col4a1 syndrome life expectancy

Axenfeld-Rieger anomaly and cataract can cause impaired vision. 30. 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). COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. TTY: (866) 411-1010 Clipboard, Search History, and several other advanced features are temporarily unavailable. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and 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. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Six alpha chains of type IV. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). 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. Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects). What is the prognosis of a genetic condition? PMC The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. 2012;21:R97-R110. Bookshelf 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. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. The number of genes implicated in epilepsy has grown rapidly in the past decade. https://www.ncbi.nlm.nih.gov/pubmed/26610912. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, (2015) 84:91826. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. 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). Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. 2018;91:e2078-e2088. ClinVar; [VCV000389182.3]. 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. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. 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. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. National Center for Biotechnology Information. The COL4A2 test was negative. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. eCollection 2021. Ultrasound in utero from IV-6 (A). Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. 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. The pathogenic mechanisms of COL4A1 mutations are not fully elucidated and may vary according to the mutation type, the affected exon (mutations responsible for systemic HANAC syndrome cluster at exon 24 and 25), the position of the mutation within the triple-helix domain, and the mutation location. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. NORD strives to open new assistance programs as funding allows. 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. 4 Both . Epub 2016 Apr 24. Epilepsy and related challenges in children with COL4A1 and - PubMed 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. The first time he came to meet us, Zeeva threw a sock at him. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Danbury, CT 06810 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. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. HANAC syndrome is a rare condition, although the exact prevalence is unknown. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. When this enzyme is elevated, it is a sign of muscle damage. This is called genotype-phenotype correlation. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus IV-3 goes to a normal school, but special schooling is required for IV-6. Ann Neurol. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). The COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. (18) and Staals et al. Berg R, Aleck A, Kaplan A. Familial porencephaly. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. At the age of 12, IV-3 underwent cerebral palsy quality of life (CPQoL) questionnaires in which they expressed a satisfactory quality of life and a good relationship with other children. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. mutations: a novel genetic multisystem disease. Fax: 203-263-9938, Washington, DC Office sharing sensitive information, make sure youre on a federal Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. Figure 3. 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 1 month of age, a neuropediatric examination disclosed normal neck muscle tonus, normal Moro reflex, bilateral placing reaction, and open hands. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Neurology. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 10.2174/092986710790936293. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. 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. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. my mom suggested we call Boston Childrens Hospital. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). 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. 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. Subsequently, it has been recognized that autosomal dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular disease, whose onset occurs from fetal life onward and whose severity may range from small-vessel disease to fatal intraparenchymal hemorrhage.,, While epilepsy is known to be a clinical feature of porencephaly, the An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Phone: 202-588-5700. No microbleeds or cystic cavities were found. (2018) 91:e207888. COL4A1 Syndrome CADASIL (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. 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 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 Would you like email updates of new search results? Front Aging Neurosci. Arch Neurol. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). It affects mainly young adults, children and more typically neonates. came with risks and was the hardest decision we had ever faced, yet we felt 100 Graefe's Arch Clin Exp Ophthalmol. (2010) 75:7479. doi: 10.1038/gim.2014.210, 3. 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. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. cuts under the microscope. Practical approach to the diagnosis of adult-onset - BMJ 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. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Autosomal Dominant Brain Small Vessel Disease. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. (No doctor had ever taken a call on their lunch break to speak with me). Federal government websites often end in .gov or .mil. Genet Med. doi: 10.1186/s12881-014-0097-2, 11. Purpose of review: 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). Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Nat Methods. MedlinePlus also links to health information from non-government Web sites. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Matrix Biol. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. The disorder causes many symptoms, not the least of which are strokes and epilepsy. 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: Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. 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. In addition to porencephaly there can be other forms of damage to the brain present at birth. (2005) 308:116771. (2015) 17:40524. Arch Ophthalmol. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. GeneReviews. Phone: 203-263-9938 Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. 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. 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. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Therapies are based on the specific symptoms in each individual. Dr. Madsen suggested Zeeva have an operation called a In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. Nearly half of these participants were diagnosed with infantile spasms. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. N Engl J Med. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. doi: 10.2214/ajr.149.2.351, 19. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. National Library of Medicine 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. can also contribute. Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation Gould Syndrome Foundation 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. Neurology. Childhood presentation of COL4A1 mutations. Keywords: COL4A1, Type IV collagen, familial porencephaly, ocular malformations, variable expressivity, Citation: Scoppettuolo P, Ligot N, Wermenbol V, Van Bogaert P and Naeije G (2020) p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Porencephaly and Severe Hypermetropia. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. 1900 Crown Colony Drive Gould Syndrome is an ultra rare genetic, multi-system disorder. Careers. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. 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. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. COL4A1 is an essential component for basal membrane stability. Accessibility 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. J Perinatol. 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). Maybe try a search? 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. 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). For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). 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. doi: 10.1056/NEJMoa053727, 7. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. To use the sharing features on this page, please enable JavaScript. Epub 2022 Apr 14. PS: wrote thi paper and performed the review of the literature under the supervision of GN. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. (2020). 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. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies, https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, https://www.ncbi.nlm.nih.gov/pubmed/28254515, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, https://www.nature.com/articles/gim2014210, https://www.ncbi.nlm.nih.gov/pubmed/23225343, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, https://www.ncbi.nlm.nih.gov/pubmed/22868088, https://www.ncbi.nlm.nih.gov/pubmed/22574627, https://www.ncbi.nlm.nih.gov/pubmed/20558831, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, https://www.ncbi.nlm.nih.gov/pubmed/26610912, https://www.ncbi.nlm.nih.gov/books/NBK7046/, https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet, https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/, https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/, https://rarediseases.org/patient-assistance-programs/caregiver-respite/, Learn more about Patient Assistance Programs >, Arginine: Glycine Amidinotransferase Deficiency, https://rarediseases.org/non-member-patient/epilepsy-foundation/, Gould Syndrome Foundation (COL4a1/COL4A2), https://rarediseases.org/non-member-patient/gould-syndrome-foundation-col4a1-col4a2/, https://rarediseases.org/non-member-patient/national-kidney-foundation/, https://rarediseases.org/non-member-patient/nih-national-eye-institute/, NIH/National Institute of Neurological Disorders and Stroke, Aromatic L-Amino Acid Decarboxylase Deficiency, https://rarediseases.org/non-member-patient/nih-national-institute-of-neurological-disorders-and-stroke/, https://rarediseases.org/non-member-patient/the-arc/, Learn more about Patient Organization & Membership >, HANAC: hereditary angiopathy, nephropathy and cramps syndrome (OMIM #611773), POREN1: autosomal dominant type 1 porencephaly; porencephaly with infantile hemiplegia (OMIM #175780, RATOR: retinal arterial tortuosity (OMIM #180000), BSVD: brain small vessel disease with or without ocular anomalies (OMIM #607595), ICH: susceptibility to intracerebral hemorrhage (OMIM #614519).