eCollection 2022. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Type IV collagen molecules attach to each other to form complex protein networks. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. Contact a health care provider if you have questions about your health. 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. 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. Contact a health care provider if you have questions about your health. Mutations in the COL4A1 gene cause HANAC syndrome. Neurology. Matrix Biol. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Epub 2016 Apr 24. Neuropediatrics. (2015) 84:91826. 2009 Jun 25 [Updated 2016 Jul 7]. Stroke. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. doi: 10.1038/jp.2013.135, 29. 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). https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES MedlinePlus also links to health information from non-government Web sites. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. II-2 had a limp since childhood attributed to forceps delivery. mutations: a novel genetic multisystem disease. National Institute of Neurological Disorders and Stroke. (1982) 40:5679. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. government site. He smiled, caught it, and asked Zeeva if he could throw it back. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. 2018;91:e2078-e2088. 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. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. MeSH 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. COL4A1 mutations are responsible for a wide range of abnormalities affecting mainly the brain and the retinal vasculature, the anterior and posterior ocular structures and the renal glomerules. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. (2015) 17:40524. Neurology. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. It affects mainly young adults, children and more typically neonates. (2010) 75:7479. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. 2008 May;192(5):971-84; discussion 984-6. In the human genome, there are 46 chromosomes. Pathology. official website and that any information you provide is encrypted Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. 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 . 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: Accessibility He would separate the two halves of her brain by Antiinflammatory therapy with canakinumab for atherosclerotic disease. 55 Kenosia Avenue 2010 Aug;41(8):e513-8. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. 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. 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. 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). Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. There are no standardized treatment protocols or guidelines for affected individuals. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. (2009) 73:187382. 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. eCollection 2021. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. Neurology. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. 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 X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. At least six affected families have been described in the scientific literature. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. 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. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. 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. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. N Engl J Med. 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. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. doi: 10.1111/cge.12543. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. Ann Neurol. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). N Engl J Med. While there are other explanations, parental mosaicism should be considered. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. How are genetic conditions treated or managed? For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). Ultrasound in utero from IV-6 (A). Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Painful muscle cramps can occur and can develop before three years of age. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Neurology. 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. Therapies are based on the specific symptoms in each individual. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. doi: 10.1056/NEJMoa1707914, 6. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. How can gene variants affect health and development? Dr. Madsen suggested Zeeva have an operation called a 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. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. doi: 10.1186/s12881-014-0097-2, 11. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. This site needs JavaScript to work properly. 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. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. 2011 The information on this site should not be used as a substitute for professional medical care or advice. For instance, retinal arteriolar tortuosity relates to mutations in the amino-terminal one-third of the protein while mutations causing cataracts and ocular morphologic alterations are more likely to occur, closer to the carboxy terminus (22), like the variant we report. J Perinatol. (1987) 8:4216. Still other individuals may not develop any symptoms until well into adulthood. The size and location of cerebral cavities contributes to clinical variability. Danbury, CT 06810 National Center for Biotechnology Information. doi: 10.1002/ajmg.10452, 18. When these ropes are secreted, they assemble into net-like structures outside the cells. Muscle cramps can be spontaneous or triggered by exercise. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review.