(1982) 40:5679. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. At least six affected families have been described in the scientific literature. 10.2174/092986710790936293. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. ACS Omega. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Changing lives of those with rare disease. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. This is called genotype-phenotype correlation. Understanding what it has taken to get her to this point, though, is close to unimaginable. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. Copyright 2023 by Gould Syndrome Foundation -. 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. FOIA Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. Clin Genet. TTY: (866) 411-1010 The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. 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. doi: 10.1136/jmg.2005.035584, 15. Please enable it to take advantage of the complete set of features! If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. doi: 10.1111/cge.12379, 13. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, 2010 Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 11:827. doi: 10.3389/fneur.2020.00827. 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. (2015) 88:46873. The risk is the same for males and females. 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. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Childhood presentation of COL4A1 mutations. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Curr Opin Neurol. Dev Med Child Neurol. eCollection 2022 Nov 8. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. for the triple helical CB3[IV] domain. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. COL4A1 Syndrome CADASIL Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. 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. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Berg R, Aleck A, Kaplan A. Familial porencephaly. Genet Med. 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. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. Epub 2014 Jan 5. However, in people with HANAC syndrome, these aneurysms typically do not burst. (2020). Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. She has regular physical, speech, and occupational therapy. Unauthorized use of these marks is strictly prohibited. The COL4A1 and COL4A2 genes were screened in proband IV-6. In people with HANAC syndrome, angiopathy affects several parts of the body. We provide education, advocacy, and resources for families and individuals affected. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, 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). 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 This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Suite 310 Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). doi: 10.2214/ajr.149.2.351, 19. 2018;91:e2078-e2088. 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. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. How are genetic conditions treated or managed? Summary. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Pathology. 2011 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. 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.) 2009 Jun 25 [updated 2016 Jul 7]. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Neurology. (2015) 17:84353. 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. What is the prognosis of a genetic condition? MeSH Thats not to say Zeeva hasnt had to work hard since the surgery. Am J Neuroradiol. 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. doi: 10.1056/NEJMoa071906, 14. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. 8600 Rockville Pike Childhood presentation of COL4A1 mutations. Individuals with HANAC syndrome also experience a variety of eye problems. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. National Library of Medicine NORD is a registered 501(c)(3) charity organization. The COL4A2 test was negative. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. doi: 10.1212/WNL.0b013e3181eee440, 28. 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. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Antiinflammatory therapy with canakinumab for atherosclerotic disease. NORD strives to open new assistance programs as funding allows. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Stroke is a leading cause of death and serious long-term disability in developed nations. This condition causes mutations in genes that produce a specific type of collagen. Type IV collagen molecules attach to each other to form complex protein networks. Years published: 2019. 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. National Center for Biotechnology Information. Arch Neurol. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. 2012;21:R97-R110. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Internet. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. Lenses corrected for hypermetropia. Suite 500 Axenfeld-Rieger anomaly and cataract can cause impaired vision. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. N Engl J Med. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach.