Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, 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. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. Resource(s) for Medical Professionals and Scientists on This Disease: Phone: 617-249-7300, Danbury, CT office Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. The disorder causes many symptoms, not the least of which are strokes and epilepsy. 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. doi: 10.2214/ajr.149.2.351, 19. Seattle, WA: University of Washington, Seattle; 1993-. Unable to load your collection due to an error, Unable to load your delegates due to an error. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. 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. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. This is called genotype-phenotype correlation. (2015) 17:84353. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. IV-3 goes to a normal school, but special schooling is required for IV-6. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. It looks like nothing was found at this location. 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). (2020). The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. In most cases, an affected person has one parent with the condition. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. A diagnosis can be confirmed through molecular genetic testing. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). 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). Danbury, CT 06810 Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Am J Med Genet. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. One patient (IV-3) was treated for spasticity and seizures with valproic acid. (2014) 11:3612. Gould Syndrome is an ultra rare genetic, multi-system disorder. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. 2010 Aug;41(8):e513-8. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Pathology. At least 50 individuals with this condition have been described in the scientific literature. Graefe's Arch Clin Exp Ophthalmol. 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. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina E. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. What are the different ways a genetic condition can be inherited? Please enable it to take advantage of the complete set of features! 2008 May;192(5):971-84; discussion 984-6. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Sue. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. In people with HANAC syndrome, angiopathy affects several parts of the body. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Migraines can occur with or without aura. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Ultrasound in utero from IV-6 (A). 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. If either parent also carries the mutation, it is considered inherited. 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 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. What is the prognosis of a genetic condition? 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. Bennett RL, French KS, Resta RG, Doyle DL. People with HANAC syndrome develop kidney disease (nephropathy). doi: 10.1001/archneur.1983.04050080067013, 17. It affects mainly young adults, children and more typically neonates. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. The COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Bone. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. This group rarely survives beyond 2 years. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. When we didnt feel we had any options left for treatment, Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. (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). COL4A1 Syndrome CADASIL 1900 Crown Colony Drive (2017) 377:111931. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Jeanne M, Gould DB. The risk is the same for males and females. Therapies are based on the specific symptoms in each individual. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) After a normal neonatal period, those affected develop a rapidly progressive course involving irritability, hyperaesthesia, visual and hearing loss, severe cognitive and motor deterioration, and seizures. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Gould Syndrome is a rare, genetic, multi-system disorder. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. J Genet Couns. eCollection 2021. January 31, 2019 Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. Firstly, it segregates within the family with the phenotype. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. Standardized (15) familiar pedigree is showed in Figure 1. COL4A1 and COL4A2 are on Chr. This condition causes mutations in genes that produce a specific type of collagen. (2006) 43:4905. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Nearly half of these participants were diagnosed with infantile spasms. 2010;17(13):1317-24. doi: Arch Ophthalmol. 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. 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, . 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. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. 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). Neurology. No microbleeds or cystic cavities were found. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. At the age of 12, IV-3 underwent cerebral palsy quality of life (CPQoL) questionnaires in which they expressed a satisfactory quality of life and a good relationship with other children. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. The number of genes implicated in epilepsy has grown rapidly in the past decade. 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 . These exceptions are nuanced and should be discussed with a genetic counselor. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. His bedside manner was incredible. National Library of Medicine The COL4A1 and COL4A2 genes were screened in proband IV-6. Hum Mol Genet. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. doi: 10.1212/WNL.0b013e3181eee440, 28. 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. Disclaimer. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Fax: 203-263-9938, Washington, DC Office How can gene variants affect health and development? Other eye problems experienced by people with COL4A1-related brain small-vessel disease include clouding of the lens of the eye (cataract) and the presence of arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eye (arterial retinal tortuosity). (2015) 88:46873. doi: 10.1016/j.matbio.2016.10.003, 23. 2018;91:e2078-e2088. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. can also contribute. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. 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). 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. 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). 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Genet Med. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel. FOIA Clin Genet. September 2003. Axenfeld-Rieger anomaly and cataract can cause impaired vision. Summary: Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. Stroke. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. Before 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). HHS Vulnerability Disclosure, Help I cannot describe the feeling of seeing your child healed. INTERNET N Engl J Med. What is the prognosis of a genetic condition? 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. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. 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. 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. Genet Med. Quincy, MA 02169 Bethesda, MD 20894, Web Policies Fetal intracerebral hemorrhage and cataract: think COL4A1. These genes are the blueprints for two proteins that wind together like a long rope inside cells. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Fax: 203-263-9938, Washington, DC Office 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. PS: wrote thi paper and performed the review of the literature under the supervision of GN. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Jeanne M, Gould DB. Berg R, Aleck A, Kaplan A. Familial porencephaly. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. 2011 In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. (2006) 354:148996. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. 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. When these ropes are secreted, they assemble into net-like structures outside the cells. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. This site needs JavaScript to work properly. 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. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. In addition to porencephaly there can be other forms of damage to the brain present at birth. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Neurology. When this enzyme is elevated, it is a sign of muscle damage. MedlinePlus also links to health information from non-government Web sites. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Zeevas brain to treat a cyst in her brain caused by porencephaly. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures, and a shunt to treat hydrocephalus by draining excess fluid from the skull. 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). Autosomal Dominant Brain Small Vessel Disease. my mom suggested we call Boston Childrens Hospital. Last updated: The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Cavalin M, Mine M, Philbert M, et al. doi: 10.1111/j.1469-8749.2011.04198.x, 26. doi: 10.1002/ajmg.10452, 18. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. Neurology. 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. 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. 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. There are no standardized treatment protocols or guidelines for affected individuals. HANAC syndrome is a rare condition, although the exact prevalence is unknown. Collagen type IV alpha 1 (COL4A1) silence hampers the invasion, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cells through blocking Hedgehog signaling pathway. official website and that any information you provide is encrypted (2005) 308:116771. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Phone: 203-263-9938 Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years.
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