In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). 55 Kenosia Avenue Various muscles can be affected and muscle strength can become weakened. (2014) 83:122834. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. 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. It affects mainly young adults, children and more typically neonates. Neurology. 30. 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. 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). What does it mean if a disorder seems to run in my family? Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. doi: 10.1055/s-0031-1275343, 24. Summary. 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. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Curr Opin Neurol. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Quincy, MA 02169 Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. January 31, 2019 Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. . COL4A1 and COL4A2 are on Chr. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. The information on this site should not be used as a substitute for professional medical care or advice. An official website of the United States government. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. Hereditary cerebral small vessel diseases: a review. Nat Methods. It is passed through families in a autosomal dominant fashion. doi: 10.1016/j.matbio.2016.10.003, 23. Phone: 617-249-7300, Danbury, CT office (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Suite 310 Role of COL4A1 in small-vessel disease and hemorrhagic stroke. doi: Disclaimer. It affects mainly young adults, children and more typically neonates. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: IV-3 was diagnosed with ventriculomegaly in utero. Jeanne M, Gould DB. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. https://www.ncbi.nlm.nih.gov/pubmed/26610912. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. 2012;21:R97-R110. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. (2004) 62:16135. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Front. Graefe's Arch Clin Exp Ophthalmol. 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. MedlinePlus also links to health information from non-government Web sites. He would separate the two halves of her brain by 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. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. 2009 Jun 25 [updated 2016 Jul 7]. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. Suite 500 Nearly half of these participants were diagnosed with infantile spasms. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Axenfeld-Rieger anomaly is associated with various other eye abnormalities, including underdevelopment and eventual tearing of the colored part of the eye (iris), and a pupil that is not in the center of the eye. Accessibility A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) National Institute of Neurological Disorders and Stroke. 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. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. II-2 had a limp since childhood attributed to forceps delivery. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). By continuing to use this website, you agree to the Terms of Service & Privacy Policy, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. 2011 If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. doi: 10.1007/s10897-008-9169-9, 16. (2014) 15:16. 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 condition causes mutations in genes that produce a specific type of collagen. doi: 10.1056/NEJMoa071906, 14. Quincy, MA 02169 Dr. Madsen suggested Zeeva have an operation called a As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. The COL4A2 test was negative. Fax: 203-263-9938, Washington, DC Office Fax: 203-263-9938, Washington, DC Office This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. 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. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. Washington, DC 20036 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. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, 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. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. The p.Gly743Val variant is a conservative substitution that occurs in a position highly conserved across species (SIFT analysis: DeleteriousScore 0, median: 4.22, highly conserved nucleotide and amino acid, up to Tetraodon considering 11 species) and affects a crucial and abundant residue within the triple-helix-forming collagenous domain of the protein, which consist of long stretches of Gly-X-Y repeats. Cavalin M, Mine M, Philbert M, et al. 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. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. To use the sharing features on this page, please enable JavaScript. 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). FOIA People with HANAC syndrome develop kidney disease (nephropathy). For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. 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. 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. Hum Mol Genet. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. 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. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES doi: 10.1212/WNL.0b013e3181eee440, 28. 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. Autosomal Dominant Brain Small Vessel Disease. Lenses corrected for hypermetropia. If we dont have a program for you now, please continue to check back with us. 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. No use, distribution or reproduction is permitted which does not comply with these terms. eCollection 2022. 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. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Zagaglia Selch C, Nisevic JR, et al. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). BMC Med Genet. Probands' father had severe hypermetropia and bilateral cataracts. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. 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. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. 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. This group rarely survives beyond 2 years. Clin Genet. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. COL4A1 Syndrome CADASIL Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. Acute urinary retention due to a novel collagen COL4A1 mutation. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. can also contribute. PS: wrote thi paper and performed the review of the literature under the supervision of GN. 