In people with HANAC syndrome, angiopathy affects several parts of the body. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. Teaching families how to advocate for their loved ones and access medical information. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Front. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. 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). Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Neurology. Depending on the cell type that acquires the mutation and when the mutation arises, the individual may have many or few cells with the mutation. my mom suggested we call Boston Childrens Hospital. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Quincy, MA 02169 COL4A1 is an essential component for basal membrane stability. Recent findings: Am J Neuroradiol. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Epub 2016 Apr 24. Affected individuals may have no observable symptoms or only isolated migraines with aura. These genes are the blueprints for two proteins that wind together like a long rope inside cells. 1900 Crown Colony Drive The signs and symptoms can manifest at almost any age from before birth to old age. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Ann Neurol. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. 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. Zagaglia Selch C, Nisevic JR, et al. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. (2014) 15:16. Nearly half of these participants were diagnosed with infantile spasms. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. The COL4A1 and COL4A2 genes were screened in proband IV-6. Curr Opin Neurol. 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). The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659.
The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists.
COL4A1 -Related Disorders - PubMed Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. 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, . doi: 10.1001/archophthalmol.2010.42, 10. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Hum Mol Genet. MedlinePlus also links to health information from non-government Web sites. Cavalin M, Mine M, Philbert M, et al. doi: 10.1056/NEJMoa1707914, 6. 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).
What does it mean to have a COL4A1 - Little Braveheart | Facebook HANAC syndrome is caused by genetic changes in the COL4A1 gene. Last updated: Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. 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.
Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization In cases where the mutation is inherited, the carrier parent is often clinically unaffected. Neurology. Understanding what it has taken to get her to this point, though, is close to unimaginable. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). In addition to porencephaly there can be other forms of damage to the brain present at birth. 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. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). 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: https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. Eur J Med Genet. Clin Neurol Neurosurg. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 (2012) 54:56974. 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. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. (19). Progressive cerebral atrophies in three children with COL4A1 mutations. doi: To use the sharing features on this page, please enable JavaScript.
Clinical spectrum of type IV collagen (COL4A1) mutations: a novel 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Dr. Madsen suggested Zeeva have an operation called a Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. 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 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. It is ubiquitously expressed in many tissues and cell types. COL4A1 mutations as a monogenic cause of cerebral doi: 10.1212/01.WNL.0000123113.46672.68, 25. (2015) 88:46873. Eur J Paediatr Neurol. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. FOIA Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Here we report a family in which three siblings presented severe hypermetropia and porencephaly. For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures, and a shunt to treat hydrocephalus by draining excess fluid from the skull. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Firstly, it segregates within the family with the phenotype. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. These protein networks are the main component of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. 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 IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. Doctors and researchers to bring research and medical therapeutic options to those affected. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 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.
Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome Autosomal Dominant Brain Small Vessel Disease. 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). (1987) 8:4216. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 55 Kenosia Avenue 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. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. (2006) 354:148996. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. The https:// ensures that you are connecting to the
Frontiers | p.Gly743Val Mutation in COL4A1 Is Responsible for Familial (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, COL4A1 Syndrome CADASIL mutations: a novel genetic multisystem disease. 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. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Phone: 202-588-5700. Maybe try a search? Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Congenital Cephalic Disorders Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. 1779 Massachusetts Avenue Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories. He smiled, caught it, and asked Zeeva if he could throw it back. doi: 10.1212/WNL.0000000000000837, 20. Phone: 617-249-7300, Danbury, CT office Stroke. PS: wrote thi paper and performed the review of the literature under the supervision of GN. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. 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. Neuropediatrics. Danbury, CT 06810 Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. 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. Graefe's Arch Clin Exp Ophthalmol. GeneReviews. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. This condition causes mutations in genes that produce a specific type of collagen.
Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke He would separate the two halves of her brain by doi: 10.2214/ajr.149.2.351, 19. Ophthalmological features associated with COL4A1 mutations. (2014) 11:3612. official website and that any information you provide is encrypted How are genetic conditions treated or managed? Lenses corrected for hypermetropia. In most cases, an affected person has one parent with the condition. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS.
Finding the best care for Zeeva - Boston Children's Answers 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. Zeevas brain to treat a cyst in her brain caused by porencephaly. 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. 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 inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Unauthorized use of these marks is strictly prohibited. functional hemispherectomy. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. Treatment 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. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. 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. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. Jeanne M, Gould DB. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Plaisier E, Ronco P. COL4A1-Related Disorders. Please note that NORD provides this information for the benefit of the rare disease community. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. Ann Gould Syndrome is a rare, genetic, multi-system disorder. 1A-B). doi: 10.1002/ana.23736, 4. (2015) 17:84353. 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. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. This site needs JavaScript to work properly. Genet Med. eCollection 2022. Neurology. 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. cutting tissue called the corpus callosum, then make some additional delicate Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. We describe here the phenotype of a likely pathogenic gene variant, p.Gly743Val, which is responsible for a missense mutation in the COL4A1 gene exon 30 in a three generation family with severe hypermetropia and highly penetrant porencephaly in the absence of systemic manifestations. He also wanted to remove a shunt that was implanted in Muscle cramps can be spontaneous or triggered by exercise. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI.
COL4A1/A2-Related Disorders - Symptoms, Causes, Treatment | NORD Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium). His bedside manner was incredible. 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. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al.
Epilepsy and related challenges in children with COL4A1 and - PubMed Jeanne M, Gould DB. doi: 10.1111/cge.12379, 13. (1982) 40:5679. Mutations in the COL4A1 gene cause HANAC syndrome. 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. The number of genes implicated in epilepsy has grown rapidly in the past decade. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. As a result, the skin around the affected area may turn white or blue for a brief period of time and the area may tingle or throb. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Neurol. 2018;61:765-772. People with COL4A1-related brain small vessel disease 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). HHS Vulnerability Disclosure, Help 30. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. (2017) 377:111931. Fetal intracerebral hemorrhage and cataract: think COL4A1. eCollection 2021. doi: 10.1038/nmeth.2890, 22. The surgery 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). We describe, here, the phenotype of a likely pathologic variant (p.Gly743Val) in exon 30 of the COL4A1 gene, responsible for an oculo-cerebral phenotype characterized by severe hypermetropia and highly penetrant porencephaly in absence of other systemic complications. 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. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. (2007) 357:268795. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages.
Col4a1 mutation generates vascular abnormalities correlated with