col4a1 syndrome life expectancy

Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. cuts under the microscope. COL4A1 mutations in patients with sporadic late-onset intracerebral Doctors and researchers to bring research and medical therapeutic options to those affected. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. The retina is the light-sensitive membrane that lines the inside of the eyes. Finding the best care for Zeeva - Boston Children's Answers Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. doi: 10.1111/cge.12543. Neurology. In the human genome, there are 46 chromosomes. What does it mean to have a COL4A1 - Little Braveheart | Facebook Clin Genet. However, in people with HANAC syndrome, these aneurysms typically do not burst. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Am J Med Genet. Berg R, Aleck A, Kaplan A. Familial porencephaly. Nearly half of these participants were diagnosed with infantile spasms. What does it mean if a disorder seems to run in my family? functional hemispherectomy. Neurol. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. Nat Methods. Clinical Testing and Workup Therapies are based on the specific symptoms in each individual. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. (2009) 73:187382. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Mutations in the COL4A1 gene cause HANAC syndrome. (2015) 17:40524. Please note that NORD provides this information for the benefit of the rare disease community. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. Neurology. (2004) 62:16135. However, there are exceptions that depend on precisely when and where the mutation arose. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. 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. Matrix Biol. Hereditary cerebral small vessel diseases: a review. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus 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). Bethesda, MD 20894, Web Policies Eur J Med Genet. Plaisier E, Ronco P. COL4A1-Related Disorders. 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. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Resource(s) for Medical Professionals and Scientists on This Disease: Contact a health care provider if you have questions about your health. Please enable it to take advantage of the complete set of features! III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. The information on this site should not be used as a substitute for professional medical care or advice. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. mutations: a novel genetic multisystem disease. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Gould Syndrome is a rare, genetic, multi-system disorder. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. Practical approach to the diagnosis of adult-onset - BMJ 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. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps 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. Neurology. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Suite 310 It is ubiquitously expressed in many tissues and cell types. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Fax: 203-263-9938, Washington, DC Office Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. official website and that any information you provide is encrypted Dr. Madsen suggested Zeeva have an operation called a No use, distribution or reproduction is permitted which does not comply with these terms. (2015) 17:84353. (18) and Staals et al. It looks like nothing was found at this location. Front Aging Neurosci. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. The risk is the same for males and females. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Stroke. Other eye problems experienced by people with COL4A1-related brain small-vessel disease include clouding of the lens of the eye (cataract) and the presence of arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eye (arterial retinal tortuosity). PMC 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. Bookshelf [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. TTY: (866) 411-1010 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). Affected individuals may have no observable symptoms or only isolated migraines with aura. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. National Center for Biotechnology Information. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. Careers. Progressive cerebral atrophies in three children with COL4A1 mutations. He also wanted to remove a shunt that was implanted in Rarely, affected individuals will have a condition called Raynaud phenomenon in which the blood vessels in the fingers and toes temporarily narrow, restricting blood flow to the fingertips and the ends of the toes. These genes are the blueprints for two proteins that wind together like a long rope inside cells. Neurology. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. Congenital Cephalic Disorders IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). HANAC syndrome is a rare condition, although the exact prevalence is unknown. 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. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Type IV collagen molecules attach to each other to form complex protein networks. (2008) 17:42433. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Frontiers | p.Gly743Val Mutation in COL4A1 Is Responsible for Familial 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. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. The COL4A1 stroke syndrome. 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). When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. This is called genotype-phenotype correlation. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. and transmitted securely. Dev Med Child Neurol. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. eCollection 2022. 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. Childhood presentation of COL4A1 mutations. Understanding what it has taken to get her to this point, though, is close to unimaginable. 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). 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. 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. Our review highlights that COL4A1 mutations can present for the first time in adult life with features of cerebral SVD, including subcortical hemorrhage and ischemic stroke, . Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. At 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. Col4a1 mutation generates vascular abnormalities correlated with Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Bennett RL, French KS, Resta RG, Doyle DL. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, 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. Disease Overview. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. COL4A1/A2-Related Disorders - Symptoms, Causes, Treatment | NORD doi: 10.1001/archneur.1983.04050080067013, 17. 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. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Sue. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Phone: 617-249-7300, Danbury, CT office 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. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. 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. 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. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. HANAC syndrome is caused by genetic changes in the COL4A1 gene. 11:827. doi: 10.3389/fneur.2020.00827. Zagaglia Selch C, Nisevic JR, et al. 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. 2011 COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. 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. An official website of the United States government. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Figure 3. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. 1779 Massachusetts Avenue Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes. IV-3 was diagnosed with ventriculomegaly in utero. doi: 10.1007/s00417-014-2800-6, 12. This condition causes mutations in genes that produce a specific type of collagen. The surgery Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. COL4A1 and COL4A2 are on Chr. His bedside manner was incredible. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. doi: 10.1136/jmg.2005.035584, 15. 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. 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. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. J Med Genet. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Stroke. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and can also contribute. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. BMC Med Genet. (2014) 11:3612. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. doi: 10.1212/WNL.0000000000000837, 20. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). 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. 128:4839. Clipboard, Search History, and several other advanced features are temporarily unavailable. COL4A1 mutations as a monogenic cause of cerebral A diagnosis can be confirmed through molecular genetic testing. (2020). doi: 10.1055/s-0031-1275343, 24. She has regular physical, speech, and occupational therapy. 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. 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: doi: 10.1038/jp.2013.135, 29. 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. 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 ( 2 - 4 ), hemorrhage ( 2, 5 - 7) and aneurysms ( 8 )], ophthalmological The severity of the condition varies greatly among affected individuals. 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). for the triple helical CB3[IV] domain. 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. Ultrasound in utero from IV-6 (A). 1. This site needs JavaScript to work properly. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: 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. 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. These exceptions are nuanced and should be discussed with a genetic counselor. Federal government websites often end in .gov or .mil. Washington, DC 20036 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). HHS Vulnerability Disclosure, Help COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. Teaching families how to advocate for their loved ones and access medical information. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. After a normal neonatal period, those affected develop a rapidly progressive course involving irritability, hyperaesthesia, visual and hearing loss, severe cognitive and motor deterioration, and seizures. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al.