2010;17(13):1317-24. doi: 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). Berg R, Aleck A, Kaplan A. Familial porencephaly. official website and that any information you provide is encrypted Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. This condition causes mutations in genes that produce a specific type of collagen. This condition causes mutations in genes that produce a specific type of collagen. Unauthorized use of these marks is strictly prohibited. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. 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. The risk is the same for males and females. 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. It is not uncommon for an unaffected parent to have a severely affected child. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant thus, Gould Syndrome is considered Autosomal Dominant. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Our data testing the effects of established mutations on collagen biosynthesis suggest that the intracellular retention of mutant COL4A1 proteins at the expense of their secretion appears to be a common effect of many COL4A1 mutations. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. doi: 10.1126/science.1109418, 5. Phone: 203-263-9938 Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Bone. At least 50 individuals with this condition have been described in the scientific literature. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. The degree of mosaicism is highly variable ranging from only a small percent of cells with the mutation to nearly all cells carrying the mutation and depends on the stage during development that the mutation occurred. Federal government websites often end in .gov or .mil. 2017;57-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. Gould Syndrome is often 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. 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. Phone: 617-249-7300, Danbury, CT 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. Jeanne M, Gould DB. TTY: (866) 411-1010 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. Front. However, there are exceptions that depend on precisely when and where the mutation arose. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. 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). 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. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Danbury, CT 06810 Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. HANAC syndrome is a rare condition, although the exact prevalence is unknown. 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). 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. Gould Syndrome is an ultra rare genetic, multi-system disorder. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. doi: 10.1136/jmg.2005.035584, 15. 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). It is passed through families in a autosomal dominant fashion. 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. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). This site needs JavaScript to work properly. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Disclaimer. Affected individuals may have no observable symptoms or only isolated migraines with aura. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. 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. Eur J Med Genet. This page is currently unavailable. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. (2014) 11:3612. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. 128:4839. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Fax: 203-263-9938, Washington, DC Office Childhood presentation of COL4A1 mutations. Clinical Testing and Workup Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 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. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. Prenatal clinical manifestations in individuals with COL4A1/2 variants. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. 4 Both . The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. Arch Neurol. 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). (2011) 42:13. Fetal intracerebral hemorrhage and cataract: think COL4A1. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. 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. (1987) 8:4216. NORD gratefully acknowledges Douglas Gould, PhD, Professor, Director of Research, Denise B. Evans Endowed Chair in Ophthalmology, Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, and the COL4A1 Foundation, for assistance in the preparation of this report. There are no standardized treatment protocols or guidelines for affected individuals. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). 2012;21:R97-R110. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. These exceptions are nuanced and should be discussed with a genetic counselor. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. The severity of the condition varies greatly among affected individuals. 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. At least six affected families have been described in the scientific literature. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. (2008) 17:42433. 2010 Aug;41(8):e513-8. . The signs and symptoms can manifest at almost any age from before birth to old age. Neurol. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Contact a health care provider if you have questions about your health. Changing lives of those with rare disease. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Neurology. 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. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. 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. mutations: a novel genetic multisystem disease. What does it mean if a disorder seems to run in my family? Stroke. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. 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. (2015) 84:91826. Years published: 2019. Bethesda, MD 20894, Web Policies 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. 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. 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). Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. One patient (IV-3) was treated for spasticity and seizures with valproic acid. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. cutting tissue called the corpus callosum, then make some additional delicate 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. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. 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. In the brain, intracerebral hemorrhage is the most frequent phenotype. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Hereditary cerebral small vessel diseases: a review. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. 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.) (2008) 23:17. eCollection 2022. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. Progressive cerebral atrophies in three children with COL4A1 mutations. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. 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). 1900 Crown Colony Drive Therapies are based on the specific symptoms in each individual. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. 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. Arch Ophthalmol. Type IV collagen molecules attach to each other to form complex protein networks. 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.
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