functional hemispherectomy. Ann COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Please note that NORD provides this information for the benefit of the rare disease community. 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. January 31, 2019 In the brain, intracerebral hemorrhage is the most frequent phenotype. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. Your support helps to ensure everyones free access to NORDs rare disease reports. 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. 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). Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. The information on this site should not be used as a substitute for professional medical care or advice. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Purpose of review: Genet Med. Science. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. In the human genome, there are 46 chromosomes. Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects). Front Aging Neurosci. (2002) 112:198202. Plaisier E, Ronco P. COL4A1-Related Disorders. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. IV-3 was diagnosed with ventriculomegaly in utero. 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. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. mutations: a novel genetic multisystem disease. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. 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. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). 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. doi: 10.1111/cge.12379, 13. Contact a health care provider if you have questions about your health. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. doi: 10.1038/nmeth.2890, 22. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Last updated: Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). Firstly, it segregates within the family with the phenotype. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, 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 . However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures, and a shunt to treat hydrocephalus by draining excess fluid from the skull. It is passed through families in a autosomal dominant fashion. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. 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. It is not uncommon for an unaffected parent to have a severely affected child. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, 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. 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. N Engl J Med. 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 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. Stroke. 2011 Neurology. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . doi: 10.1002/ana.23736, 4. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. 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. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES 30. 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. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. came with risks and was the hardest decision we had ever faced, yet we felt 100 eCollection 2021. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. 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). Figure 3. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. doi: 10.1212/WNL.0b013e3181eee440, 28. A diagnosis can be confirmed through molecular genetic testing. II-2 had a limp since childhood attributed to forceps delivery. (2005) 308:116771. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. . One patient (IV-3) was treated for spasticity and seizures with valproic acid. doi: 10.1111/j.1469-8749.2011.04198.x, 26. Summary: Various muscles can be affected and muscle strength can become weakened. Ann Neurol. 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. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. Facebook: https://www.facebook.com/Col4A1Foundation Please Note Copyright 2023 by Gould Syndrome Foundation -. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. 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). Years published: 2019. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Resource(s) for Medical Professionals and Scientists on This Disease: 2010 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. 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. These genes are the blueprints for two proteins that wind together like a long rope inside cells. Teaching families how to advocate for their loved ones and access medical information. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. doi: Cereb Circ Cogn Behav. Lenses corrected for hypermetropia. Acute urinary retention due to a novel collagen COL4A1 mutation. Further refinement of COL4A1 and COL4A2 related cortical malformations. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. 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). Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Neurology. Curr Opin Neurol. (2018) 91:e207888. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. At least 50 individuals with this condition have been described in the scientific literature. ACS Omega. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Suite 310 J Perinatol. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Neuropediatrics. So far, it appears as though mutations in COL4A1 and COL4A2 lead to identical disease, however, for reasons that are not yet understood, mutations in COL4A2 are much less frequent than those in COL4A1. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Migraines can occur with or without aura. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). 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. 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). 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. doi: 10.1056/NEJMoa071906, 14. While there are other explanations, parental mosaicism should be considered. 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. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Neurology. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. Axenfeld-Rieger anomaly and cataract can cause impaired vision. Childhood presentation of COL4A1 mutations. Changing lives of those with rare disease. doi: 10.1002/ajmg.10452, 18. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Contact a health care provider if you have questions about your health. doi: 10.1126/science.1109418, 5. The information on this site should not be used as a substitute for professional medical care or advice. Genet Med. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Dev Med Child Neurol. His bedside manner was incredible. 4 Both . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. 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). 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. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. 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. Fax: 203-263-9938, Washington, DC Office mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al.