Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. ClinVar; [VCV000389182.3]. By continuing to use this website, you agree to the Terms of Service & Privacy Policy, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. 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. Bethesda, MD 20894, Web Policies She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. eCollection 2022. January 31, 2019 Role of COL4A1 in small-vessel disease and hemorrhagic stroke. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. How are genetic conditions treated or managed? Quincy, MA 02169 Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. The .gov means its official. The severity of the condition varies greatly among affected individuals. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Danbury, CT 06810 eCollection 2021. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. 2008 May;192(5):971-84; discussion 984-6. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. 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. Neurology. Last updated: (2014) 15:16. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. This condition causes mutations in genes that produce a specific type of collagen. No microbleeds or cystic cavities were found. Please enable it to take advantage of the complete set of features! 4 Both . COL4A1 is an essential component for basal membrane stability. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. Clinically, COL4A1 mutations are responsible for different overlapping phenotypes including porencephaly (24), brain small vessel disease (2, 57) with or without ocular anomalies, HANAC (13) (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome, ophthalmological abnormalities (912), and non-syndromic autosomal dominant congenital cataracts (10). The retina is the light-sensitive membrane that lines the inside of the eyes. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. doi: 10.1111/cge.12379, 13. (2006) 354:148996. She, then, developed seizures which were controlled by valproic acid. 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). Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Stroke. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. How can gene variants affect health and development? Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. At least 50 individuals with this condition have been described in the scientific literature. Plaisier E, Ronco P. COL4A1-Related Disorders. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Berg R, Aleck A, Kaplan A. Familial porencephaly. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Six alpha chains of type IV. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. COL4A1 mutations as a monogenic cause of cerebral Clin Genet. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. J Neurol Sci. Treatment trials will be critical to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COL4A1/A2-related disorders. 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. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. 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, . Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical relating to specific areas of the brain supplied by deep small arteries (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. doi: 10.1212/01.WNL.0000123113.46672.68, 25. The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date. Internet. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Please note that NORD provides this information for the benefit of the rare disease community. 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. Epub 2022 Apr 14. Ann When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. IV-3 goes to a normal school, but special schooling is required for IV-6. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. The https:// ensures that you are connecting to the Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Neurology. 2012;21:R97-R110. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. If we dont have a program for you now, please continue to check back with us. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Ultrasound in utero from IV-6 (A). COL4A1 brain small-vessel disease is an autosomal dominant condition resulting from a mutation to the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen 1-6. What is the prognosis of a genetic condition? Suite 500 COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. NORD is a registered 501(c)(3) charity organization. The COL4A2 test was negative. Pediatr Neurol. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Various muscles can be affected and muscle strength can become weakened. Here, we report a patient with schizencephaly, detected by fetal ultrasonography and fetal magnetic resonance imaging, with a de novo novel mutation in COL4A1 (c.2645_2646delinsAA, p.Gly882Glu). In most cases, an affected person has one parent with the condition. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Washington, DC 20036 Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. People with HANAC syndrome develop kidney disease (nephropathy). Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. doi: 10.1038/gim.2015.30, 21. For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office: Toll-free: (800) 411-1222 (2014) 11:3612. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Affected individuals may have no observable symptoms or only isolated migraines with aura. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Thats not to say Zeeva hasnt had to work hard since the surgery. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, 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). COL4A1/A2-related disorders are dominant genetic disorders. Am J Neuroradiol. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Facebook: https://www.facebook.com/Col4A1Foundation Please Note Summary. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. (2013) 73:4857. Some individuals develop cysts on the kidney. In a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). Disease Overview. 2011 doi: 10.1212/WNL.0b013e3181c3fd12, 9. 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). 1A-B). COL4A1/A2-related disorders are rare, genetic, multi-system disorders. National Institute of Neurological Disorders and Stroke. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Teaching families how to advocate for their loved ones and access medical information. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. Disclaimer. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. In the brain, intracerebral hemorrhage is the most frequent phenotype. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. BMC Med Genet. 11:827. doi: 10.3389/fneur.2020.00827. Would you like email updates of new search results? Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Resource(s) for Medical Professionals and Scientists on This Disease: NORD is a registered 501(c)(3) charity organization. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. U.S. Department of Health and Human Services, Autosomal dominant familial hematuria, retinal arteriolar tortuosity, contractures, Hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome. The risk is the same for males and females. (2011) 42:13. doi: 10.1002/ana.23736, 4. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Still other individuals may not develop any symptoms until well into adulthood. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. 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. Suite 310 Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Neurology. Figure 3. Contact a health care provider if you have questions about your health. 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. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). 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. doi: 10.1136/jmg.2005.035584, 15. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). 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. N Engl J Med. 1779 Massachusetts Avenue NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. mutations: a novel genetic multisystem disease. These genes are the blueprints for two proteins that wind together like a long rope inside cells. Genet Med. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. The signs and symptoms can manifest at almost any age from before birth to old age. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. (2008) 17:42433. Phone: 202-588-5700. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. 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). *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Science. IV-3 had a left hemisphere porencephalic cyst and the lack of evidence of a left corticospinal tract on tractography (Figures 3E,F), IV-5 had a porencephalic cyst on the right lateral ventricle (Figure 3C), and III-3 had leukoencephalopathy (Figure 3D). Antiinflammatory therapy with canakinumab for atherosclerotic disease. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Lanfranconi S, Markus HS. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Contact a health care provider if you have questions about your health. (2010) 14:1827. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. iain watson weight loss,
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