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Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. Ophthalmological features associated with COL4A1 mutations. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. This site needs JavaScript to work properly. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Axenfeld-Rieger anomaly is associated with various other eye abnormalities, including underdevelopment and eventual tearing of the colored part of the eye (iris), and a pupil that is not in the center of the eye. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Lenses corrected for hypermetropia. Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation Gould Syndrome Foundation We are a registered 501 (c)3 Nonprofit dedicated to providing hope and help to children and adults with Gould Syndrome; affecting COL4A1 and COL4A2 genes. Childhood presentation of COL4A1 mutations. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. COL4A1 is an essential component for basal membrane stability and exon mutations of COL4A1 gene mutations are responsible for a broad spectrum of systemic manifestations characterized by small vessel involvement of variable severity, including neurological ( 1) [porencephaly ( 2 - 4 ), hemorrhage ( 2, 5 - 7) and aneurysms ( 8 )], ophthalmological To better define pathology caused by Col4a1 mutations, we characterized myopathy in two different Col4a1 mutant mouse strainsCol4a1 ex41 and Col4a1 G394V.We selected these strains from an allelic series of Col4a1 mutant mice because they showed the most severe myopathy according to NPN quantification in quadriceps while having different effects on [1(IV)] 2 2(IV) secretion. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. 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. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. 1779 Massachusetts Avenue Migraines can occur with or without aura. 2010;17(13):1317-24. doi: She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. for the triple helical CB3[IV] domain. doi: 10.1002/ajmg.10452, 18. Matrix Biol. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. In a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). Quincy, MA 02169 Gould Syndrome is a rare, genetic, multi-system disorder. doi: 10.1002/ana.23736, 4. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Suite 310 For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Danbury, CT 06810 Various treatments have been reported in the medical literature as part of single case reports or small series of patients. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. In the human genome, there are 46 chromosomes. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. By continuing to use this website, you agree to the Terms of Service & Privacy Policy, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. (2004) 62:16135. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Summary. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. She also showed severe hypermetropia. 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. National Taiwan University Hospital, Taiwan, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Carrera de Medicina, Universidad Cientfica del Sur, Peru, Federal University of Rio Grande do Sul, Brazil. 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. Autosomal Dominant Familial Porencephaly Type I. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role 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. Changing lives of those with rare disease. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. At least 50 individuals with this condition have been described in the scientific literature. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. 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 (2013) 73:4857. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. COL4A1 is an essential component for basal membrane stability and exon mutations of COL4A1 gene mutations are responsible for a broad spectrum of systemic manifestations characterized by small vessel involvement of variable severity, including neurological (1) [porencephaly (24), hemorrhage (2, 57) and aneurysms (8)], ophthalmological (912) (retinal artery tortuosity, Axenfeld Rieger anomalies, cataracts, and severe hypermetropia), renal (13) (renal cysts, and microscopic hematuria), and systemic (13) findings (cramps with a high creatine kinase level [CK], Raynaud's phenomenon, and arrhythmias). Danbury, CT 06810 FOIA Individuals with this condition are at increased risk of having more than one stroke in their lifetime. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. 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. What are the different ways a genetic condition can be inherited? Firstly, it segregates within the family with the phenotype. Patients must rely on the personal and individualized medical advice of their qualified health care professionals before seeking any information related to their particular diagnosis, cure or treatment of a condition or disorder. Nearly half of these participants were diagnosed with infantile spasms. INTERNET Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. doi: 10.1186/s12881-014-0097-2, 11. Clin Neurol Neurosurg. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. doi: 10.1056/NEJMoa053727, 7. It affects mainly young adults, children and more typically neonates. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. If either parent also carries the mutation, it is considered inherited. Phone: 203-263-9938 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. doi: 10.1007/s10897-008-9169-9, 16. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. Bennett RL, French KS, Resta RG, Doyle DL. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. NORD is a registered 501(c)(3) charity organization. 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). One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Neurology. In the brain, intracerebral hemorrhage is the most frequent phenotype. GeneReviews. In her first six years of life, Zeeva spent hundreds of nights in the hospital, had 13 operations and countless procedures, (from eye surgeries to Achilles heel, a shunt placed in her brain, and spine surgery). Fax: 203-263-9938, Washington, DC Office 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. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. 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. National Institute of Neurological Disorders and Stroke. No use, distribution or reproduction is permitted which does not comply with these terms. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Am J Neuroradiol. doi: 10.1001/archneur.1983.04050080067013, 17. (2010) 14:1827. Arch Neurol. doi: 10.1212/WNL.0000000000000837, 20. 