What does it mean if a disorder seems to run in my family? 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. Lenses corrected for hypermetropia. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. 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 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. Surgery may be necessary for individuals with severe cataracts. 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 severity of the condition varies greatly among affected individuals. eCollection 2022. 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). 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Phone: 202-588-5700. Gould Syndrome is an ultra rare genetic, multi-system disorder. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. Firstly, it segregates within the family with the phenotype. 2010 Aug;41(8):e513-8. Unable to load your collection due to an error, Unable to load your delegates due to an error. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. doi: 10.1111/cge.12379, 13. These genes are the blueprints for two proteins that wind together like a long rope inside cells. INTERNET Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Type IV collagen molecules attach to each other to form complex protein networks. Teaching families how to advocate for their loved ones and access medical information. Please enable it to take advantage of the complete set of features! III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Lanfranconi S, Markus HS. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. (2009) 73:187382. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, The first reports of human COL4A1 mutations were in patients with autosomal dominant porencephaly and a more recent study found that COL4A1 mutations were found in ~16% of patients with porencephaly. eCollection 2022. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. To better define pathology caused by Col4a1 mutations, we characterized myopathy in two different Col4a1 mutant mouse strainsCol4a1 ex41 and Col4a1 G394V.We selected these strains from an allelic series of Col4a1 mutant mice because they showed the most severe myopathy according to NPN quantification in quadriceps while having different effects on [1(IV)] 2 2(IV) secretion. Prenatal clinical manifestations in individuals with COL4A1/2 variants. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Therapies are based on the specific symptoms in each individual. 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). Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. If we dont have a program for you now, please continue to check back with us. 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 is an ultra rare genetic, multi-system disorder. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Plaisier E, Ronco P. COL4A1-Related Disorders. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Gould Syndrome is often 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 information on this site should not be used as a substitute for professional medical care or advice. (2018) 91:e207888. Acute urinary retention due to a novel collagen COL4A1 mutation. (2015) 88:46873. 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). Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. GeneReviews. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. 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. In the human genome, there are 46 chromosomes. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. 1779 Massachusetts Avenue Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot. Neurology. Neurology. If either parent also carries the mutation, it is considered inherited. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. 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). Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. The surgery 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. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. 2011 How are genetic conditions treated or managed? Dr. Joseph Madsen was as wonderful in person as he had been on the phone. 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-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . Arch Ophthalmol. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. MeSH We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Neurology. The disorder causes many symptoms, not the least of which are strokes and epilepsy. These exceptions are nuanced and should be discussed with a genetic counselor. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. came with risks and was the hardest decision we had ever faced, yet we felt 100 Phone: 203-263-9938 Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: People listened to us and to Zeeva in a very different and proactive way. doi: 10.1001/archneur.1983.04050080067013, 17. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Purpose of review: Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, (2010) 75:7479. NORD is a registered 501(c)(3) charity organization. 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. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. doi: 10.1016/j.matbio.2016.10.003, 23. (2006) 43:4905. The COL4A1 and COL4A2 genes were screened in proband IV-6. In most cases, an affected person has one parent with the condition. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. 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.) (2005) 308:116771. (No doctor had ever taken a call on their lunch break to speak with me). Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Cesarean delivery for pregnancies with fetus at risk for a COL4A1-related disorder is recommended to prevent brain vascular injury attributable to birth trauma during delivery (6). https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. my mom suggested we call Boston Childrens Hospital. Suite 500 seizure activity. sharing sensitive information, make sure youre on a federal https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. Probands' father had severe hypermetropia and bilateral cataracts. 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. This condition causes mutations in genes that produce a specific type of collagen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The pathogenic mechanisms of COL4A1 mutations are not fully elucidated and may vary according to the mutation type, the affected exon (mutations responsible for systemic HANAC syndrome cluster at exon 24 and 25), the position of the mutation within the triple-helix domain, and the mutation location. