The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. When we didnt feel we had any options left for treatment, Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Plaisier E, Ronco P. COL4A1-Related Disorders. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. He would separate the two halves of her brain by Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Therapies are based on the specific symptoms in each individual. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. Stroke. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. (2010) 14:1827. In the human genome, there are 46 chromosomes. 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. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Summary. Fax: 203-263-9938, Washington, DC Office 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. 128:4839. 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. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Recent findings: The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. 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). Neurol. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. 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). Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. 55 Kenosia Avenue (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Gould Syndrome is an ultra rare genetic, multi-system disorder. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Jeanne M, Gould DB. 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. COL4A1 mutations in patients with sporadic late-onset intracerebral She has regular physical, speech, and occupational therapy. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. COL4A1-related brain small-vessel disease - MedlinePlus my mom suggested we call Boston Childrens Hospital. Facebook: https://www.facebook.com/Col4A1Foundation Please Note 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. These exceptions are nuanced and should be discussed with a genetic counselor. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. The signs and symptoms can manifest at almost any age from before birth to old age. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Pediatr Neurol. People listened to us and to Zeeva in a very different and proactive way. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. HHS Vulnerability Disclosure, Help J Neurol Sci. doi: 10.1056/NEJMoa1707914, 6. (2009) 73:187382. doi: 10.1055/s-0031-1275343, 24. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Clinical spectrum of type IV collagen (COL4A1) mutations: a novel Figure 3. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Ann Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Epub 2014 Jan 5. https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, For information about clinical trials sponsored by private sources, contact: This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. If either parent also carries the mutation, it is considered inherited. sharing sensitive information, make sure youre on a federal 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). 8600 Rockville Pike Curr Med Chem. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Gould Syndrome is an ultra rare genetic, multi-system disorder. I cannot describe the feeling of seeing your child healed. In addition to porencephaly there can be other forms of damage to the brain present at birth. 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. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Dr. Madsen suggested Zeeva have an operation called a After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Summary: Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. 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. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. This site needs JavaScript to work properly. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. doi: 10.1136/jmg.2005.035584, 15. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). 1779 Massachusetts Avenue There are no standardized treatment protocols or guidelines for affected individuals. Six alpha chains of type IV. 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. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Dev Med Child Neurol. 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%). Danbury, CT 06810 Quincy, MA 02169 (2014) 11:3612. Agenesis of the Corpus Callosum | National Institute of Neurological 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). Last updated: The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. FOIA Orphanet: 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. In the human genome, there are 46 chromosomes. In the brain, intracerebral hemorrhage is the most frequent phenotype. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation Gould Syndrome Foundation 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. He smiled, caught it, and asked Zeeva if he could throw it back. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 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, . A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Type IV collagen molecules attach to each other to form complex protein networks. What are the different ways a genetic condition can be inherited? Genet Med. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Firstly, it segregates within the family with the phenotype. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. 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. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. 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. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. PS: wrote thi paper and performed the review of the literature under the supervision of GN. Maybe try a search? Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies, https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, https://www.ncbi.nlm.nih.gov/pubmed/28254515, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, https://www.nature.com/articles/gim2014210, https://www.ncbi.nlm.nih.gov/pubmed/23225343, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, https://www.ncbi.nlm.nih.gov/pubmed/22868088, https://www.ncbi.nlm.nih.gov/pubmed/22574627, https://www.ncbi.nlm.nih.gov/pubmed/20558831, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, https://www.ncbi.nlm.nih.gov/pubmed/26610912, https://www.ncbi.nlm.nih.gov/books/NBK7046/, https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet, https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/, https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/, https://rarediseases.org/patient-assistance-programs/caregiver-respite/, Learn more about Patient Assistance Programs >, Arginine: Glycine Amidinotransferase Deficiency, https://rarediseases.org/non-member-patient/epilepsy-foundation/, Gould Syndrome Foundation (COL4a1/COL4A2), https://rarediseases.org/non-member-patient/gould-syndrome-foundation-col4a1-col4a2/, https://rarediseases.org/non-member-patient/national-kidney-foundation/, https://rarediseases.org/non-member-patient/nih-national-eye-institute/, NIH/National Institute of Neurological Disorders and Stroke, Aromatic L-Amino Acid Decarboxylase Deficiency, https://rarediseases.org/non-member-patient/nih-national-institute-of-neurological-disorders-and-stroke/, https://rarediseases.org/non-member-patient/the-arc/, Learn more about Patient Organization & Membership >, HANAC: hereditary angiopathy, nephropathy and cramps syndrome (OMIM #611773), POREN1: autosomal dominant type 1 porencephaly; porencephaly with infantile hemiplegia (OMIM #175780, RATOR: retinal arterial tortuosity (OMIM #180000), BSVD: brain small vessel disease with or without ocular anomalies (OMIM #607595), ICH: susceptibility to intracerebral hemorrhage (OMIM #614519). 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. 11:827. doi: 10.3389/fneur.2020.00827. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. doi: 10.1016/j.matbio.2016.10.003, 23. The site is secure. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. HANAC syndrome is a rare condition, although the exact prevalence is unknown. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. What is the prognosis of a genetic condition? NCI CPTC Antibody Characterization Program. small vessel disease: a systematic review. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). 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. (2005) 308:116771. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. The first time he came to meet us, Zeeva threw a sock at him. 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). Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. This is called genotype-phenotype correlation. The surgery Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization Fetal intracerebral hemorrhage and cataract: think COL4A1. 2010;17(13):1317-24. doi: (2013) 73:4857. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles.
The Knightstrider Tenerife Latest News,
Container Homes Companies,
Phil Harding Time Team Married,
Studio Apartments In Crescent City, Ca,
Sunrise Church Rialto Pastor,
Articles C