Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. 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. (2011) 42:13. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. The retina is the light-sensitive membrane that lines the inside of the eyes. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. MeSH COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. NCI CPTC Antibody Characterization Program. 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. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. 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 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. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Epub 2022 Apr 14. Individuals with HANAC syndrome also experience a variety of eye problems. 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. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. 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. N Engl J Med. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. PMC 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. 2010 Copyright 2023 by Gould Syndrome Foundation -. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. Probands' father had severe hypermetropia and bilateral cataracts. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Surgery may be necessary for individuals with severe cataracts. Migraines can occur with or without aura. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. This is called genotype-phenotype correlation. 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 . Written informed consent was obtained from the patient and the patient's parents for publication of this case report. 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. An official website of the United States government. 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. It is important to discuss these concepts with a genetic counselor and understand their implications. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. 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. 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. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). 30. for the triple helical CB3[IV] domain. (2017) 377:111931. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina E. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. Plaisier E, Ronco P. COL4A1-Related Disorders. (E,F) IV-3Brain MRI showed left frontotemporal dilatation and diffusion tensor imaging (DTI) sequences demonstrated no left corticospinal tract (cranio-caudal fibers, indigo, with arrows). Quincy, MA 02169 government site. 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. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Understanding what it has taken to get her to this point, though, is close to unimaginable. The number of genes implicated in epilepsy has grown rapidly in the past decade. II-2 had a limp since childhood attributed to forceps delivery. the basement membranes surrounding the body's blood vessels, National Organization for Rare Disorders (NORD), BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. IV-3 goes to a normal school, but special schooling is required for IV-6. Nat Methods. (No doctor had ever taken a call on their lunch break to speak with me). Please note that NORD provides this information for the benefit of the rare disease community. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Bethesda, MD 20894, Web Policies Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Hum Mol Genet. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Unauthorized use of these marks is strictly prohibited. Accessibility (2009) 73:187382. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. The information on this site should not be used as a substitute for professional medical care or advice. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. 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. 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). Last updated: Bone. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Molecular analysis in the father disclosed a heterozygous variant c.2228G>T (p.Gly743Val) in exon 30 of the COL4A1 gene that segregated with the phenotype. Acute urinary retention due to a novel collagen COL4A1 mutation. https://www.ncbi.nlm.nih.gov/pubmed/26610912. 10.2174/092986710790936293. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. What is the prognosis of a genetic condition? Doctors and researchers to bring research and medical therapeutic options to those affected. (2008) 23:17. 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. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. doi: 10.1002/ana.23736, 4. mutations: a novel genetic multisystem disease. (2006) 43:4905. 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). Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. 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). Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. Teaching families how to advocate for their loved ones and access medical information. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. This site needs JavaScript to work properly. Gould Syndrome is a rare, genetic, multi-system disorder. Your support helps to ensure everyones free access to NORDs rare disease reports. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Axenfeld-Rieger anomaly is associated with various other eye abnormalities, including underdevelopment and eventual tearing of the colored part of the eye (iris), and a pupil that is not in the center of the eye. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. In the brain, intracerebral hemorrhage is the most frequent phenotype. Please note that NORD provides this information for the benefit of the rare disease community. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . In addition to porencephaly there can be other forms of damage to the brain present at birth. She, then, developed seizures which were controlled by valproic acid. HANAC syndrome is a rare condition, although the exact prevalence is unknown. However, in people with HANAC syndrome, these aneurysms typically do not burst. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Pediatr Neurol. 2010 Aug;41(8):e513-8. The size and location of cerebral cavities contributes to clinical variability. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. 55 Kenosia Avenue COL4A1/A2-related disorders are believed to affect females and males in equal numbers. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Am J Neuroradiol. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. The severity of the condition varies greatly among affected individuals. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. In the human genome, there are 46 chromosomes. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Arch Ophthalmol. Matrix Biol. 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. He smiled, caught it, and asked Zeeva if he could throw it back. We provide education, advocacy, and resources for families and individuals affected. Recent findings: For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. Arch Neurol. Federal government websites often end in .gov or .mil. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. GeneReviews. 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. doi: 10.1016/j.ejpn.2009.04.010, 27. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. small vessel disease: a systematic review. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. She has regular physical, speech, and occupational therapy. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. This group rarely survives beyond 2 years. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. 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. HHS Vulnerability Disclosure, Help January 31, 2019 Neurology. 2008 May;192(5):971-84; discussion 984-6. Curr Med Chem. percent confident in Dr. Madsen and the epilepsy team. Type IV collagen molecules attach to each other to form complex protein networks. my mom suggested we call Boston Childrens Hospital. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. (18) and Staals et al. doi: 10.1126/science.1109418, 5. Am J Med Genet A. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. (19). doi: 10.1001/archneur.1983.04050080067013, 17. Neurol. She also showed severe hypermetropia. Washington, DC 20036 The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Neurology. Disease Overview. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. 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. doi: The signs and symptoms can manifest at almost any age from before birth to old age. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Neurology. J Neurol Sci. 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. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI).
Dangers Of Charismatic Movement, Love2shop Exchange For E Gift Card, Charlottesville Forest School, Is Detroit Become Human 60fps On Ps5, Lily Prudhomme Copple Eric Copple, Articles C