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Contact a health care provider if you have questions about your health. Finding the best care for Zeeva - Boston Children's Answers 30. BMC Med Genet. Neurol. 2010;41:e513-518. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Early intervention is important in ensuring that children with reach their highest potential. Matrix Biol. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Changing lives of those with rare disease. When these ropes are secreted, they assemble into net-like structures outside the cells. INTERNET PS: wrote thi paper and performed the review of the literature under the supervision of GN. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. doi: 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. doi: 10.1111/j.1469-8749.2011.04198.x, 26. COL4A1 is an essential component for basal membrane stability. If either parent also carries the mutation, it is considered inherited. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Am J Neuroradiol. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories. Phone: 202-588-5700. Gould Syndrome is an ultra rare genetic, multi-system disorder. Neurology. (2010) 75:7479. Muscle cramps can be spontaneous or triggered by exercise. J Neurol Sci. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. (2014) 252:178994. 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. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Your support helps to ensure everyones free access to NORDs rare disease reports. doi: 10.1001/archneur.1983.04050080067013, 17. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. Copyright 2023 by Gould Syndrome Foundation -. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Phone: 617-249-7300, Danbury, CT office The disorder causes many symptoms, not the least of which are strokes and epilepsy. Epub 2014 Jan 5. 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. doi: 10.1016/j.ejpn.2009.04.010, 27. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Thats not to say Zeeva hasnt had to work hard since the surgery. Contact a health care provider if you have questions about your health. PMC An official website of the United States government. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Suite 310 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . COL4A1 mutations in patients with sporadic late-onset intracerebral 4 Both . doi: 10.1212/WNL.0b013e3181c3fd12, 9. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date. doi: 10.1007/s10897-008-9169-9, 16. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. Federal government websites often end in .gov or .mil. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. government site. 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). Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 2010 Aug;41(8):e513-8. (2017) 377:111931. small vessel disease: a systematic review. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. mutations: a novel genetic multisystem disease. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. This page is currently unavailable. Collagen type IV alpha 1 (COL4A1) silence hampers the invasion, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cells through blocking Hedgehog signaling pathway. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. 1779 Massachusetts Avenue Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. 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. 128:4839. To use the sharing features on this page, please enable JavaScript. 2011 Summary: Danbury, CT 06810 Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. (2018) 91:e207888. Quincy, MA 02169 Curr Opin Neurol. 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. The information on this site should not be used as a substitute for professional medical care or advice. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) 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. The signs and symptoms can manifest at almost any age from before birth to old age. doi: 10.1001/archophthalmol.2010.42, 10. People with HANAC syndrome develop kidney disease (nephropathy). MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Acute urinary retention due to a novel collagen COL4A1 mutation. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Affected individuals may have no observable symptoms or only isolated migraines with aura. The first time he came to meet us, Zeeva threw a sock at him. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. doi: 10.1111/cge.12379, 13. Neurologic phenotypes associated with COL4A1/2 mutations 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). 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Progressive cerebral atrophies in three children with COL4A1 mutations. Fetal intracerebral hemorrhage and cataract: think COL4A1. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Bookshelf The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. Genet Med. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. https://www.ncbi.nlm.nih.gov/pubmed/26610912. Unauthorized use of these marks is strictly prohibited. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. (No doctor had ever taken a call on their lunch break to speak with me). 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. 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. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Dev Med Child Neurol. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Six alpha chains of type IV. Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus This site needs JavaScript to work properly. for the triple helical CB3[IV] domain. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. Lenses corrected for hypermetropia. Cephalic Disorders Fact Sheet. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. Stroke is a leading cause of death and serious long-term disability in developed nations. Am J Med Genet A. In most people, small vessel disease in the brain does not cause symptoms. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. eCollection 2021. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. When we didnt feel we had any options left for treatment, It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. What does it mean if a disorder seems to run in my family? COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. The site is secure. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. In the brain, intracerebral hemorrhage is the most frequent phenotype. Clinical spectrum of type IV collagen (COL4A1) mutations: a novel People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Sue. 1900 Crown Colony Drive The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Purpose of review: View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Front Aging Neurosci. Ophthalmological features associated with COL4A1 mutations. 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 Neurology. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. 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. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. 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. 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. COL4A1 Mutations Cause Neuromuscular Disease with - ScienceDirect Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. 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). J Med Genet. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. What does it mean to have a COL4A1 - Little Braveheart | Facebook This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. Neurology. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. 2008 May;192(5):971-84; discussion 984-6. 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. His bedside manner was incredible. doi: 10.1056/NEJMoa1707914, 6. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. GeneReviews. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. 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. (2006) 43:4905. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). (2017) 5758:2944. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. 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). Migraines can occur with or without aura. Dr. Madsen suggested Zeeva have an operation called a J Perinatol. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. Autosomal Dominant Familial Porencephaly Type I. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. When this enzyme is elevated, it is a sign of muscle damage. How can gene variants affect health and development? What is the prognosis of a genetic condition? (2011) 42:13. Careers. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. What is the prognosis of a genetic condition? MeSH 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. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Collagen, type IV, alpha 1 - Wikipedia Genet Med. 2011 Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. doi: 10.1016/j.matbio.2016.10.003, 23. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. 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. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. 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. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. doi: 10.1038/gim.2014.210, 3. Therapies are based on the specific symptoms in each individual. 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. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. She, then, developed seizures which were controlled by valproic acid. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. 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. Hum Mol Genet. 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. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Would you like email updates of new search results? Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. 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). Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Mutations in the COL4A1 gene cause HANAC syndrome. National Taiwan University Hospital, Taiwan, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Carrera de Medicina, Universidad Cientfica del Sur, Peru, Federal University of Rio Grande do Sul, Brazil. 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. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. doi: 10.1002/ana.23736, 4. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Disclaimer. Neurology. Bethesda, MD 20894, Web Policies Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. This group rarely survives beyond 2 years. Understanding what it has taken to get her to this point, though, is close to unimaginable. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). 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. 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. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Neurology. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: