The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Epub 2022 Apr 14. 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. 1. and transmitted securely. September 2003. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Washington, DC 20036 Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. official website and that any information you provide is encrypted However, in people with HANAC syndrome, these aneurysms typically do not burst. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Summary: *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). People listened to us and to Zeeva in a very different and proactive way. Understanding what it has taken to get her to this point, though, is close to unimaginable. U.S. Department of Health and Human Services, Autosomal dominant familial hematuria, retinal arteriolar tortuosity, contractures, Hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome. 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. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Patients must rely on the personal and individualized medical advice of their qualified health care professionals before seeking any information related to their particular diagnosis, cure or treatment of a condition or disorder. This group rarely survives beyond 2 years. 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. January 31, 2019 Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. The COL4A1 stroke syndrome. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Treatment Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). TTY: (866) 411-1010 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 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. doi: 10.2214/ajr.149.2.351, 19. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. 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. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. doi: 10.1212/WNL.0000000000000837, 20. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Ann Neurol. Cephalic Disorders Fact Sheet. Last updated: By continuing to use this website, you agree to the Terms of Service & Privacy Policy. 2012;21:R97-R110. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients even among members of a family who carry the same gene mutation. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Gould Syndrome is a rare, genetic, multi-system disorder. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. Neurol. Berg R, Aleck A, Kaplan A. Familial porencephaly. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant thus, Gould Syndrome is considered Autosomal Dominant. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Jeanne M, Gould DB. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. Dev Med Child Neurol. Early intervention is important in ensuring that children with reach their highest potential. Contact a health care provider if you have questions about your health. Washington, DC 20036 Various muscles can be affected and muscle strength can become weakened. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Accessibility Copyright 2023 by Gould Syndrome Foundation -. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. doi: 10.1002/ajmg.10452, 18. doi: 10.1136/jmg.2005.035584, 15. In the human genome, there are 46 chromosomes. (2012) 54:56974. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Danbury, CT 06810 We believe that the variant p.Gly743Val is likely pathogenic for several reasons. 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). Cereb Circ Cogn Behav. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Bennett RL, French KS, Resta RG, Doyle DL. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Phone: 203-263-9938 IV-3 and IV-6 are closely followed by a neuropediatrician (VW). Type IV collagen molecules attach to each other to form complex protein networks. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. National Library of Medicine She also showed severe hypermetropia. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. Probands' father had severe hypermetropia and bilateral cataracts. 11:827. doi: 10.3389/fneur.2020.00827. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. 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). The disorder causes many symptoms, not the least of which are strokes and epilepsy. Muscle cramps can be spontaneous or triggered by exercise. By continuing to use this website, you agree to the Terms of Service & Privacy Policy, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. It is not uncommon for an unaffected parent to have a severely affected child. Type IV collagen molecules attach to each other to form complex protein networks. 4 Both . Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. for the triple helical CB3[IV] domain. doi: 10.1056/NEJMoa053727, 7. National Institute of Neurological Disorders and Stroke. mutations: a novel genetic multisystem disease. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. How are genetic conditions treated or managed? In most cases, an affected person has one parent with the condition. In the brain, intracerebral hemorrhage is the most frequent phenotype. Ophthalmological features associated with COL4A1 mutations. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). 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. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. 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 As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Curr Med Chem. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. doi: 10.1016/j.matbio.2016.10.003, 23. NORD strives to open new assistance programs as funding allows. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. II-2 had a limp since childhood attributed to forceps delivery. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Phone: 202-588-5700. doi: 10.1212/WNL.0b013e3181eee440, 28. 2008 May;192(5):971-84; discussion 984-6. Suite 500 Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. J Neurol Sci. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. 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. The .gov means its official. 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. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Some individuals develop cysts on the kidney. NCI CPTC Antibody Characterization Program. 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. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. 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. Please enable it to take advantage of the complete set of features! Nat Methods. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. The COL4A1 and COL4A2 genes were screened in proband IV-6. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. Ultrasound in utero from IV-6 (A). Antiinflammatory therapy with canakinumab for atherosclerotic disease. Jeanne M, Gould DB. How are genetic conditions treated or managed? N Engl J Med. 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). 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.) Bookshelf 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). 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. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). He also wanted to remove a shunt that was implanted in doi: 10.1111/j.1469-8749.2011.04198.x, 26. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Painful muscle cramps can occur and can develop before three years of age. MedlinePlus also links to health information from non-government Web sites. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. 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. Zagaglia Selch C, Nisevic JR, et al. (2014) 83:122834. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Cavalin M, Mine M, Philbert M, et al. 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). Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Migraines can occur with or without aura. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Before (2010). 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. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Epub 2014 Jan 5. 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. 2018;91:e2078-e2088. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. In people with HANAC syndrome, angiopathy affects several parts of the body. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. doi: 10.1038/gim.2014.210, 3. It is important to discuss these concepts with a genetic counselor and understand their implications. Fetal intracerebral hemorrhage and cataract: think COL4A1. It affects mainly young adults, children and more typically neonates. Clinical Testing and Workup 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. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Epub 2010 Jun 17. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. (2010) 75:7479. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). 2010 COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. When this enzyme is elevated, it is a sign of muscle damage. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients.
Disneyland Paris Rock 'n' Roller Coaster Reopening,
Articles C
