This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Jeanne M, Gould DB. How are genetic conditions treated or managed? He was confident this would reduce or stop the Arch Ophthalmol. government site. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. (2015) 17:40524. In the brain, intracerebral hemorrhage is the most frequent phenotype. The signs and symptoms can manifest at almost any age from before birth to old age. Washington, DC 20036 Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Gould Syndrome is a rare, genetic, multi-system disorder. 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. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. can also contribute. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. 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. Hereditary cerebral small vessel diseases: a review. (2010). National Library of Medicine She has regular physical, speech, and occupational therapy. 1779 Massachusetts Avenue (1982) 40:5679. 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. Neurology. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Am J Neuroradiol. Am J Med Genet A. Curr Opin Neurol. 2018;61:765-772. It is ubiquitously expressed in many tissues and cell types. 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. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. Autosomal Dominant Familial Porencephaly Type I. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). (19). Epub 2014 Jan 5. COL4A1/A2-Related Disorders - Symptoms, Causes, Treatment | NORD COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. Facebook: https://www.facebook.com/Col4A1Foundation Please Note Neurology. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. 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. Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus 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. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. 2012;21:R97-R110. Epub 2010 Jun 17. doi: 10.1007/s10897-008-9169-9, 16. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. An official website of the United States government. Unauthorized use of these marks is strictly prohibited. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. The COL4A1 stroke syndrome. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Full ophthalmological evaluations including slit lamp and fundoscopy were realized and disclosed for bilateral hypermetropia in IV-3 [15 dioptre (D)], IV-6 (8.5 D), IV-5 (10 D), and III-3 (7 D). IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). Maybe try a search? When this enzyme is elevated, it is a sign of muscle damage. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. 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). Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. Neurology. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Would you like email updates of new search results? Agenesis of the Corpus Callosum | National Institute of Neurological 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). COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. A diagnosis can be confirmed through molecular genetic testing. Matrix Biol. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. GeneReviews. Early intervention is important in ensuring that children with reach their highest potential. 2018;91:e2078-e2088. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. National Institute of Neurological Disorders and Stroke. 55 Kenosia Avenue Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Autosomal Dominant Brain Small Vessel Disease. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). doi: Stroke is a leading cause of death and serious long-term disability in developed nations. 2010;41:e513-518. https://www.ncbi.nlm.nih.gov/pubmed/26610912. In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. Dev Med Child Neurol. See our, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome, URL of this page: https://medlineplus.gov/genetics/condition/hereditary-angiopathy-with-nephropathy-aneurysms-and-muscle-cramps-syndrome/. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). INTERNET In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. Genetic counseling will be proposed when IV-3 and IV-6 intend to start a family as there is a 50% risk of mutation transmission to the next generation and potential obstetrical complications. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Phone: 203-263-9938 Quincy, MA 02169 doi: 10.1111/cge.12543. Curr Med Chem. Suite 310 doi: 10.1038/nmeth.2890, 22. If either parent also carries the mutation, it is considered inherited. Purpose of review: In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. eCollection 2022 Nov 8. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. cutting tissue called the corpus callosum, then make some additional delicate doi: 10.1212/WNL.0b013e3181c3fd12, 9. Standardized (15) familiar pedigree is showed in Figure 1. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Understanding what it has taken to get her to this point, though, is close to unimaginable. Matrix Biol. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Neurology. my mom suggested we call Boston Childrens Hospital. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. 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. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. doi: 10.1111/j.1469-8749.2011.04198.x, 26. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel - Stroke She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). No microbleeds or cystic cavities were found. This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network. Orphanet: HANAC syndrome Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. doi: 10.1212/01.WNL.0000123113.46672.68, 25. He also wanted to remove a shunt that was implanted in Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Jeanne M, Gould DB. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. 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: 10.1016/j.matbio.2016.10.003, 23. 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 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. Changing lives of those with rare disease. Genet Med. Gould Syndrome is an ultra rare genetic, multi-system disorder. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. 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). Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. 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 Neuropediatrics. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. (2015) 84:91826. 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. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. doi: 10.1002/ana.23736, 4. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Washington, DC 20036 COL4A1/A2-related disorders are dominant genetic disorders. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. The COL4A1 and COL4A2 genes were screened in proband IV-6. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. What does it mean to have a COL4A1 - Little Braveheart | Facebook Stroke. mutations: a novel genetic multisystem disease. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. At least six affected families have been described in the scientific literature. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Unable to load your collection due to an error, Unable to load your delegates due to an error. 2010 Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. 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). Clipboard, Search History, and several other advanced features are temporarily unavailable. percent confident in Dr. Madsen and the epilepsy team. To use the sharing features on this page, please enable JavaScript. He smiled, caught it, and asked Zeeva if he could throw it back. In the human genome, there are 46 chromosomes. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. J Med Genet. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). 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. We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. The .gov means its official. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Rarely, affected individuals will have a condition called Raynaud phenomenon in which the blood vessels in the fingers and toes temporarily narrow, restricting blood flow to the fingertips and the ends of the toes. Bull Acad Natl Med. Last updated: Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. (2015) 17:84353. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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. 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. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. 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). The COL4A1 gene provides instructions for making one component of a protein called type IV collagen.
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