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. (2008) 17:42433. Front Aging Neurosci. Clin Genet. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. doi: 10.1055/s-0031-1275343, 24. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies, https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, https://www.ncbi.nlm.nih.gov/pubmed/28254515, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, https://www.nature.com/articles/gim2014210, https://www.ncbi.nlm.nih.gov/pubmed/23225343, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, https://www.ncbi.nlm.nih.gov/pubmed/22868088, https://www.ncbi.nlm.nih.gov/pubmed/22574627, https://www.ncbi.nlm.nih.gov/pubmed/20558831, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, https://www.ncbi.nlm.nih.gov/pubmed/26610912, https://www.ncbi.nlm.nih.gov/books/NBK7046/, https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet, https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/, https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/, https://rarediseases.org/patient-assistance-programs/caregiver-respite/, Learn more about Patient Assistance Programs >, Arginine: Glycine Amidinotransferase Deficiency, https://rarediseases.org/non-member-patient/epilepsy-foundation/, Gould Syndrome Foundation (COL4a1/COL4A2), https://rarediseases.org/non-member-patient/gould-syndrome-foundation-col4a1-col4a2/, https://rarediseases.org/non-member-patient/national-kidney-foundation/, https://rarediseases.org/non-member-patient/nih-national-eye-institute/, NIH/National Institute of Neurological Disorders and Stroke, Aromatic L-Amino Acid Decarboxylase Deficiency, https://rarediseases.org/non-member-patient/nih-national-institute-of-neurological-disorders-and-stroke/, https://rarediseases.org/non-member-patient/the-arc/, Learn more about Patient Organization & Membership >, HANAC: hereditary angiopathy, nephropathy and cramps syndrome (OMIM #611773), POREN1: autosomal dominant type 1 porencephaly; porencephaly with infantile hemiplegia (OMIM #175780, RATOR: retinal arterial tortuosity (OMIM #180000), BSVD: brain small vessel disease with or without ocular anomalies (OMIM #607595), ICH: susceptibility to intracerebral hemorrhage (OMIM #614519). Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. (2010). Fetal intracerebral hemorrhage and cataract: think COL4A1. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Internet. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. 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. mutations: a novel genetic multisystem disease. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. When these ropes are secreted, they assemble into net-like structures outside the cells. (1987) 8:4216. We provide education, advocacy, and resources for families and individuals affected. 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. mutations: a novel genetic multisystem disease. 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. It affects mainly young adults, children and more typically neonates. Neurology. 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. Phone: 617-249-7300, Danbury, CT office Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. MedlinePlus also links to health information from non-government Web sites. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. 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. The degree of mosaicism is highly variable ranging from only a small percent of cells with the mutation to nearly all cells carrying the mutation and depends on the stage during development that the mutation occurred. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Bone. This page is currently unavailable. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. Genet Med. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Front. The .gov means its official. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Ann Neurol. To use the sharing features on this page, please enable JavaScript. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. FOIA Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. doi: 10.1002/ana.23736, 4. (19). January 31, 2019 Early intervention is important in ensuring that children with reach their highest potential. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: The https:// ensures that you are connecting to the 11:827. doi: 10.3389/fneur.2020.00827. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. (2017) 5758:2944. HANAC syndrome is a rare condition, although the exact prevalence is unknown. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). Ultrasound in utero from IV-6 (A). 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. N Engl J Med. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) (2006) 354:148996. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. (2014) 11:3612. 1. BMC Med Genet. Quincy, MA 02169 Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. 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). doi: 10.1056/NEJMoa1707914, 6. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. doi: 10.1038/jp.2013.135, 29. (2011) 42:13. (2014) 15:16. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. National Library of Medicine Doctors and researchers to bring research and medical therapeutic options to those affected. Hum Mol Genet. 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. In the brain, intracerebral hemorrhage is the most frequent phenotype. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. 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. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. 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. percent confident in Dr. Madsen and the epilepsy team. Muscle cramps can be spontaneous or triggered by exercise. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Seattle, WA: University of Washington, Seattle; 1993-. How are genetic conditions treated or managed? 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 ( 2 - 4 ), hemorrhage ( 2, 5 - 7) and aneurysms ( 8 )], ophthalmological U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Painful muscle cramps can occur and can develop before three years of age. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Danbury, CT 06810 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). 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. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. 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. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population.
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