NORD is a registered 501(c)(3) charity organization. (2008) 17:42433. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. When these ropes are secreted, they assemble into net-like structures outside the cells. The surgery He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). The severity of the condition varies greatly among affected individuals. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) 10.2174/092986710790936293. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. 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). Collagen type IV alpha 1 (COL4A1) silence hampers the invasion, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cells through blocking Hedgehog signaling pathway. Ophthalmological features associated with COL4A1 mutations. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Phone: 202-588-5700. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. 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. doi: 10.1111/cge.12379, 13. Unauthorized use of these marks is strictly prohibited. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. NORD strives to open new assistance programs as funding allows. mutations: a novel genetic multisystem disease. Gould Syndrome is an ultra rare genetic, multi-system disorder. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. 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: 30. 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. Autosomal Dominant Familial Porencephaly Type I. (2008) 23:17. 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). No use, distribution or reproduction is permitted which does not comply with these terms. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Quincy, MA 02169 The signs and symptoms can manifest at almost any age from before birth to old age. Molecular analysis in the father disclosed a heterozygous variant c.2228G>T (p.Gly743Val) in exon 30 of the COL4A1 gene that segregated with the phenotype. Neurology. Disclaimer. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. 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. The https:// ensures that you are connecting to the Depending on the cell type that acquires the mutation and when the mutation arises, the individual may have many or few cells with the mutation. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Bone. 2018;61:765-772. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. official website and that any information you provide is encrypted COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Neurology. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. 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 Summary: 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). J Genet Couns. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. 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). Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. She also showed severe hypermetropia. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). Neurol. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. The risk is the same for males and females. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. 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. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. Phone: 202-588-5700. Axenfeld-Rieger anomaly and cataract can cause impaired vision. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Contact a health care provider if you have questions about your health. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. This site needs JavaScript to work properly. 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. The number of genes implicated in epilepsy has grown rapidly in the past decade. eCollection 2022. MeSH (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. 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.) In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). It looks like nothing was found at this location. 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. Danbury, CT 06810 Figure 3. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. What is the prognosis of a genetic condition? Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Facebook: https://www.facebook.com/Col4A1Foundation Please Note 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. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. can also contribute. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. The site is secure. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. The size and location of cerebral cavities contributes to clinical variability. doi: 10.1007/s00417-014-2800-6, 12. 2009 Jun 25 [updated 2016 Jul 7]. doi: 10.1038/nmeth.2890, 22. (19). Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. There are no standardized treatment protocols or guidelines for affected individuals. Childhood presentation of COL4A1 mutations. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. These genes are the blueprints for two proteins that wind together like a long rope inside cells. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. COL4A1 is an essential component for basal membrane stability. I cannot describe the feeling of seeing your child healed. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. If we dont have a program for you now, please continue to check back with us. Fetal intracerebral hemorrhage and cataract: think COL4A1. 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. Phone: 617-249-7300, Danbury, CT office Firstly, it segregates within the family with the phenotype. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. It is not uncommon for an unaffected parent to have a severely affected child. 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). COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. 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. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 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 COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. 2017;57-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. 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.