col4a1 syndrome life expectancy

Last updated: doi: 10.1126/science.1109418, 5. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. The signs and symptoms can manifest at almost any age from before birth to old age. doi: 10.1055/s-0031-1275343, 24. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. 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. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. 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. Neurology. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Clin Genet. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Congenital Cephalic Disorders These exceptions are nuanced and should be discussed with a genetic counselor. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. (2010). The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Dev Med Child Neurol. eCollection 2022. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Some individuals develop cysts on the kidney. Internet. Accessibility Painful muscle cramps can occur and can develop before three years of age. 8600 Rockville Pike Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Cephalic Disorders Fact Sheet. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. January 31, 2019 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. (2006) 43:4905. Contact a health care provider if you have questions about your health. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). 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. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Ophthalmological features associated with COL4A1 mutations. They are typically characterized by abnormal blood vessels in the brain (cerebral vasculature defects), eye development defects (ocular dysgenesis), muscle disease (myopathy), and kidney abnormalities (renal pathology); however, many other aspects of the syndrome including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. 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 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. 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. The retina is the light-sensitive membrane that lines the inside of the eyes. Unauthorized use of these marks is strictly prohibited. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Surgery may be necessary for individuals with severe cataracts. 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. In addition to porencephaly there can be other forms of damage to the brain present at birth. doi: 10.1212/WNL.0b013e3181eee440, 28. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. Pediatr Neurol. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. 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. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Years published: 2019. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. No microbleeds or cystic cavities were found. Still other individuals may not develop any symptoms until well into adulthood. 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. Childhood presentation of COL4A1 mutations. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms. She also showed severe hypermetropia. 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). 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. There are no standardized treatment protocols or guidelines for affected individuals. 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. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. This site needs JavaScript to work properly. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. doi: 10.1056/NEJMoa1707914, 6. Ann Neurol. (2006) 354:148996. 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. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. 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. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. II-2 had a limp since childhood attributed to forceps delivery. 1900 Crown Colony Drive small vessel disease: a systematic review. Graefe's Arch Clin Exp Ophthalmol. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Prenatal clinical manifestations in individuals with COL4A1/2 variants. doi: 10.1056/NEJMoa053727, 7. doi: 10.1111/j.1469-8749.2011.04198.x, 26. Before (2007) 357:268795. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. (2015) 84:91826. 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. 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. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Type IV collagen molecules attach to each other to form complex protein networks. Hereditary cerebral small vessel diseases: a review. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. About half of people with this condition 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). In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. However, there are exceptions that depend on precisely when and where the mutation arose. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Am J Med Genet. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Bookshelf doi: 10.2214/ajr.149.2.351, 19. 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. Axenfeld-Rieger anomaly and cataract can cause impaired vision. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). COL4A1 mutations as a monogenic cause of cerebral The https:// ensures that you are connecting to the To use the sharing features on this page, please enable JavaScript. (2004) 62:16135. 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. Neurology. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. GeneReviews. 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. 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). NCI CPTC Antibody Characterization Program. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. What does it mean to have a COL4A1 gene mutation: The COL4A1 gene provides instructions for making one component of type IV collagen, which is a flexible protein important in the structure of many. Epub 2016 Apr 24. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. doi: 10.1016/j.matbio.2016.10.003, 23. N Engl J Med. 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. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. 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. J Genet Couns. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. (2014) 83:122834. mutations: a novel genetic multisystem disease. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Suite 310 Thats not to say Zeeva hasnt had to work hard since the surgery. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. 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. Plaisier E, Ronco P. COL4A1-Related Disorders. The COL4A1 stroke syndrome. doi: 10.1056/NEJMoa071906, 14. 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. Am J Med Genet A. Disease Overview. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Nearly half of these participants were diagnosed with infantile spasms. 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. What does it mean if a disorder seems to run in my family? Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. INTERNET FOIA Neurology. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. When we didnt feel we had any options left for treatment, 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: Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. 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. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. HANAC syndrome is caused by genetic changes in the COL4A1 gene. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Maybe try a search? IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. However, in people with HANAC syndrome, these aneurysms typically do not burst. doi: 10.1016/j.ejpn.2009.04.010, 27. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. See our, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome, URL of this page: https://medlineplus.gov/genetics/condition/hereditary-angiopathy-with-nephropathy-aneurysms-and-muscle-cramps-syndrome/. ClinVar; [VCV000389182.3]. (2014) 15:16. eCollection 2021. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. This condition causes mutations in genes that produce a specific type of collagen. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. The .gov means its official. ACS Omega. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Affected individuals may have no observable symptoms or only isolated migraines with aura. 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. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Changing lives of those with rare disease. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). National Library of Medicine In people with HANAC syndrome, angiopathy affects several parts of the body. Neurology. (2011) 42:13. Muscle cramps can be spontaneous or triggered by exercise. The information on this site should not be used as a substitute for professional medical care or advice. 1900 Crown Colony Drive (E,F) IV-3Brain MRI showed left frontotemporal dilatation and diffusion tensor imaging (DTI) sequences demonstrated no left corticospinal tract (cranio-caudal fibers, indigo, with arrows). Matrix Biol. Stroke. The first reports of human COL4A1 mutations were in patients with autosomal dominant porencephaly and a more recent study found that COL4A1 mutations were found in ~16% of patients with porencephaly. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, 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. How can gene variants affect health and development? What is the prognosis of a genetic condition? His bedside manner was incredible. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. 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. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits).

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