col4a1 syndrome life expectancy col4a1 syndrome life expectancy

Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: In most people, small vessel disease in the brain does not cause symptoms. Children with the most severe brain malformations may have: Intellectual impairment Seizures Hydrocephalus Spasticity People who have a disorder of the corpus callosum typically have: 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. 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. The COL4A1 and COL4A2 genes were screened in proband IV-6. The surgery 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). When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Last updated: Muscle cramps can be spontaneous or triggered by exercise. Prenatal clinical manifestations in individuals with COL4A1/2 variants. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. doi: 10.1212/WNL.0b013e3181eee440, 28. Surgery may be necessary for individuals with severe cataracts. Congenital Cephalic Disorders IV-3 had a left hemisphere porencephalic cyst and the lack of evidence of a left corticospinal tract on tractography (Figures 3E,F), IV-5 had a porencephalic cyst on the right lateral ventricle (Figure 3C), and III-3 had leukoencephalopathy (Figure 3D). 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. People listened to us and to Zeeva in a very different and proactive way. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. percent confident in Dr. Madsen and the epilepsy team. Internet. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. 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. 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. Changing lives of those with rare disease. He also wanted to remove a shunt that was implanted in We provide education, advocacy, and resources for families and individuals affected. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. 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. The information on this site should not be used as a substitute for professional medical care or advice. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. 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). 1779 Massachusetts Avenue The information on this site should not be used as a substitute for professional medical care or advice. 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. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. Hereditary cerebral small vessel diseases: a review. COL4A1 is an essential component for basal membrane stability. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Am J Med Genet. 2010 Aug;41(8):e513-8. official website and that any information you provide is encrypted Zeevas brain to treat a cyst in her brain caused by porencephaly. 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. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. Autosomal Dominant Brain Small Vessel Disease. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. Neurol. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Neurology. N Engl J Med. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. FOIA 1. In people with HANAC syndrome, angiopathy affects several parts of the body. Clinically, COL4A1 mutations are responsible for different overlapping phenotypes including porencephaly (24), brain small vessel disease (2, 57) with or without ocular anomalies, HANAC (13) (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome, ophthalmological abnormalities (912), and non-syndromic autosomal dominant congenital cataracts (10). COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. and transmitted securely. 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). Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. 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. He smiled, caught it, and asked Zeeva if he could throw it back. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Diseases Information Center National Center for Advancing Translational Sciences Browse by Disease About GARD Contact Us We recently launched the new GARD website and are still developing specific pages. (18) and Staals et al. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. Cavalin M, Mine M, Philbert M, et al. Am J Med Genet A. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. The https:// ensures that you are connecting to the Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. She, then, developed seizures which were controlled by valproic acid. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. The risk is the same for males and females. 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). However, there are exceptions that depend on precisely when and where the mutation arose. 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. He would separate the two halves of her brain by IV-3 and IV-6 are closely followed by a neuropediatrician (VW). (2015) 17:40524. 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 . 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. doi: 10.1111/cge.12379, 13. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. 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/. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. eCollection 2022. In the human genome, there are 46 chromosomes. Affected individuals may have no observable symptoms or only isolated migraines with aura. Clinical Testing and Workup Copyright 2023 by Gould Syndrome Foundation -. J Neurol Sci. Nat Methods. The COL4A2 test was negative. The size and location of cerebral cavities contributes to clinical variability. Stroke. It looks like nothing was found at this location. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. 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. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Clin Neurol Neurosurg. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role Washington, DC 20036 Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. National Library of Medicine Unable to load your collection due to an error, Unable to load your delegates due to an error. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. 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. Painful muscle cramps can occur and can develop before three years of age. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Hum Mol Genet. When we didnt feel we had any options left for treatment, Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. The number of genes implicated in epilepsy has grown rapidly in the past decade. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: COL4A1/A2-related disorders are rare, genetic, multi-system disorders. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Nearly half of these participants were diagnosed with infantile spasms. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. 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. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES 4 Both . Eur J Med Genet. Ann Neurol. Neurology. (2009) 73:187382. 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. J Genet Couns. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. doi: 10.1212/01.WNL.0000123113.46672.68, 25. Ann Neurol. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. doi: 10.1136/jmg.2005.035584, 15. Cereb Circ Cogn Behav. (1987) 8:4216. Neurology. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. cuts under the microscope. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Neuropediatrics. 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. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. 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. 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. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. 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. Suite 310 Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Bookshelf Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. 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. eCollection 2021. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. doi: 10.2214/ajr.149.2.351, 19. Seattle, WA: University of Washington, Seattle; 1993-. Type IV collagen molecules attach to each other to form complex protein networks. 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. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients even among members of a family who carry the same gene mutation. 11:827. doi: 10.3389/fneur.2020.00827. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. 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. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. Dev Med Child Neurol. 2018;61:765-772. Neurol. doi: 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). Recent findings: functional hemispherectomy. sharing sensitive information, make sure youre on a federal NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Plaisier E, Ronco P. COL4A1-Related Disorders. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. When these ropes are secreted, they assemble into net-like structures outside the cells. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Stroke is a leading cause of death and serious long-term disability in developed nations. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. 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 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. (2015) 84:91826. (2015) 88:46873. 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. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. J Perinatol. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. 2008 May;192(5):971-84; discussion 984-6. ACS Omega. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. This group rarely survives beyond 2 years. seizure activity. (2008) 17:42433. 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. 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. I cannot describe the feeling of seeing your child healed. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Ann Arch Ophthalmol. The signs and symptoms can manifest at almost any age from before birth to old age. Smoking, which also increases the risk of stroke, physical activities that can cause head trauma such as contact sports, and the use of anti-clotting (anticoagulant) medications, should be avoided. Bethesda, MD 20894, Web Policies The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. can also contribute. Zagaglia Selch C, Nisevic JR, et al. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. How are genetic conditions treated or managed? 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. HHS Vulnerability Disclosure, Help