col4a1 syndrome life expectancy col4a1 syndrome life expectancy

In most people, small vessel disease in the brain does not cause symptoms. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). (No doctor had ever taken a call on their lunch break to speak with me). J Neurol Sci. doi: 10.1038/nmeth.2890, 22. 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 age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Arch Neurol. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. can also contribute. What are the different ways a genetic condition can be inherited? Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Dev Med Child Neurol. (2010) 14:1827. Clin Neurol Neurosurg. Lanfranconi S, Markus HS. doi: 10.1212/01.WNL.0000123113.46672.68, 25. One patient (IV-3) was treated for spasticity and seizures with valproic acid. (1982) 40:5679. for the triple helical CB3[IV] domain. No use, distribution or reproduction is permitted which does not comply with these terms. Smoking, which also increases the risk of stroke, physical activities that can cause head trauma such as contact sports, and the use of anti-clotting (anticoagulant) medications, should be avoided. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. 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. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. No microbleeds or cystic cavities were found. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. We describe here the phenotype of a likely pathogenic gene variant, p.Gly743Val, which is responsible for a missense mutation in the COL4A1 gene exon 30 in a three generation family with severe hypermetropia and highly penetrant porencephaly in the absence of systemic manifestations. He smiled, caught it, and asked Zeeva if he could throw it back. Please note that NORD provides this information for the benefit of the rare disease community. This condition causes mutations in genes that produce a specific type of collagen. Disclaimer. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Progressive cerebral atrophies in three children with COL4A1 mutations. Quincy, MA 02169 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). IV-3 and IV-6 are closely followed by a neuropediatrician (VW). 1779 Massachusetts Avenue It is important to discuss these concepts with a genetic counselor and understand their implications. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. COL4A1 mutations as a monogenic cause of cerebral The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. 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). The COL4A1 stroke syndrome. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. 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. While there are other explanations, parental mosaicism should be considered. 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. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. 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. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . 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. 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. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Thats not to say Zeeva hasnt had to work hard since the surgery. 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 ( 2 - 4 ), hemorrhage ( 2, 5 - 7) and aneurysms ( 8 )], ophthalmological Bone. HANAC syndrome is caused by genetic changes in the COL4A1 gene. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: The https:// ensures that you are connecting to the Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. doi: 10.1056/NEJMoa1707914, 6. NORD is not a medical provider or health care facility and thus can neither diagnose any disease or disorder nor endorse or recommend any specific medical treatments. 55 Kenosia Avenue Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. Nearly half of these participants were diagnosed with infantile spasms. 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 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. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. 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. (2006) 43:4905. Any muscle may be affected, and cramps usually last from a few seconds to a few minutes, although in some cases they can last for several hours. 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. Summary: Doctors and researchers to bring research and medical therapeutic options to those affected. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. 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). Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Epub 2014 Jan 5. NORD is a registered 501(c)(3) charity organization. (2014) 34:757. came with risks and was the hardest decision we had ever faced, yet we felt 100 doi: 10.1056/NEJMoa053727, 7. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. functional hemispherectomy. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Purpose of review: Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. 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. 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. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. People with HANAC syndrome develop kidney disease (nephropathy). The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. (2015) 84:91826. It is ubiquitously expressed in many tissues and cell types. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. It looks like nothing was found at this location. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Arch Ophthalmol. The retina is the light-sensitive membrane that lines the inside of the eyes. GeneReviews. 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. Phone: 203-263-9938 Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. There are 28 different types of collagen in your body and mutations in the genes that encode these proteins lead to multiple, highly diverse diseases. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. seizure activity. 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). Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. Neurology. 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. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). Neuropediatrics. 2009 Jun 25 [updated 2016 Jul 7]. 1A-B). Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Therapies are based on the specific symptoms in each individual. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. Pediatr Neurol. COL4A1/A2-related disorders are dominant genetic disorders. Bull Acad Natl Med. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. 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%). Eur J Med Genet. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Neurol. This site needs JavaScript to work properly. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Migraines can occur with or without aura. Epub 2010 Jun 17. When we didnt feel we had any options left for treatment, Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. 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. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. II-2 had a limp since childhood attributed to forceps delivery. Clinically, COL4A1 mutations are responsible for different overlapping phenotypes including porencephaly (24), brain small vessel disease (2, 57) with or without ocular anomalies, HANAC (13) (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome, ophthalmological abnormalities (912), and non-syndromic autosomal dominant congenital cataracts (10). Suite 310 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. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. (2020). (2006) 354:148996. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. 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. To use the sharing features on this page, please enable JavaScript. Gould Syndrome is an ultra rare genetic, multi-system disorder. (2008) 23:17. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. N Engl J Med. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). Phone: 617-249-7300, Danbury, CT office Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Hum Mol Genet. 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. 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. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. 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. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . 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. To use the sharing features on this page, please enable JavaScript. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. This condition causes mutations in genes that produce a specific type of collagen. PS: wrote thi paper and performed the review of the literature under the supervision of GN. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. In the human genome, there are 46 chromosomes. official website and that any information you provide is encrypted COL4A1 is an essential component for basal membrane stability. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Axenfeld-Rieger anomaly and cataract can cause impaired vision. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. 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. The information on this site should not be used as a substitute for professional medical care or advice. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. NORD is a registered 501(c)(3) charity organization. Genet Med. NORD strives to open new assistance programs as funding allows. How can gene variants affect health and development? doi: 10.1002/ajmg.10452, 18. 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 . Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. 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. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. 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. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. 8600 Rockville Pike Federal government websites often end in .gov or .mil. COL4A1 brain small-vessel disease is an autosomal dominant condition resulting from a mutation to the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen 1-6. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Firstly, it segregates within the family with the phenotype. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. my mom suggested we call Boston Childrens Hospital. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. Clinical Testing and Workup 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. 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. 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. 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.