col4a1 syndrome life expectancy

COL4A1-related brain small-vessel disease - MedlinePlus Phone: 617-249-7300, Danbury, CT office Dev Med Child Neurol. J Perinatol. (2010) 75:7479. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. Unable to load your collection due to an error, Unable to load your delegates due to an error. The COL4A1 and COL4A2 genes were screened in proband IV-6. 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. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. What are the different ways a genetic condition can be inherited? Prenatal clinical manifestations in individuals with COL4A1/2 variants. Neurol. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Doctors and researchers to bring research and medical therapeutic options to those affected. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. (2005) 308:116771. COL4A1 and COL4A2 are on Chr. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. 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. mutations: a novel genetic multisystem disease. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. The risk is the same for males and females. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. Congenital Cephalic Disorders The number of genes implicated in epilepsy has grown rapidly in the past decade. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. Berg R, Aleck A, Kaplan A. Familial porencephaly. (No doctor had ever taken a call on their lunch break to speak with me). The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. GeneReviews. 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. The severity of the condition varies greatly among affected individuals. doi: 10.1001/archneur.1983.04050080067013, 17. In the brain, intracerebral hemorrhage is the most frequent phenotype. (2009) 73:187382. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. https://www.ncbi.nlm.nih.gov/pubmed/26610912. In most cases, an affected person has one parent with the condition. cuts under the microscope. Neurology. In most people, small vessel disease in the brain does not cause symptoms. Careers. The https:// ensures that you are connecting to the NCI CPTC Antibody Characterization Program. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. (2011) 42:13. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Further refinement of COL4A1 and COL4A2 related cortical malformations. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. How are genetic conditions treated or managed? Stroke. Type IV collagen molecules attach to each other to form complex protein networks. (1982) 40:5679. MedlinePlus also links to health information from non-government Web sites. and transmitted securely. 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. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. (2006) 354:148996. Suite 310 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%). 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Neurol. These genes are the blueprints for two proteins that wind together like a long rope inside cells. Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot. Understanding what it has taken to get her to this point, though, is close to unimaginable. Disclaimer. Ophthalmological features associated with COL4A1 mutations. The first time he came to meet us, Zeeva threw a sock at him. (2014) 83:122834. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Cereb Circ Cogn Behav. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). doi: 10.2214/ajr.149.2.351, 19. Ultrasound in utero from IV-6 (A). It looks like nothing was found at this location. Migraines can occur with or without aura. Epub 2016 Apr 24. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Stroke is a leading cause of death and serious long-term disability in developed nations. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for 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. At least six affected families have been described in the scientific literature. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. PS: wrote thi paper and performed the review of the literature under the supervision of GN. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. The site is secure. Contact a health care provider if you have questions about your health. Resource(s) for Medical Professionals and Scientists on This Disease: 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. eCollection 2022 Nov 8. 1779 Massachusetts Avenue Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. 2011 sharing sensitive information, make sure youre on a federal Ann Neurol. The information on this site should not be used as a substitute for professional medical care or advice. Am J Med Genet A. 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. eCollection 2021. The size and location of cerebral cavities contributes to clinical variability. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Phone: 203-263-9938 Years published: 2019. However, there are exceptions that depend on precisely when and where the mutation arose. Cephalic Disorders Fact Sheet. Autosomal Dominant Brain Small Vessel Disease. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. 2018;61:765-772. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). What is the prognosis of a genetic condition? The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. (2006) 43:4905. Fax: 203-263-9938, Washington, DC Office 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. doi: 10.1055/s-0031-1275343, 24. IV-3 was diagnosed with ventriculomegaly in utero. National Center for Biotechnology Information. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. 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. The disorder causes many symptoms, not the least of which are strokes and epilepsy. For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: Toll-free: (800) 411-1222 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. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. 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. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. BMC Med Genet. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. doi: 10.1212/WNL.0b013e3181eee440, 28. She, then, developed seizures which were controlled by valproic acid. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Last updated: 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 in COL4A1 or COL4A2 cause Gould Syndrome and, because these two proteins are found in almost all tissues; nearly any organ can be affected. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. 2011 Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. Please note that NORD provides this information for the benefit of the rare disease community. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. Plaisier E, Ronco P. COL4A1-Related Disorders. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus There are no standardized treatment protocols or guidelines for affected individuals. PMC What does it mean if a disorder seems to run in my family? 55 Kenosia Avenue Treatment 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. January 31, 2019 N Engl J Med. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Graefe's Arch Clin Exp Ophthalmol. Therapies are based on the specific symptoms in each individual. To use the sharing features on this page, please enable JavaScript. doi: 10.1111/j.1469-8749.2011.04198.x, 26. 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. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. 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. Your support helps to ensure everyones free access to NORDs rare disease reports. doi: 10.1007/s00417-014-2800-6, 12. IV-3 goes to a normal school, but special schooling is required for IV-6. doi: 10.1186/s12881-014-0097-2, 11. Phone: 202-588-5700. Arch Ophthalmol. We provide education, advocacy, and resources for families and individuals affected. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Pediatr Neurol. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). Recent findings: Zeevas brain to treat a cyst in her brain caused by porencephaly. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Dev Med Child Neurol. 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. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 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. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. 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/. 128:4839. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. 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. She has regular physical, speech, and occupational therapy. 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. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. doi: 10.1056/NEJMoa053727, 7. 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. While there are other explanations, parental mosaicism should be considered. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. 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). Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation 2010;41:e513-518. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Arch Neurol. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. 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). Suite 310 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 . Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. HHS Vulnerability Disclosure, Help An official website of the United States government. COL4A1 Mutations Cause Neuromuscular Disease with - ScienceDirect It is passed through families in a autosomal dominant fashion. 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. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Ann Neurol. Neurologic phenotypes associated with COL4A1/2 mutations Muscle cramps can be spontaneous or triggered by exercise. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Probands' father had severe hypermetropia and bilateral cataracts. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. 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. He was confident this would reduce or stop the 4 Both . As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. COL4A1 is an essential component for basal membrane stability. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. 2008 May;192(5):971-84; discussion 984-6. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. 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. It affects mainly young adults, children and more typically neonates. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. The .gov means its official. Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. (2002) 112:198202. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. MeSH COL4A1/A2-Related Disorders - Symptoms, Causes, Treatment | NORD Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel - Stroke Thats not to say Zeeva hasnt had to work hard since the surgery. 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). Science. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. 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. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. COL4A1 mutations in patients with sporadic late-onset intracerebral my mom suggested we call Boston Childrens Hospital. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. 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). Clinical spectrum of type IV collagen (COL4A1) mutations: a novel 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. His bedside manner was incredible. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Neurology. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. 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. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms.

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