Jeanne M, Gould DB. What is the prognosis of a genetic condition? The number of genes implicated in epilepsy has grown rapidly in the past decade. She, then, developed seizures which were controlled by valproic acid. Hum Mol Genet. (2010). 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. 55 Kenosia Avenue *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Phone: 202-588-5700. 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. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). 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. Clinically, COL4A1 mutations are responsible for different overlapping phenotypes including porencephaly (24), brain small vessel disease (2, 57) with or without ocular anomalies, HANAC (13) (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome, ophthalmological abnormalities (912), and non-syndromic autosomal dominant congenital cataracts (10). 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. A diagnosis can be confirmed through molecular genetic testing. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. 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. 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). 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. sharing sensitive information, make sure youre on a federal 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://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: The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. NORD strives to open new assistance programs as funding allows. National Center for Biotechnology Information. Genet Med. 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. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. NORD is a registered 501(c)(3) charity organization. Facebook: https://www.facebook.com/Col4A1Foundation Please Note 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 . View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina E. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. . All authors contributed to the article and approved the submitted version. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Neurology. 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. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. (2012) 54:56974. Pediatr Neurol. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Congenital Cephalic Disorders 1A-B). Disease Overview. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. He also wanted to remove a shunt that was implanted in The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. The disorder causes many symptoms, not the least of which are strokes and epilepsy. 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). Last updated: Rarely, new mutations in the gene occur in people with no history of the disorder in their family. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. NORD is a registered 501(c)(3) charity organization. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. doi: 10.1055/s-0031-1275343, 24. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. The information on this site should not be used as a substitute for professional medical care or advice. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. It is ubiquitously expressed in many tissues and cell types. (2015) 88:46873. 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. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. doi: 10.1212/WNL.0b013e3181c3fd12, 9. People listened to us and to Zeeva in a very different and proactive way. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. HHS Vulnerability Disclosure, Help Science. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. Epub 2014 Jan 5. 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. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. GeneReviews. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. PMC When this enzyme is elevated, it is a sign of muscle damage. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Doctors and researchers to bring research and medical therapeutic options to those affected. Clin Neurol Neurosurg. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. 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. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. ACS Omega. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. Autosomal Dominant Brain Small Vessel Disease. 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. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. 30. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. 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). The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . TTY: (866) 411-1010 III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. Ophthalmological features associated with COL4A1 mutations. Am J Neuroradiol. 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. doi: 10.1212/WNL.0b013e3181eee440, 28. Surgery may be necessary for individuals with severe cataracts. 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). Axenfeld-Rieger anomaly and cataract can cause impaired vision. Curr Opin Neurol. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. (2015) 17:40524. Full ophthalmological evaluations including slit lamp and fundoscopy were realized and disclosed for bilateral hypermetropia in IV-3 [15 dioptre (D)], IV-6 (8.5 D), IV-5 (10 D), and III-3 (7 D). Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, 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. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients even among members of a family who carry the same gene mutation. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. 4 Both . doi: 10.1056/NEJMoa071906, 14. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. The blood vessels as well as thin sheet-like structures called basement membranes that separate and support cells are weakened and more susceptible to breakage. Purpose of review: 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. He was confident this would reduce or stop the Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. September 2003. Neuropediatrics. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Keywords: COL4A1, Type IV collagen, familial porencephaly, ocular malformations, variable expressivity, Citation: Scoppettuolo P, Ligot N, Wermenbol V, Van Bogaert P and Naeije G (2020) p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Porencephaly and Severe Hypermetropia. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. https://www.ncbi.nlm.nih.gov/pubmed/26610912. Resource(s) for Medical Professionals and Scientists on This Disease: Gould Syndrome is a rare, genetic, multi-system disorder. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. With input from doctors, researchers, and the US Food & Drug Administration, NORD has created IAMRARE to facilitate patient-powered natural history studies to shape rare disease research and treatments. 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. We provide education, advocacy, and resources for families and individuals affected. ClinVar; [VCV000389182.3]. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. Accessibility Epub 2010 Jun 17. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. doi: 10.1038/nmeth.2890, 22. In addition to porencephaly there can be other forms of damage to the brain present at birth. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Quincy, MA 02169 III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Changing lives of those with rare disease. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. doi: 10.1002/ajmg.10452, 18. 1779 Massachusetts Avenue Therapies are based on the specific symptoms in each individual. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). Danbury, CT 06810 Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. What are the different ways a genetic condition can be inherited? 1900 Crown Colony Drive my mom suggested we call Boston Childrens Hospital. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Nat Methods. The information on this site should not be used as a substitute for professional medical care or advice. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. (2005) 308:116771. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. COL4A1 is an essential component for basal membrane stability. Years published: 2019. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Six alpha chains of type IV. In most cases, an affected person has one parent with the condition. 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. The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Suite 500 can also contribute. J Perinatol. 2011 (2011) 42:13. The signs and symptoms can manifest at almost any age from before birth to old age. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Type IV collagen molecules attach to each other to form complex protein networks. In the brain, intracerebral hemorrhage is the most frequent phenotype. To use the sharing features on this page, please enable JavaScript. People with COL4A1-related brain small vessel disease 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).