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). For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). In addition to porencephaly there can be other forms of damage to the brain present at birth. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. 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. 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). 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. At least six affected families have been described in the scientific literature. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. Neurology. 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 . Bethesda, MD 20894, Web Policies To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). 1. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. eCollection 2022. doi: 10.1038/nmeth.2890, 22. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. 2018;91:e2078-e2088. 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. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. doi: 10.1038/jp.2013.135, 29. 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). The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Science. (2008) 23:17. Lenses corrected for hypermetropia. 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. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. 2011 September 2003. Children with the most severe brain malformations may have: Intellectual impairment Seizures Hydrocephalus Spasticity People who have a disorder of the corpus callosum typically have: There are no standardized treatment protocols or guidelines for affected individuals. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). This condition causes mutations in genes that produce a specific type of collagen. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. It is passed through families in a autosomal dominant fashion. The signs and symptoms can manifest at almost any age from before birth to old age. Quincy, MA 02169 The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Acute urinary retention due to a novel collagen COL4A1 mutation. Matrix Biol. 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). Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. (2015) 88:46873. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Ann Neurol. Clinical Testing and Workup doi: 10.1126/science.1109418, 5. 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. ClinVar; [VCV000389182.3]. Clin Genet. Careers. She, then, developed seizures which were controlled by valproic acid. GeneReviews. The risk is the same for males and females. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. When this enzyme is elevated, it is a sign of muscle damage. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. ACS Omega. This is called genotype-phenotype correlation. Arch Neurol. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. 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. What does it mean if a disorder seems to run in my family? View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. 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). Eur J Paediatr Neurol. National Center for Biotechnology Information. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). official website and that any information you provide is encrypted At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. 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. 11:827. doi: 10.3389/fneur.2020.00827. doi: 10.1002/ana.23736, 4. doi: 10.1001/archneur.1983.04050080067013, 17. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Disease Overview. doi: 10.1007/s00417-014-2800-6, 12. Zagaglia Selch C, Nisevic JR, et al. doi: 10.1038/gim.2014.210, 3. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. seizure activity. NORD is a registered 501(c)(3) charity organization. The .gov means its official. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. At least 50 individuals with this condition have been described in the scientific literature. It looks like nothing was found at this location. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. The surgery Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. Fax: 203-263-9938, Washington, DC Office Nat Methods. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Type IV collagen molecules attach to each other to form complex protein networks. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Antiinflammatory therapy with canakinumab for atherosclerotic disease. 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. Resource(s) for Medical Professionals and Scientists on This Disease: The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. 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. doi: 10.1056/NEJMoa071906, 14. doi: 10.1136/jmg.2005.035584, 15. NORD strives to open new assistance programs as funding allows. He also wanted to remove a shunt that was implanted in Ann Neurol. I dont think we will ever be able to truly articulate our appreciation for Dr. Madsen and Boston Childrens for all that they did for Zeeva and our family. Firstly, it segregates within the family with the phenotype. Stroke. This condition causes mutations in genes that produce a specific type of collagen. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. Neurology. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Fetal intracerebral hemorrhage and cataract: think COL4A1. 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. 1900 Crown Colony Drive 30. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. The information on this site should not be used as a substitute for professional medical care or advice. 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. 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. For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: Toll-free: (800) 411-1222 Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. (2006) 354:148996. Surgery may be necessary for individuals with severe cataracts. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. 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. Neurology. (2013) 73:4857. doi: 10.1212/WNL.0000000000001309, 8. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Progressive cerebral atrophies in three children with COL4A1 mutations. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. 10.2174/092986710790936293. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. 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 In the brain, intracerebral hemorrhage is the most frequent phenotype. doi: 10.1001/archophthalmol.2010.42, 10. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Congenital Cephalic Disorders Matrix Biol. Federal government websites often end in .gov or .mil. The COL4A1 stroke syndrome. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. doi: 10.2214/ajr.149.2.351, 19. (2012) 54:56974. 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. What is the prognosis of a genetic condition? Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. (2010) 75:7479. Contact a health care provider if you have questions about your health. (2006) 43:4905. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. PS: wrote thi paper and performed the review of the literature under the supervision of GN. HANAC syndrome is caused by genetic changes in the COL4A1 gene. N Engl J Med. came with risks and was the hardest decision we had ever faced, yet we felt 100 Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Mutations in the COL4A1 gene cause HANAC syndrome. doi: 10.1038/gim.2015.30, 21. 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. cuts under the microscope. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. 1900 Crown Colony Drive Phone: 617-249-7300, Danbury, CT office 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. MedlinePlus also links to health information from non-government Web sites. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Suite 310 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). This group rarely survives beyond 2 years. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Standardized (15) familiar pedigree is showed in Figure 1. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. 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. What are the different ways a genetic condition can be inherited? Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. Am J Med Genet A. Clin Neurol Neurosurg. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. 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. Phone: 202-588-5700. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. Neurology. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium). COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. 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). When these ropes are secreted, they assemble into net-like structures outside the cells.
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