2009 Jun 25 [updated 2016 Jul 7]. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. IV-3 had a left hemisphere porencephalic cyst and the lack of evidence of a left corticospinal tract on tractography (Figures 3E,F), IV-5 had a porencephalic cyst on the right lateral ventricle (Figure 3C), and III-3 had leukoencephalopathy (Figure 3D). It is not uncommon for an unaffected parent to have a severely affected child. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). doi: 10.1007/s00417-014-2800-6, 12. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. eCollection 2021. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). 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. Lanfranconi S, Markus HS. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, How are genetic conditions treated or managed? Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Neurology. Fetal intracerebral hemorrhage and cataract: think COL4A1. Ultrasound in utero from IV-6 (A). basement membranes surrounding the body's blood vessels, Genetic Testing Registry: Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, National Organization for Rare Disorders (NORD), ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS. 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. Disclaimer. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes. Careers. We are a registered 501(c)3 Nonprofit dedicated to providing hope and help to children and adults with Gould Syndrome; affecting COL4A1 and COL4A2 genes. 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. Front Aging Neurosci. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. Type IV collagen molecules attach to each other to form complex protein networks. Genet Med. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. In the brain, intracerebral hemorrhage is the most frequent phenotype. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Jeanne M, Gould DB. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. We provide education, advocacy, and resources for families and individuals affected. Purpose of review: Surgery or endovascular therapy can be used to treat intracranial hemorrhage. 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. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: 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. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. He would separate the two halves of her brain by Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. Neurol. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 (2005) 308:116771. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. This group rarely survives beyond 2 years. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. 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. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). Unable to load your collection due to an error, Unable to load your delegates due to an error. 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. September 2003. 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. doi: 10.1111/cge.12379, 13. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Plaisier E, Ronco P. COL4A1-Related Disorders. Eur J Med Genet. (2006) 354:148996. These exceptions are nuanced and should be discussed with a genetic counselor. 2011 (18) and Staals et al. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. eCollection 2022 Nov 8. This condition causes mutations in genes that produce a specific type of collagen. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. Front. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. Contact a health care provider if you have questions about your health. Neurology. 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. NORD strives to open new assistance programs as funding allows. Curr Opin Neurol. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. 11:827. doi: 10.3389/fneur.2020.00827. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. He was confident this would reduce or stop the These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Autosomal Dominant Brain Small Vessel Disease. 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. The information on this site should not be used as a substitute for professional medical care or advice. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. doi: 10.1212/WNL.0b013e3181eee440, 28. (2014) 15:16. Muscle cramps can be spontaneous or triggered by exercise. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Curr Opin Neurol. 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: 8600 Rockville Pike (2017) 377:111931. (2014) 34:757. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical relating to specific areas of the brain supplied by deep small arteries (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. percent confident in Dr. Madsen and the epilepsy team. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. U.S. Department of Health and Human Services, Autosomal dominant familial hematuria, retinal arteriolar tortuosity, contractures, Hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome. It is passed through families in a autosomal dominant fashion. Arch Ophthalmol. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. came with risks and was the hardest decision we had ever faced, yet we felt 100 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. It is important to discuss these concepts with a genetic counselor and understand their implications. COL4A1 is an essential component for basal membrane stability. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Suite 500 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. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. 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. can also contribute. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. In most cases, an affected person has one parent with the condition. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). doi: 10.1038/nmeth.2890, 22. The severity of the condition varies greatly among affected individuals. 2010 Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. 2012;21:R97-R110. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Therapies are based on the specific symptoms in each individual. No microbleeds or cystic cavities were found. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. One patient (IV-3) was treated for spasticity and seizures with valproic acid. 30. 4 Both . Phone: 202-588-5700. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Cereb Circ Cogn Behav. Hum Mol Genet. doi: 10.1212/WNL.0b013e3181c3fd12, 9. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture.