Here we report a family in which three siblings presented severe hypermetropia and porencephaly. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. HHS Vulnerability Disclosure, Help 128:4839. This condition causes mutations in genes that produce a specific type of collagen. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. Phone: 202-588-5700. official website and that any information you provide is encrypted Curr Opin Neurol. INTERNET The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual (called sporadic or de novo). doi: 10.1126/science.1109418, 5. He smiled, caught it, and asked Zeeva if he could throw it back. An official website of the United States government. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Eur J Paediatr Neurol. MedlinePlus also links to health information from non-government Web sites. While there are other explanations, parental mosaicism should be considered. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). IV-3 was diagnosed with ventriculomegaly in utero. Zagaglia Selch C, Nisevic JR, et al. All individuals with this condition have arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eyes (arterial retinal tortuosity). Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. doi: 10.1212/01.WNL.0000123113.46672.68, 25. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. Berg R, Aleck A, Kaplan A. Familial porencephaly. 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). Axenfeld-Rieger anomaly and cataract can cause impaired vision. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Summary: 2012;21:R97-R110. What is the prognosis of a genetic condition? This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. (2006) 43:4905. Standardized (15) familiar pedigree is showed in Figure 1. Gould Syndrome is a rare, genetic, multi-system disorder. Federal government websites often end in .gov or .mil. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Type IV collagen molecules attach to each other to form complex protein networks. Clin Genet. COL4A1/A2-related disorders are dominant genetic disorders. (19). Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. 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). Bennett RL, French KS, Resta RG, Doyle DL. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. Maybe try a search? 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. What does it mean if a disorder seems to run in my family? 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 the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. 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. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). These genes are the blueprints for two proteins that wind together like a long rope inside cells. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). doi: 10.1001/archophthalmol.2010.42, 10. Not only did Dr. Madsen, help heal Zeevas brain, but he was instrumental in supporting us as we founded the Gould Syndrome Foundation, a 501(c)(3) non-profit that promotes education, advocacy, and medical advancements in Gould Syndrome, COL4A1/COL4A2 diseases. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. 11:827. doi: 10.3389/fneur.2020.00827. 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 The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel. Fax: 203-263-9938, Washington, DC Office Fax: 203-263-9938, Washington, DC Office doi: 10.1002/ana.23736, 4. Migraines can occur with or without aura. The size and location of cerebral cavities contributes to clinical variability. doi: 10.1212/WNL.0b013e3181c3fd12, 9. What does it mean to have a COL4A1 gene mutation: The COL4A1 gene provides instructions for making one component of type IV collagen, which is a flexible protein important in the structure of many. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. IV-3 goes to a normal school, but special schooling is required for IV-6. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Still other individuals may not develop any symptoms until well into adulthood. 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. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. doi: 10.1056/NEJMoa1707914, 6. We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. (2014) 34:757. eCollection 2021. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Neurology. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. (2007) 357:268795. 10.2174/092986710790936293. Understanding what it has taken to get her to this point, though, is close to unimaginable. 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. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . Seattle, WA: University of Washington, Seattle; 1993-. Suite 310 The signs and symptoms can manifest at almost any age from before birth to old age. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. 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). Am J Med Genet A. doi: 10.1212/WNL.0000000000000837, 20. What does it mean if a disorder seems to run in my family? Treatment Childhood presentation of COL4A1 mutations. Changing lives of those with rare disease. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Matrix Biol. Type IV collagen molecules attach to each other to form complex protein networks. doi: 10.1038/gim.2014.210, 3. 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. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. (18) and Staals et al. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Phone: 203-263-9938 It is ubiquitously expressed in many tissues and cell types. Some individuals develop cysts on the kidney. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Bookshelf Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Ann 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. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. Eur J Med Genet. Autosomal Dominant Brain Small Vessel Disease. People listened to us and to Zeeva in a very different and proactive way. GeneReviews. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Curr Med Chem. Participants with epilepsy frequently reported developmental delays (88.6%), stroke (60.0%), cerebral palsy (65.7%), and constipation (57.1%). This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. When these ropes are secreted, they assemble into net-like structures outside the cells. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. How can gene variants affect health and development? No microbleeds or cystic cavities were found. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. Purpose of review: Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Recent findings: (2010). (2004) 62:16135. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. At least 50 individuals with this condition have been described in the scientific literature. Please note that NORD provides this information for the benefit of the rare disease community. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. 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 conditions in this group have a range of signs and symptoms that involve fragile blood vessels. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. 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: The severity of the condition varies greatly among affected individuals. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. What are the different ways a genetic condition can be inherited? The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. 2011 Epub 2014 Jan 5. (2009) 73:187382. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Further refinement of COL4A1 and COL4A2 related cortical malformations. 2009 Jun 25 [updated 2016 Jul 7]. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. In the human genome, there are 46 chromosomes. 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. Lanfranconi S, Markus HS. Graefe's Arch Clin Exp Ophthalmol. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. 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). In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. 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. Stroke is a leading cause of death and serious long-term disability in developed nations. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. J Genet Couns. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. He also wanted to remove a shunt that was implanted in Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. Your support helps to ensure everyones free access to NORDs rare disease reports. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Am J Neuroradiol. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. She has regular physical, speech, and occupational therapy. 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. Suite 310 Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Changing lives of those with rare disease. 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. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Clin Neurol Neurosurg. 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). View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. eCollection 2022. To use the sharing features on this page, please enable JavaScript. https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, For information about clinical trials sponsored by private sources, contact: can also contribute. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. Please note that NORD provides this information for the benefit of the rare disease community. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. N Engl J Med. The disorder causes many symptoms, not the least of which are strokes and epilepsy. N Engl J Med. She, then, developed seizures which were controlled by valproic acid. 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. Genet Med. Neurology. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. However, there are exceptions that depend on precisely when and where the mutation arose. eCollection 2022. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists.