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. COL4A1 mutations in patients with sporadic late-onset intracerebral Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. (2014) 83:122834. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Finding the best care for Zeeva - Boston Children's Answers In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Sue. https://www.ncbi.nlm.nih.gov/pubmed/26610912. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. eCollection 2021. Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke Gould Syndrome is an ultra rare genetic, multi-system disorder. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. Neuropediatrics. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 30. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). In the brain, intracerebral hemorrhage is the most frequent phenotype. No use, distribution or reproduction is permitted which does not comply with these terms. doi: 10.1056/NEJMoa053727, 7. The number of genes implicated in epilepsy has grown rapidly in the past decade. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. COL4A1 and COL4A2 are on Chr. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . PV and VW followed the children at the Neuropediatrics clinic of the same hospital. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). Painful muscle cramps can occur and can develop before three years of age. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. 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. Childhood presentation of COL4A1 mutations. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. NCI CPTC Antibody Characterization Program. government site. 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. The risk is the same for males and females. It affects mainly young adults, children and more typically neonates. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. Genet Med. Careers. doi: 10.1055/s-0031-1275343, 24. 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). 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. 1779 Massachusetts Avenue Curr Opin Neurol. This condition causes mutations in genes that produce a specific type of collagen. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. COL4A1 -Related Disorders - PubMed Clinical Testing and Workup Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Washington, DC 20036 COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Bookshelf Ann COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. 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. Firstly, it segregates within the family with the phenotype. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. 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 Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. (2007) 357:268795. Suite 500 1900 Crown Colony Drive January 31, 2019 Some individuals develop cysts on the kidney. doi: 10.1016/j.matbio.2016.10.003, 23. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. We provide education, advocacy, and resources for families and individuals affected. doi: 10.1056/NEJMoa071906, 14. N Engl J Med. Still other individuals may not develop any symptoms until well into adulthood. Accessibility Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. 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. 1779 Massachusetts Avenue In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. In most people, small vessel disease in the brain does not cause symptoms. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. 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. 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. mutations: a novel genetic multisystem disease. J Perinatol. Collagen, type IV, alpha 1 - Wikipedia J Neurol Sci. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. IV-3 was diagnosed with ventriculomegaly in utero. 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 doi: 10.1111/cge.12543. Please enable it to take advantage of the complete set of features! Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. FOIA Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Muscle cramps can be spontaneous or triggered by exercise. These genes are the blueprints for two proteins that wind together like a long rope inside cells. (2010) 75:7479. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome 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. doi: 10.1111/cge.12379, 13. 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). In affected individuals, stroke is usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke), although either type can occur. Jeanne M, Gould DB. One patient (IV-3) was treated for spasticity and seizures with valproic acid. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. MedlinePlus also links to health information from non-government Web sites. 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. Early intervention is important in ensuring that children with reach their highest potential. In most cases, an affected person has one parent with the condition. 2009 Jun 25 [Updated 2016 Jul 7]. 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.) This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Hum Mol Genet. Front. The first time he came to meet us, Zeeva threw a sock at him. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Science. Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects). Please note that NORD provides this information for the benefit of the rare disease community. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Various muscles can be affected and muscle strength can become weakened. Practical approach to the diagnosis of adult-onset - BMJ Bull Acad Natl Med. Suite 310 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. Matrix Biol. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. In the brain, intracerebral hemorrhage is the most frequent phenotype. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. 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. 10.1161/STROKEAHA.110.581918. Fax: 203-263-9938, Washington, DC Office 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). The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. COL4A1 brain small-vessel disease - Radiopaedia (2008) 17:42433. Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDs mission. She also showed severe hypermetropia. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization 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. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. Zagaglia Selch C, Nisevic JR, et al. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. The severity of the condition varies greatly among affected individuals. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. 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). NORD is a registered 501(c)(3) charity organization. Facebook: https://www.facebook.com/Col4A1Foundation Please Note (1982) 40:5679. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. NORD strives to open new assistance programs as funding allows. Thats not to say Zeeva hasnt had to work hard since the surgery. doi: Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Neurol. This is called genotype-phenotype correlation. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. 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. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Lenses corrected for hypermetropia. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. In the human genome, there are 46 chromosomes. 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. A diagnosis can be confirmed through molecular genetic testing. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Neurology. 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: 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). This site needs JavaScript to work properly. Neurology. It looks like nothing was found at this location. The disorder causes many symptoms, not the least of which are strokes and epilepsy. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. doi: 10.1136/jmg.2005.035584, 15. Further refinement of COL4A1 and COL4A2 related cortical malformations. 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). People listened to us and to Zeeva in a very different and proactive way. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Other patients have been reported with cysts on the liver, irregular heartbeats (supraventricular arrhythmia), and Raynaud phenomenon, which is in which the fingers or toes become numb or have a prickly sensation in response to cold due to narrowing of blood vessels. Dev Med Child Neurol. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial 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. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. What is the prognosis of a genetic condition? doi: 10.1212/WNL.0000000000000837, 20. doi: 10.1038/nmeth.2890, 22. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Jeanne M, Gould DB. COL4A1 Mutations Cause Neuromuscular Disease with - ScienceDirect Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. doi: 10.1002/ana.23736, 4. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Bethesda, MD 20894, Web Policies 2018;91:e2078-e2088. Hereditary cerebral small vessel diseases: a review. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Am J Med Genet A. How can gene variants affect health and development? 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. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. Stroke is a leading cause of death and serious long-term disability in developed nations. It is passed through families in a autosomal dominant fashion. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. Summary: The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. Autosomal Dominant Brain Small Vessel Disease. 55 Kenosia Avenue These exceptions are nuanced and should be discussed with a genetic counselor. She, then, developed seizures which were controlled by valproic acid. (2017) 5758:2944. Type IV collagen molecules attach to each other to form complex protein networks. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Unauthorized use of these marks is strictly prohibited. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. cutting tissue called the corpus callosum, then make some additional delicate 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. 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). Bone. Copyright 2023 by Gould Syndrome Foundation -. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. Prenatal clinical manifestations in individuals with COL4A1/2 variants. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Disease Overview. Cereb Circ Cogn Behav. Changing lives of those with rare disease. 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. 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. COL4A1/A2-related disorders are dominant genetic disorders. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. 11:827. doi: 10.3389/fneur.2020.00827. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels.

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