my mom suggested we call Boston Childrens Hospital. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Cereb Circ Cogn Behav. percent confident in Dr. Madsen and the epilepsy team. I cannot describe the feeling of seeing your child healed. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Fax: 203-263-9938, Washington, DC Office Bull Acad Natl Med. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. (E,F) IV-3Brain MRI showed left frontotemporal dilatation and diffusion tensor imaging (DTI) sequences demonstrated no left corticospinal tract (cranio-caudal fibers, indigo, with arrows). Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. PMC 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. It is passed through families in a autosomal dominant fashion. Doctors and researchers to bring research and medical therapeutic options to those affected. N Engl J Med. 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). In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Resource(s) for Medical Professionals and Scientists on This Disease: The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). 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. 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. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Hereditary cerebral small vessel diseases: a review. Unauthorized use of these marks is strictly prohibited. For example, an individual may carry genetic variants elsewhere in their genome that confers protection or susceptibly to the mutation and environmental experiences (trauma, anticoagulant use, physical exertion etc.) 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. IV-3 goes to a normal school, but special schooling is required for IV-6. COL4A1 is an essential component for basal membrane stability. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Front Aging Neurosci. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. (2014) 252:178994. Matrix Biol. doi: 10.1002/ajmg.10452, 18. When we didnt feel we had any options left for treatment, Thats not to say Zeeva hasnt had to work hard since the surgery. People listened to us and to Zeeva in a very different and proactive way. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). The risk is the same for males and females. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. 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. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. These exceptions are nuanced and should be discussed with a genetic counselor. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. 2011 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. Clin Genet. cuts under the microscope. 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). If either parent also carries the mutation, it is considered inherited. 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%). These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Epub 2014 Jan 5. (2008) 23:17. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, January 31, 2019 Gould Syndrome is an ultra rare genetic, multi-system disorder. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. 30. Summary. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. 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. (2015) 88:46873. The disorder causes many symptoms, not the least of which are strokes and epilepsy. ACS Omega. Your support helps to ensure everyones free access to NORDs rare disease reports. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. The COL4A2 test was negative. 2010;17(13):1317-24. doi: One patient (IV-3) was treated for spasticity and seizures with valproic acid. Gould Syndrome is an ultra rare genetic, multi-system disorder. Facebook: https://www.facebook.com/Col4A1Foundation Please Note Changing lives of those with rare disease. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. He would separate the two halves of her brain by Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Disease Overview. The https:// ensures that you are connecting to the 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). III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. 2010 Aug;41(8):e513-8. 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. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. If we dont have a program for you now, please continue to check back with us. Plaisier E, Ronco P. COL4A1-Related Disorders. Am J Neuroradiol. How can gene variants affect health and development? It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. came with risks and was the hardest decision we had ever faced, yet we felt 100 doi: 10.1001/archophthalmol.2010.42, 10. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Acute urinary retention due to a novel collagen COL4A1 mutation. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. How are genetic conditions treated or managed? Most individuals diagnosed with a COL4A1-related disorder have an affected parent. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. doi: 10.1056/NEJMoa071906, 14. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. 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). (2015) 17:40524. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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. Accessibility (No doctor had ever taken a call on their lunch break to speak with me). Neurol. 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. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. 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). (2006) 43:4905. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. Phone: 617-249-7300, Danbury, CT office Dev Med Child Neurol. Unable to load your collection due to an error, Unable to load your delegates due to an error. Painful muscle cramps can occur and can develop before three years of age. 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 . A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. https://www.ncbi.nlm.nih.gov/pubmed/26610912. 10.2174/092986710790936293. Muscle cramps can be spontaneous or triggered by exercise. COL4A1 Syndrome CADASIL COL4A1 and COL4A2 are on Chr. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Bethesda, MD 20894, Web Policies Surgery may be necessary for individuals with severe cataracts. 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). doi: 10.1212/WNL.0000000000001309, 8. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. The information on this site should not be used as a substitute for professional medical care or advice. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. He also wanted to remove a shunt that was implanted in With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. (2008) 17:42433. The information on this site should not be used as a substitute for professional medical care or advice. 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. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. Neurology. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. doi: 10.1007/s10897-008-9169-9, 16. However, there are exceptions that depend on precisely when and where the mutation arose. In most cases, an affected person has one parent with the condition. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. What are the different ways a genetic condition can be inherited? Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Last updated: The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. doi: 10.1038/gim.2014.210, 3. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Six alpha chains of type IV. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Washington, DC 20036 Dr. Madsen suggested Zeeva have an operation called a It affects mainly young adults, children and more typically neonates. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. 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). 10.1161/STROKEAHA.110.581918. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 2017;57-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. 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. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. mutations: a novel genetic multisystem disease. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. The .gov means its official. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Copyright 2023 by Gould Syndrome Foundation -. (2007) 357:268795. Secondly, the p.Gly743Val variant is a missense mutation that shares features with other missense pathogenic mutations that occur in the COL4A1 gene exon 30: congenital porencephaly, epilepsy, and neuropsychological anomalies in p.Gly749Ser (23, 24), ophthalmologic defects and neuropsychological deficits in absence of systemic signs in variant p.Gly755Arg (2527), and antenatal fetal intracerebral hemorrhage, ocular anomalies associated to cerebral leukoencephalopathy in variant p.Gly773Arg (12, 28, 29). We provide education, advocacy, and resources for families and individuals affected. We describe, here, the phenotype of a likely pathologic variant (p.Gly743Val) in exon 30 of the COL4A1 gene, responsible for an oculo-cerebral phenotype characterized by severe hypermetropia and highly penetrant porencephaly in absence of other systemic complications. 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. Ophthalmological features associated with COL4A1 mutations. For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Arch Neurol. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. 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). NORD is a registered 501(c)(3) charity organization. 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. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Matrix Biol. 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 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. doi: 10.1212/01.WNL.0000123113.46672.68, 25. 8600 Rockville Pike Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Congenital Cephalic Disorders For instance, retinal arteriolar tortuosity relates to mutations in the amino-terminal one-third of the protein while mutations causing cataracts and ocular morphologic alterations are more likely to occur, closer to the carboxy terminus (22), like the variant we report. government site. Bone. 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. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. HHS Vulnerability Disclosure, Help One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). Standardized (15) familiar pedigree is showed in Figure 1. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Maybe try a search? In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. sharing sensitive information, make sure youre on a federal Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. (2010). 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. It is important to discuss these concepts with a genetic counselor and understand their implications. doi: 10.1111/cge.12379, 13. 2009 Jun 25 [updated 2016 Jul 7]. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. NORD is a registered 501(c)(3) charity organization. functional hemispherectomy. Individuals with HANAC syndrome also experience a variety of eye problems. Contact a health care provider if you have questions about your health. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Quincy, MA 02169 Neurology. 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.
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