Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Accessibility Quincy, MA 02169 The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. 2011 What does it mean if a disorder seems to run in my family? Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. 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. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Gould Syndrome is an ultra rare genetic, multi-system disorder. 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). Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. Arch Ophthalmol. Please enable it to take advantage of the complete set of features! official website and that any information you provide is encrypted Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. 1779 Massachusetts Avenue Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 PV and VW followed the children at the Neuropediatrics clinic of the same hospital. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network. 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. For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: Toll-free: (800) 411-1222 This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Six alpha chains of type IV. 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. In people with HANAC syndrome, angiopathy affects several parts of the body. 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. 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. An official website of the United States government. 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. Before Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and 128:4839. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. COL4A1/A2-related disorders are dominant genetic disorders. (2014) 34:757. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. He smiled, caught it, and asked Zeeva if he could throw it back. (2005) 308:116771. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 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). Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Your support helps to ensure everyones free access to NORDs rare disease reports. Ultrasound in utero from IV-6 (A). Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Neurology. There are no standardized treatment protocols or guidelines for affected individuals. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. (2011) 42:13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. Fetal intracerebral hemorrhage and cataract: think COL4A1. Phone: 203-263-9938 The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, In most cases, an affected person has one parent with the condition. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. doi: 10.1212/WNL.0b013e3181c3fd12, 9. To better define pathology caused by Col4a1 mutations, we characterized myopathy in two different Col4a1 mutant mouse strainsCol4a1 ex41 and Col4a1 G394V.We selected these strains from an allelic series of Col4a1 mutant mice because they showed the most severe myopathy according to NPN quantification in quadriceps while having different effects on [1(IV)] 2 2(IV) secretion. my mom suggested we call Boston Childrens Hospital. 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. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. eCollection 2022. Washington, DC 20036 Individuals with HANAC syndrome also experience a variety of eye problems. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Matrix Biol. 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). J Neurol Sci. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps 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. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. 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. NORD is a registered 501(c)(3) charity organization. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. 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. 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. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. doi: 10.1038/gim.2015.30, 21. NORD strives to open new assistance programs as funding allows. 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. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. IV-3 goes to a normal school, but special schooling is required for IV-6. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) 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. Zeevas brain to treat a cyst in her brain caused by porencephaly. Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization Ann Neurol. J Med Genet. HANAC syndrome is a rare condition, although the exact prevalence is unknown. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Understanding what it has taken to get her to this point, though, is close to unimaginable. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. When these ropes are secreted, they assemble into net-like structures outside the cells. A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium). In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Resource(s) for Medical Professionals and Scientists on This Disease: This page is currently unavailable. https://www.ncbi.nlm.nih.gov/pubmed/26610912. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Congenital Cephalic Disorders Curr Opin Neurol. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Am J Med Genet. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Internet. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Copyright 2023 by Gould Syndrome Foundation -. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Changing lives of those with rare disease. Bookshelf Front Aging Neurosci. COL4A1 -Related Disorders - PubMed Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Agenesis of the Corpus Callosum | National Institute of Neurological People with HANAC syndrome develop kidney disease (nephropathy). One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. 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. Autosomal Dominant Brain Small Vessel Disease. The disorder causes many symptoms, not the least of which are strokes and epilepsy. (19). Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Neurology. COL4A1 is an essential component for basal membrane stability. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDs mission. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. and transmitted securely. CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. Migraines can occur with or without aura. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Gould Syndrome is a rare, genetic, multi-system disorder. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. She has regular physical, speech, and occupational therapy. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). (2017) 377:111931. Disease Overview. doi: 10.1002/ana.23736, 4. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. 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: doi: 10.1001/archophthalmol.2010.42, 10. Probands' father had severe hypermetropia and bilateral cataracts. How are genetic conditions treated or managed? Neurol. 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). eCollection 2022 Nov 8. Summary. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. The .gov means its official. Various muscles can be affected and muscle strength can become weakened. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. The site is secure. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Other patients have been reported with cysts on the liver, irregular heartbeats (supraventricular arrhythmia), and Raynaud phenomenon, which is in which the fingers or toes become numb or have a prickly sensation in response to cold due to narrowing of blood vessels. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0.