly, ocular malformations, variable expressivity, Citation: Scoppettuolo P, Ligot N, Wermenbol V, Van Bogaert P and Naeije G (2020) p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Porencephaly and Severe Hypermetropia. Maybe try a search? HANAC syndrome is a rare condition, although the exact prevalence is unknown. 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. When these ropes are secreted, they assemble into net-like structures outside the cells. How are genetic conditions treated or managed? 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 At least 50 individuals with this condition have been described in the scientific literature. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role 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). Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) 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. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. doi: 10.1056/NEJMoa071906, 14. Federal government websites often end in .gov or .mil. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. Doctors and researchers to bring research and medical therapeutic options to those affected. The COL4A2 test was negative. Surgery may be necessary for individuals with severe cataracts. Berg R, Aleck A, Kaplan A. Familial porencephaly. Neurology. 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). These genes are the blueprints for two proteins that wind together like a long rope inside cells. 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). Neurology. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. The site is secure. When we didnt feel we had any options left for treatment, The size and location of cerebral cavities contributes to clinical variability. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. Suite 500 (2007) 357:268795. 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). Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. 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. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. It is important to discuss these concepts with a genetic counselor and understand their implications. doi: 10.1212/01.WNL.0000123113.46672.68, 25. By continuing to use this website, you agree to the Terms of Service & Privacy Policy, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. 2011 Fetal intracerebral hemorrhage and cataract: think COL4A1. II-2 had a limp since childhood attributed to forceps delivery. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, 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. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. 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. MedlinePlus also links to health information from non-government Web sites. NORD strives to open new assistance programs as funding allows. J Genet Couns. government site. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. 1900 Crown Colony Drive Pediatr Neurol. The COL4A1 stroke syndrome. Gould Syndrome is a rare, genetic, multi-system disorder. doi: 10.1111/j.1469-8749.2011.04198.x, 26. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. (2002) 112:198202. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. Phone: 203-263-9938 Axenfeld-Rieger anomaly and cataract can cause impaired vision. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. doi: 10.1007/s10897-008-9169-9, 16. 30. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. What does it mean to have a COL4A1 gene mutation: The COL4A1 gene provides instructions for making one component of type IV collagen, which is a flexible protein important in the structure of many. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). However, there are exceptions that depend on precisely when and where the mutation arose. doi: 10.1007/s00417-014-2800-6, 12. The risk is the same for males and females. 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). Epub 2014 Jan 5. Neurology. Clin Genet. doi: 10.1212/WNL.0b013e3181c3fd12, 9. Years published: 2019. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. 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. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. Gould Syndrome is an ultra rare genetic, multi-system disorder. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. 1900 Crown Colony Drive Suite 500 The first time he came to meet us, Zeeva threw a sock at him. MedlinePlus also links to health information from non-government Web sites. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Prenatal clinical manifestations in individuals with COL4A1/2 variants. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. The .gov means its official. Quincy, MA 02169 COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Recent findings: Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. 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. Therapies are based on the specific symptoms in each individual. How can gene variants affect health and development? Type IV collagen molecules attach to each other to form complex protein networks. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. Danbury, CT 06810 (2005) 308:116771. Antiinflammatory therapy with canakinumab for atherosclerotic disease. As a result, the skin around the affected area may turn white or blue for a brief period of time and the area may tingle or throb. 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. 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. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. 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). Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Patients must rely on the personal and individualized medical advice of their qualified health care professionals before seeking any information related to their particular diagnosis, cure or treatment of a condition or disorder. People listened to us and to Zeeva in a very different and proactive way. 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. We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. The COL4A1 and COL4A2 genes were screened in proband IV-6. small vessel disease: a systematic review. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Facebook: https://www.facebook.com/Col4A1Foundation Please Note The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. and transmitted securely. Zagaglia Selch C, Nisevic JR, et al. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. 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).
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