What is the prognosis of a genetic condition? Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. 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. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. 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. Fax: 203-263-9938, Washington, DC Office Neurology. COL4A1 Mutations Cause Neuromuscular Disease with - ScienceDirect The disorder causes many symptoms, not the least of which are strokes and epilepsy. The https:// ensures that you are connecting to the This group rarely survives beyond 2 years. (2010) 14:1827. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Antiinflammatory therapy with canakinumab for atherosclerotic disease. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. doi: 10.1007/s00417-014-2800-6, 12. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Painful muscle cramps can occur and can develop before three years of age. 2011 The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). Dr. Joseph Madsen was as wonderful in person as he had been on the phone. 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. Washington, DC 20036 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. What are the different ways a genetic condition can be inherited? (2008) 17:42433. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Clin Genet. The signs and symptoms can manifest at almost any age from before birth to old age. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: 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. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. Migraines can occur with or without aura. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. Resource(s) for Medical Professionals and Scientists on This Disease: 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). Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Teaching families how to advocate for their loved ones and access medical information. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. 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). Matrix Biol. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Our data testing the effects of established mutations on collagen biosynthesis suggest that the intracellular retention of mutant COL4A1 proteins at the expense of their secretion appears to be a common effect of many COL4A1 mutations. COL4A1 is an essential component for basal membrane stability. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. The surgery doi: 10.1056/NEJMoa1707914, 6. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Keywords: COL4A1, Type IV collagen, familial porencephaly, ocular malformations, variable expressivity, Citation: Scoppettuolo P, Ligot N, Wermenbol V, Van Bogaert P and Naeije G (2020) p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Porencephaly and Severe Hypermetropia. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Disease Overview. basement membranes surrounding the body's blood vessels, Genetic Testing Registry: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, National Organization for Rare Disorders (NORD), ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Bull Acad Natl Med. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). 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. 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. doi: 10.1055/s-0031-1275343, 24. COL4A1 and COL4A2 are on Chr. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Danbury, CT 06810 Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 She also showed severe hypermetropia. Dev Med Child Neurol. Jeanne M, Gould DB. doi: 10.1007/s10897-008-9169-9, 16. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Col4a1 mutation generates vascular abnormalities correlated with I dont think we will ever be able to truly articulate our appreciation for Dr. Madsen and Boston Childrens for all that they did for Zeeva and our family. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. This condition causes mutations in genes that produce a specific type of collagen. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. Epub 2022 Apr 14. Still other individuals may not develop any symptoms until well into adulthood. 128:4839. Purpose of review: Axenfeld-Rieger anomaly involves underdevelopment and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye. doi: 10.1111/cge.12379, 13. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. All individuals with this condition have arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eyes (arterial retinal tortuosity). Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. (2002) 112:198202. Clipboard, Search History, and several other advanced features are temporarily unavailable. Phone: 617-249-7300, Danbury, CT office For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). Various muscles can be affected and muscle strength can become weakened. 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). Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Therapies are based on the specific symptoms in each individual. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. IV-3 had a left hemisphere porencephalic cyst and the lack of evidence of a left corticospinal tract on tractography (Figures 3E,F), IV-5 had a porencephalic cyst on the right lateral ventricle (Figure 3C), and III-3 had leukoencephalopathy (Figure 3D). (2018) 91:e207888. 2012;21:R97-R110. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. The site is secure. Bookshelf The COL4A1 and COL4A2 genes were screened in proband IV-6. COL4A1-related brain small-vessel disease - MedlinePlus doi: 10.1111/cge.12543. What is the prognosis of a genetic condition? Plaisier E, Ronco P. COL4A1-Related Disorders. Facebook: https://www.facebook.com/Col4A1Foundation Please Note 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. Clinical Testing and Workup The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. PMC Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Zeevas brain to treat a cyst in her brain caused by porencephaly. (2014) 83:122834. Stroke is a leading cause of death and serious long-term disability in developed nations. However, there are exceptions that depend on precisely when and where the mutation arose. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. 2010;17(13):1317-24. doi: 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. Ann Neurol. doi: 10.1111/j.1469-8749.2011.04198.x, 26. (2006) 43:4905. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Not only did Dr. Madsen, help heal Zeevas brain, but he was instrumental in supporting us as we founded the Gould Syndrome Foundation, a 501(c)(3) non-profit that promotes education, advocacy, and medical advancements in Gould Syndrome, COL4A1/COL4A2 diseases. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. It affects mainly young adults, children and more typically neonates. 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%). Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). (2014) 11:3612. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. How are genetic conditions treated or managed? Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. The number of genes implicated in epilepsy has grown rapidly in the past decade. Quincy, MA 02169 Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. 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. doi: 10.1136/jmg.2005.035584, 15. doi: 10.1126/science.1109418, 5. Thats not to say Zeeva hasnt had to work hard since the surgery. Bone. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. (2014) 252:178994. (2015) 88:46873. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Nearly half of these participants were diagnosed with infantile spasms. Ultrasound in utero from IV-6 (A). Gould Syndrome is an ultra rare genetic, multi-system disorder. 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). In most cases, an affected person has one parent with the condition. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). No microbleeds or cystic cavities were found. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. IV-3 goes to a normal school, but special schooling is required for IV-6. An official website of the United States government. Changing lives of those with rare disease. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. 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. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. Childhood presentation of COL4A1 mutations. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Gould Syndrome is an ultra rare genetic, multi-system disorder. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 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. Affected individuals may have no observable symptoms or only isolated migraines with aura. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. 1779 Massachusetts Avenue The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. doi: 10.1056/NEJMoa053727, 7. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. She, then, developed seizures which were controlled by valproic acid. N Engl J Med. 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. COL4A1 mutations in patients with sporadic late-onset intracerebral 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. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. Summary: CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical relating to specific areas of the brain supplied by deep small arteries (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. doi: 10.1002/ajmg.10452, 18. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps 30. Changing lives of those with rare disease. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Years published: 2019. doi: 10.1038/jp.2013.135, 29. (2005) 308:116771. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. 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. Individuals with HANAC syndrome also experience a variety of eye problems. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. NORD strives to open new assistance programs as funding allows. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Careers. 8600 Rockville Pike PV and VW followed the children at the Neuropediatrics clinic of the same hospital. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. (2020). In the brain, intracerebral hemorrhage is the most frequent phenotype. 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).