J Perinatol. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. eCollection 2022. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. ACS Omega. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. COL4A1 mutations as a monogenic cause of cerebral HANAC syndrome is a rare condition, although the exact prevalence is unknown. Neurology. cuts under the microscope. https://www.ncbi.nlm.nih.gov/pubmed/26610912. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. 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. 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. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). 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). Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Epub 2022 Apr 14. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. doi: 10.1126/science.1109418, 5. To use the sharing features on this page, please enable JavaScript. 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. Firstly, it segregates within the family with the phenotype. Neuropediatrics. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Ultrasound in utero from IV-6 (A). This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Disease Overview. 1779 Massachusetts Avenue HHS Vulnerability Disclosure, Help 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: doi: 10.1001/archophthalmol.2010.42, 10. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. functional hemispherectomy. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. N Engl J Med. Progressive cerebral atrophies in three children with COL4A1 mutations. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. 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 basement membranes surrounding the body's blood vessels, National Organization for Rare Disorders (NORD), BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES. Thats not to say Zeeva hasnt had to work hard since the surgery. Please note that NORD provides this information for the benefit of the rare disease community. eCollection 2021. eCollection 2022 Nov 8. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. 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 COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. Stroke is a leading cause of death and serious long-term disability in developed nations. Standardized (15) familiar pedigree is showed in Figure 1. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Childhood presentation of COL4A1 mutations. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). (E,F) IV-3Brain MRI showed left frontotemporal dilatation and diffusion tensor imaging (DTI) sequences demonstrated no left corticospinal tract (cranio-caudal fibers, indigo, with arrows). Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. There are no standardized treatment protocols or guidelines for affected individuals. Summary: As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 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 . Early intervention is important in ensuring that children with reach their highest potential. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Suite 310 Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Am J Med Genet A. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. The COL4A1 stroke syndrome. 55 Kenosia Avenue Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. Suite 500 MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. INTERNET Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. 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. 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. 128:4839. doi: 10.1016/j.ejpn.2009.04.010, 27. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. COL4A1 brain small-vessel disease is an autosomal dominant condition resulting from a mutation to the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen 1-6. COL4A1 and COL4A2 are on Chr. The information on this site should not be used as a substitute for professional medical care or advice. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Ann We describe here the phenotype of a likely pathogenic gene variant, p.Gly743Val, which is responsible for a missense mutation in the COL4A1 gene exon 30 in a three generation family with severe hypermetropia and highly penetrant porencephaly in the absence of systemic manifestations. Please enable it to take advantage of the complete set of features! 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. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. This group rarely survives beyond 2 years. MeSH Arch Neurol. This condition causes mutations in genes that produce a specific type of collagen. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. We provide education, advocacy, and resources for families and individuals affected. The severity of the condition varies greatly among affected individuals. If we dont have a program for you now, please continue to check back with us. official website and that any information you provide is encrypted 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). Summary. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. These exceptions are nuanced and should be discussed with a genetic counselor. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. doi: 10.1007/s10897-008-9169-9, 16. Facebook: https://www.facebook.com/Col4A1Foundation Please Note Epub 2010 Jun 17. While there are other explanations, parental mosaicism should be considered. The first time he came to meet us, Zeeva threw a sock at him. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. Subsequently, it has been recognized that autosomal dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular disease, whose onset occurs from fetal life onward and whose severity may range from small-vessel disease to fatal intraparenchymal hemorrhage.,, While epilepsy is known to be a clinical feature of porencephaly, the NCI CPTC Antibody Characterization Program. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. N Engl J Med. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. ClinVar; [VCV000389182.3]. Doctors and researchers to bring research and medical therapeutic options to those affected. Before Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. When this enzyme is elevated, it is a sign of muscle damage. Last updated: Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. (2012) 54:56974. The information on this site should not be used as a substitute for professional medical care or advice. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. It is passed through families in a autosomal dominant fashion. Dev Med Child Neurol. 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. 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. Clin Neurol Neurosurg. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. 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. In addition to porencephaly there can be other forms of damage to the brain present at birth. 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. 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. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Phone: 203-263-9938 Ophthalmological features associated with COL4A1 mutations. How are genetic conditions treated or managed? She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. In the human genome, there are 46 chromosomes. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. HANAC syndrome is caused by genetic changes in the COL4A1 gene. I cannot describe the feeling of seeing your child healed. Prenatal clinical manifestations in individuals with COL4A1/2 variants. People listened to us and to Zeeva in a very different and proactive way. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical relating to specific areas of the brain supplied by deep small arteries (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. This site needs JavaScript to work properly. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation Gould Syndrome Foundation 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. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. cutting tissue called the corpus callosum, then make some additional delicate 2010 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. His bedside manner was incredible. Still other individuals may not develop any symptoms until well into adulthood. In most cases, an affected person has one parent with the condition. 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. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. 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. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. January 31, 2019 It affects mainly young adults, children and more typically neonates. Ann Neurol. 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).
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