col4a1 syndrome life expectancy

This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. 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. How can gene variants affect health and development? 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. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Neurology. https://www.ncbi.nlm.nih.gov/pubmed/26610912. 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). Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). Washington, DC 20036 Figure 3. 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). He also wanted to remove a shunt that was implanted in This condition causes mutations in genes that produce a specific type of collagen. Recent findings: mutations: a novel genetic multisystem disease. doi: 10.1038/gim.2015.30, 21. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Eur J Med Genet. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Epub 2010 Jun 17. Genet Med. The .gov means its official. 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). Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). Epub 2022 Apr 14. 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. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. He smiled, caught it, and asked Zeeva if he could throw it back. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. 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). It affects mainly young adults, children and more typically neonates. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Disease Overview. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. 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. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. 2010;17(13):1317-24. doi: Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Phone: 203-263-9938 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. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). Fetal intracerebral hemorrhage and cataract: think COL4A1. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). GeneReviews. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Resource(s) for Medical Professionals and Scientists on This Disease: NORD is a registered 501(c)(3) charity organization. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. 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. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. (2006) 43:4905. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. doi: 10.2214/ajr.149.2.351, 19. Still other individuals may not develop any symptoms until well into adulthood. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Neurology. Front Aging Neurosci. Smoking, which also increases the risk of stroke, physical activities that can cause head trauma such as contact sports, and the use of anti-clotting (anticoagulant) medications, should be avoided. It is important to discuss these concepts with a genetic counselor and understand their implications. What does it mean if a disorder seems to run in my family? (1987) 8:4216. 2011 Neuropediatrics. 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. How are genetic conditions treated or managed? 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. Clinically, COL4A1 mutations are responsible for different overlapping phenotypes including porencephaly (24), brain small vessel disease (2, 57) with or without ocular anomalies, HANAC (13) (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome, ophthalmological abnormalities (912), and non-syndromic autosomal dominant congenital cataracts (10). Any muscle may be affected, and cramps usually last from a few seconds to a few minutes, although in some cases they can last for several hours. (2015) 17:84353. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. 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. Type IV collagen molecules attach to each other to form complex protein networks. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. Clin Neurol Neurosurg. Arch Ophthalmol. Disclaimer. doi: 10.1038/jp.2013.135, 29. Early intervention is important in ensuring that children with reach their highest potential. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. cuts under the microscope. 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. 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%). The severity of the condition varies greatly among affected individuals. 55 Kenosia Avenue (2012) 54:56974. Neurology. Standardized (15) familiar pedigree is showed in Figure 1. doi: 10.1016/j.matbio.2016.10.003, 23. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Therapies are based on the specific symptoms in each individual. 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. Seattle, WA: University of Washington, Seattle; 1993-. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Unable to load your collection due to an error, Unable to load your delegates due to an error. The disorder causes many symptoms, not the least of which are strokes and epilepsy. 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. 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). Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. To use the sharing features on this page, please enable JavaScript. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. January 31, 2019 If we dont have a program for you now, please continue to check back with us. This site needs JavaScript to work properly. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. Suite 500 doi: 10.1056/NEJMoa071906, 14. doi: 10.1126/science.1109418, 5. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. MedlinePlus also links to health information from non-government Web sites. government site. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Nat Methods. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). In most cases, an affected person has one parent with the condition. Neurology. my mom suggested we call Boston Childrens Hospital. Federal government websites often end in .gov or .mil. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. Neurology. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. What is the prognosis of a genetic condition? Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. Purpose of review: Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. 1900 Crown Colony Drive eCollection 2021. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. 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. (2004) 62:16135. Autosomal Dominant Familial Porencephaly Type I. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. 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. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Bethesda, MD 20894, Web Policies (2014) 252:178994. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. doi: 10.1002/ajmg.10452, 18. doi: NORD is not a medical provider or health care facility and thus can neither diagnose any disease or disorder nor endorse or recommend any specific medical treatments. Cavalin M, Mine M, Philbert M, et al. Jeanne M, Gould DB. He would separate the two halves of her brain by 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. doi: 10.1111/cge.12543. mutations: a novel genetic multisystem disease. 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). 2009 Jun 25 [updated 2016 Jul 7]. 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. Washington, DC 20036 The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. 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. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. 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. She, then, developed seizures which were controlled by valproic acid. What are the different ways a genetic condition can be inherited? Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. How can gene variants affect health and development? doi: 10.1007/s00417-014-2800-6, 12. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. Hereditary cerebral small vessel diseases: a review. (2008) 23:17. (2009) 73:187382. cutting tissue called the corpus callosum, then make some additional delicate Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Ultrasound in utero from IV-6 (A). J Perinatol. We provide education, advocacy, and resources for families and individuals affected. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. 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). This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). can also contribute. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. 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: 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). CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. A diagnosis can be confirmed through molecular genetic testing. functional hemispherectomy. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. ClinVar; [VCV000389182.3]. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. 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. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 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). MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Phone: 203-263-9938 This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes.

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