To use the sharing features on this page, please enable JavaScript. Purpose of review: Bull Acad Natl Med. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. 1900 Crown Colony Drive Danbury, CT 06810 Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). Lanfranconi S, Markus HS. 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. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. While there are other explanations, parental mosaicism should be considered. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Please note that NORD provides this information for the benefit of the rare disease community. The .gov means its official. 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 (24), hemorrhage (2, 57) and aneurysms (8)], ophthalmological (912) (retinal artery tortuosity, Axenfeld Rieger anomalies, cataracts, and severe hypermetropia), renal (13) (renal cysts, and microscopic hematuria), and systemic (13) findings (cramps with a high creatine kinase level [CK], Raynaud's phenomenon, and arrhythmias). 55 Kenosia Avenue 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. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. Stroke. 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. (2015) 88:46873. What is the prognosis of a genetic condition? (2010) 14:1827. Plaisier E, Ronco P. COL4A1-Related Disorders. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. The number of genes implicated in epilepsy has grown rapidly in the past decade. Ann Neurol. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Before 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. PS: wrote thi paper and performed the review of the literature under the supervision of GN. However, in people with HANAC syndrome, these aneurysms typically do not burst. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. Surgery may be necessary for individuals with severe cataracts. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. 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 the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. He also wanted to remove a shunt that was implanted in Clinical spectrum of type IV collagen (COL4A1) mutations: a novel HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. (1982) 40:5679. 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. In most cases, an affected person has one parent with the condition. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. 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). doi: 10.1007/s00417-014-2800-6, 12. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. NORD is a registered 501(c)(3) charity organization. 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). Unable to load your collection due to an error, Unable to load your delegates due to an error. came with risks and was the hardest decision we had ever faced, yet we felt 100 This page is currently unavailable. National Center for Biotechnology Information. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. (2015) 17:84353. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. 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. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. 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. INTERNET Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. 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). Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. What does it mean to have a COL4A1 - Little Braveheart | Facebook Suite 500 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. Muscle cramps can be spontaneous or triggered by exercise. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). eCollection 2021. Stroke. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. and transmitted securely. 1779 Massachusetts Avenue Six alpha chains of type IV. (2018) 91:e207888. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. 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. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: Neurology. Changing lives of those with rare disease. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. . We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Various muscles can be affected and muscle strength can become weakened. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Further refinement of COL4A1 and COL4A2 related cortical malformations. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. 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). Disclaimer. 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. Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation 10.1161/STROKEAHA.110.581918. In addition to porencephaly there can be other forms of damage to the brain present at birth. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. 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 Col4a1 mutation generates vascular abnormalities correlated with There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). 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. Facebook: https://www.facebook.com/Col4A1Foundation Please Note Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. MedlinePlus also links to health information from non-government Web sites. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. 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 collagen type IV alpha 1 chain [ (human)] - National Center for NCI CPTC Antibody Characterization Program. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. The p.Gly743Val variant is a conservative substitution that occurs in a position highly conserved across species (SIFT analysis: DeleteriousScore 0, median: 4.22, highly conserved nucleotide and amino acid, up to Tetraodon considering 11 species) and affects a crucial and abundant residue within the triple-helix-forming collagenous domain of the protein, which consist of long stretches of Gly-X-Y repeats. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. (2007) 357:268795. 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. Eur J Med Genet. Childhood presentation of COL4A1 mutations. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Clinical Testing and Workup What is the prognosis of a genetic condition? 2010 eCollection 2022. Collagen type IV alpha 1 (COL4A1) silence hampers the invasion, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cells through blocking Hedgehog signaling pathway. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. doi: 10.1001/archophthalmol.2010.42, 10. The size and location of cerebral cavities contributes to clinical variability. 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. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. HHS Vulnerability Disclosure, Help Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. (2014) 34:757. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. Some individuals develop cysts on the kidney. doi: 10.1038/jp.2013.135, 29. 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. Cereb Circ Cogn Behav. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. NORD strives to open new assistance programs as funding allows. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. If either parent also carries the mutation, it is considered inherited. seizure activity. Copyright 2023 by Gould Syndrome Foundation -. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. The signs and symptoms can manifest at almost any age from before birth to old age. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. cutting tissue called the corpus callosum, then make some additional delicate He smiled, caught it, and asked Zeeva if he could throw it back. Genet Med. The site is secure. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Practical approach to the diagnosis of adult-onset - BMJ For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Internet. Epilepsy and related challenges in children with COL4A1 and - PubMed (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke (2011) 42:13. 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. Science. BMC Med Genet. 1900 Crown Colony Drive The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. 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. Lenses corrected for hypermetropia. (18) and Staals et al. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. 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. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. Phone: 203-263-9938 HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. This condition causes mutations in genes that produce a specific type of collagen. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. Nat Methods. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. Ophthalmological features associated with COL4A1 mutations. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. In the human genome, there are 46 chromosomes. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Phone: 617-249-7300, Danbury, CT office J Med Genet. The surgery (2009) 73:187382. J Genet Couns. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. To use the sharing features on this page, please enable JavaScript. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. Curr Opin Neurol. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Gould Syndrome is an ultra rare genetic, multi-system disorder. 2018;61:765-772. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. 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. Phone: 202-588-5700. Bethesda, MD 20894, Web Policies 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.