col4a1 syndrome life expectancy

Probands' father had severe hypermetropia and bilateral cataracts. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. She, then, developed seizures which were controlled by valproic acid. 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. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps In the human genome, there are 46 chromosomes. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Please enable it to take advantage of the complete set of features! Resource(s) for Medical Professionals and Scientists on This Disease: To use the sharing features on this page, please enable JavaScript. The risk is the same for males and females. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. What does it mean to have a COL4A1 - Little Braveheart | Facebook The https:// ensures that you are connecting to the 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. 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. Autosomal Dominant Familial Porencephaly Type I. 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: Prenatal clinical manifestations in individuals with COL4A1/2 variants. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. 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. 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. 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. 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. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. J Med Genet. In the human genome, there are 46 chromosomes. Cavalin M, Mine M, Philbert M, et al. (2017) 5758:2944. 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. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Suite 500 Would you like email updates of new search results? doi: 10.1056/NEJMoa1707914, 6. 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. 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). doi: 10.1212/01.WNL.0000123113.46672.68, 25. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Understanding what it has taken to get her to this point, though, is close to unimaginable. Here, we report a patient with schizencephaly, detected by fetal ultrasonography and fetal magnetic resonance imaging, with a de novo novel mutation in COL4A1 (c.2645_2646delinsAA, p.Gly882Glu). If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Individuals with HANAC syndrome also experience a variety of eye problems. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). (18) and Staals et al. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. 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. Washington, DC 20036 No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Six alpha chains of type IV. 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. Please note that NORD provides this information for the benefit of the rare disease community. (2015) 17:40524. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. No microbleeds or cystic cavities were found. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. doi: 10.1007/s10897-008-9169-9, 16. Pathology. 2012;21:R97-R110. Antiinflammatory therapy with canakinumab for atherosclerotic disease. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. COL4A1 -Related Disorders - PubMed Neurol. Phone: 202-588-5700. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Internet. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. (No doctor had ever taken a call on their lunch break to speak with me). This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. mutations: a novel genetic multisystem disease. This group rarely survives beyond 2 years. Mutations in the COL4A1 gene cause HANAC syndrome. The first time he came to meet us, Zeeva threw a sock at him. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. COL4A1 is an essential component for basal membrane stability. 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. 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. Orphanet: HANAC syndrome Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus N Engl J Med. 55 Kenosia Avenue 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. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. 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. What does it mean if a disorder seems to run in my family? Plaisier E, Ronco P. COL4A1-Related Disorders. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. This site needs JavaScript to work properly. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Gould Syndrome is an ultra rare genetic, multi-system disorder. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. 2010;17(13):1317-24. doi: In the brain, intracerebral hemorrhage is the most frequent phenotype. 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. What is the prognosis of a genetic condition? mutations: a novel genetic multisystem disease. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) 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). Pediatr Neurol. doi: Neurology. 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. Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. PMC (2002) 112:198202. doi: 10.1056/NEJMoa071906, 14. (19). 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). People with HANAC syndrome develop kidney disease (nephropathy). Standardized (15) familiar pedigree is showed in Figure 1. Thats not to say Zeeva hasnt had to work hard since the surgery. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Gould Syndrome is a rare, genetic, multi-system disorder. Last updated: She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. These genes are the blueprints for two proteins that wind together like a long rope inside cells. Maybe try a search? Phone: 203-263-9938 PS: wrote thi paper and performed the review of the literature under the supervision of GN. eCollection 2021. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. HANAC syndrome is a rare condition, although the exact prevalence is unknown. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. 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. doi: 10.1038/gim.2014.210, 3. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for Not only did Dr. Madsen, help heal Zeevas brain, but he was instrumental in supporting us as we founded the Gould Syndrome Foundation, a 501(c)(3) non-profit that promotes education, advocacy, and medical advancements in Gould Syndrome, COL4A1/COL4A2 diseases. 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. It is ubiquitously expressed in many tissues and cell types. The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The disorder causes many symptoms, not the least of which are strokes and epilepsy. What is Gould Syndrome? - Gould Syndrome Foundation Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. COL4A1/A2-Related Disorders - Symptoms, Causes, Treatment | NORD The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. 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. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. 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. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) 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. There are no standardized treatment protocols or guidelines for affected individuals. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. In addition to porencephaly there can be other forms of damage to the brain present at birth. Please note that NORD provides this information for the benefit of the rare disease community. Cereb Circ Cogn Behav. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Years published: 2019. Painful muscle cramps can occur and can develop before three years of age. Any muscle may be affected, and cramps usually last from a few seconds to a few minutes, although in some cases they can last for several hours. How are genetic conditions treated or managed? This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. These exceptions are nuanced and should be discussed with a genetic counselor. Neurology. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. (2014) 11:3612. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. It is passed through families in a autosomal dominant fashion. Gould Syndrome is an ultra rare genetic, multi-system disorder. A diagnosis can be confirmed through molecular genetic testing. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. 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%). 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). Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. 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. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Ann Neurol. Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. What is the prognosis of a genetic condition? Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. 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. While there are other explanations, parental mosaicism should be considered. 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. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. Matrix Biol. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. 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. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. However, in people with HANAC syndrome, these aneurysms typically do not burst. Migraines can occur with or without aura. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. NORD is a registered 501(c)(3) charity organization. Graefe's Arch Clin Exp Ophthalmol. Seattle, WA: University of Washington, Seattle; 1993-. However, there are exceptions that depend on precisely when and where the mutation arose. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Neurology. 2008 May;192(5):971-84; discussion 984-6. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. doi: 10.1212/WNL.0000000000000837, 20. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Phone: 617-249-7300, Danbury, CT office doi: 10.1038/jp.2013.135, 29. doi: 10.1136/jmg.2005.035584, 15. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. 2010 Am J Med Genet. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 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. Autosomal Dominant Brain Small Vessel Disease. Bennett RL, French KS, Resta RG, Doyle DL. 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). doi: 10.1038/gim.2015.30, 21. 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). Some individuals develop cysts on the kidney. doi: 10.1002/ajmg.10452, 18. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. doi: 10.1111/cge.12543. Suite 500 For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. To use the sharing features on this page, please enable JavaScript. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. 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. Washington, DC 20036 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.

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