The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. 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. Suite 310 Please enable it to take advantage of the complete set of features! When we didnt feel we had any options left for treatment, Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. NORD is a registered 501(c)(3) charity organization. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Ophthalmological features associated with COL4A1 mutations. 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. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Understanding what it has taken to get her to this point, though, is close to unimaginable. The COL4A1 and COL4A2 genes were screened in proband IV-6. N Engl J Med. Graefe's Arch Clin Exp Ophthalmol. doi: 10.1056/NEJMoa053727, 7. Epub 2016 Apr 24. for the triple helical CB3[IV] domain. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. 10.1161/STROKEAHA.110.581918. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. However, in people with HANAC syndrome, these aneurysms typically do not burst. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. This condition causes mutations in genes that produce a specific type of collagen. 2010 Aug;41(8):e513-8. MedlinePlus also links to health information from non-government Web sites. doi: 10.1038/jp.2013.135, 29. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Clin Genet. doi: 10.1212/WNL.0000000000000837, 20. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Gould Syndrome is an ultra rare genetic, multi-system disorder. Danbury, CT 06810 doi: (2006) 43:4905. Please note that NORD provides this information for the benefit of the rare disease community. This group rarely survives beyond 2 years. While there are other explanations, parental mosaicism should be considered. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. (2014) 83:122834. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Plaisier E, Ronco P. COL4A1-Related Disorders. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. doi: 10.1016/j.ejpn.2009.04.010, 27. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. Science. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Cereb Circ Cogn Behav. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Autosomal Dominant Familial Porencephaly Type I. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. A diagnosis can be confirmed through molecular genetic testing. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. The risk is the same for males and females. Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). came with risks and was the hardest decision we had ever faced, yet we felt 100 All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Pediatr Neurol. The disorder causes many symptoms, not the least of which are strokes and epilepsy. 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.) As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Nat Methods. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. my mom suggested we call Boston Childrens Hospital. 1779 Massachusetts Avenue She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. MeSH Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 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. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. 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. 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). Last updated: 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. Years published: 2019. ClinVar; [VCV000389182.3]. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories. 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. Some individuals develop cysts on the kidney. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. 10.2174/092986710790936293. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. 2009 Jun 25 [updated 2016 Jul 7]. 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. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. doi: 10.1007/s00417-014-2800-6, 12. Axenfeld-Rieger anomaly involves underdevelopment and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. 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. 2010;17(13):1317-24. doi: Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. January 31, 2019 TTY: (866) 411-1010 128:4839. doi: 10.1007/s10897-008-9169-9, 16. NCI CPTC Antibody Characterization Program. After a normal neonatal period, those affected develop a rapidly progressive course involving irritability, hyperaesthesia, visual and hearing loss, severe cognitive and motor deterioration, and seizures. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 1900 Crown Colony Drive Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Firstly, it segregates within the family with the phenotype. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. In most people, small vessel disease in the brain does not cause symptoms. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. These exceptions are nuanced and should be discussed with a genetic counselor. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. (2013) 73:4857. 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. 8600 Rockville Pike 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: COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. doi: 10.1212/WNL.0000000000001309, 8. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. The signs and symptoms can manifest at almost any age from before birth to old age. 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. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Hum Mol Genet. There are no standardized treatment protocols or guidelines for affected individuals. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Lanfranconi S, Markus HS. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. 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. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. Gould Syndrome is an ultra rare genetic, multi-system disorder. Autosomal Dominant Brain Small Vessel Disease. Bookshelf What does it mean if a disorder seems to run in my family? She also showed severe hypermetropia. These genes are the blueprints for two proteins that wind together like a long rope inside cells. 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. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). Surgery may be necessary for individuals with severe cataracts. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. In most cases, an affected person has one parent with the condition. The number of genes implicated in epilepsy has grown rapidly in the past decade. Epub 2022 Apr 14. Washington, DC 20036 In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. Please note that NORD provides this information for the benefit of the rare disease community. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. 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. Stroke. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. percent confident in Dr. Madsen and the epilepsy team. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. Painful muscle cramps can occur and can develop before three years of age. 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. Unable to load your collection due to an error, Unable to load your delegates due to an error. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. Curr Opin Neurol. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Curr Opin Neurol. About half of people with this condition also have leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI). Bennett RL, French KS, Resta RG, Doyle DL. (19). This raises questions about what tests Liliane has a lot to be grateful for this holiday season. doi: 10.1111/j.1469-8749.2011.04198.x, 26. NORD strives to open new assistance programs as funding allows. HANAC syndrome is a rare condition, although the exact prevalence is unknown. and transmitted securely. Genet Med. Before Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Zeevas brain to treat a cyst in her brain caused by porencephaly. J Perinatol. What are the different ways a genetic condition can be inherited? (2005) 308:116771. However, there are exceptions that depend on precisely when and where the mutation arose. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. The size and location of cerebral cavities contributes to clinical variability. Epub 2010 Jun 17. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. 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. 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).