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 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. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. (2005) 308:116771. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Ann Neurol. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. Fetal intracerebral hemorrhage and cataract: think COL4A1. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. 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. What is the prognosis of a genetic condition? The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Disease Overview. Dev Med Child Neurol. 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. Danbury, CT 06810 COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. At least six affected families have been described in the scientific literature. The COL4A1 stroke syndrome. 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. 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. Type IV collagen molecules attach to each other to form complex protein networks. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. He also wanted to remove a shunt that was implanted in Maybe try a search? eCollection 2022 Nov 8. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. 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. Cephalic Disorders Fact Sheet. Gould Syndrome is an ultra rare genetic, multi-system disorder. Six alpha chains of type IV. Front Aging Neurosci. 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). Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, 2010 Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. Please enable it to take advantage of the complete set of features! The severity of the condition varies greatly among affected individuals. Migraines can occur with or without aura. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. However, there are exceptions that depend on precisely when and where the mutation arose. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. 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: 10.1212/WNL.0000000000000837, 20. MedlinePlus also links to health information from non-government Web sites. Epub 2010 Jun 17. What are the different ways a genetic condition can be inherited? Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Genet Med. 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). Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. The site is secure. COL4A1 is an essential component for basal membrane stability and exon mutations of COL4A1 gene mutations are responsible for a broad spectrum of systemic manifestations characterized by small vessel involvement of variable severity, including neurological (1) [porencephaly (24), hemorrhage (2, 57) and aneurysms (8)], ophthalmological (912) (retinal artery tortuosity, Axenfeld Rieger anomalies, cataracts, and severe hypermetropia), renal (13) (renal cysts, and microscopic hematuria), and systemic (13) findings (cramps with a high creatine kinase level [CK], Raynaud's phenomenon, and arrhythmias). 2018;91:e2078-e2088. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Eur J Paediatr Neurol. Therapies are based on the specific symptoms in each individual. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. In the human genome, there are 46 chromosomes. 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. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Genetic counseling will be proposed when IV-3 and IV-6 intend to start a family as there is a 50% risk of mutation transmission to the next generation and potential obstetrical complications. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. This condition causes mutations in genes that produce a specific type of collagen. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. What does it mean if a disorder seems to run in my family? 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 In the human genome, there are 46 chromosomes. (2010). 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Neurology. Some individuals develop cysts on the kidney. (2007) 357:268795. Stroke. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. functional hemispherectomy. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. (2017) 5758:2944. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Mutations in COL4A1 or COL4A2 cause Gould Syndrome and, because these two proteins are found in almost all tissues; nearly any organ can be affected. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 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. We provide education, advocacy, and resources for families and individuals affected. (2006) 43:4905. doi: 10.1001/archneur.1983.04050080067013, 17. came with risks and was the hardest decision we had ever faced, yet we felt 100 This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. 1A-B). Affected individuals may have no observable symptoms or only isolated migraines with aura. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. MeSH Please note that NORD provides this information for the benefit of the rare disease community. Facebook: https://www.facebook.com/Col4A1Foundation Please Note Most individuals diagnosed with a COL4A1-related disorder have an affected parent. doi: 10.1007/s00417-014-2800-6, 12. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Suite 310 cutting tissue called the corpus callosum, then make some additional delicate Suite 500 September 2003. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. 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. (2008) 17:42433. ACS Omega. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. doi: 10.1126/science.1109418, 5. doi: 10.1002/ajmg.10452, 18. 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. Subsequently, it has been recognized that autosomal dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular disease, whose onset occurs from fetal life onward and whose severity may range from small-vessel disease to fatal intraparenchymal hemorrhage.,, While epilepsy is known to be a clinical feature of porencephaly, the COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. How are genetic conditions treated or managed? No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. 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. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. With input from doctors, researchers, and the US Food & Drug Administration, NORD has created IAMRARE to facilitate patient-powered natural history studies to shape rare disease research and treatments. (2014) 34:757. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant thus, Gould Syndrome is considered Autosomal Dominant. doi: 10.1186/s12881-014-0097-2, 11. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases.