Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. September 2003. Ann During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. 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. Arch Neurol. Am J Med Genet. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. 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. 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 size and location of cerebral cavities contributes to clinical variability. 2009 Jun 25 [updated 2016 Jul 7]. (1987) 8:4216. Am J Med Genet A. Recent findings: Dr. Madsen suggested Zeeva have an operation called a Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. (1982) 40:5679. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. She, then, developed seizures which were controlled by valproic acid. Type IV collagen molecules attach to each other to form complex protein networks. (2010) 75:7479. Hum Mol Genet. 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). COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. 55 Kenosia Avenue 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. It is passed through families in a autosomal dominant fashion. COL4A1 mutations as a monogenic cause of cerebral Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. INTERNET 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. Quincy, MA 02169 The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Careers. When we didnt feel we had any options left for treatment, 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. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Gould Syndrome is a rare, genetic, multi-system disorder. my mom suggested we call Boston Childrens Hospital. 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. 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). Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. COL4A1/A2-related disorders are dominant genetic disorders. MedlinePlus also links to health information from non-government Web sites. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. 11:827. doi: 10.3389/fneur.2020.00827. doi: 10.1186/s12881-014-0097-2, 11. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. At least 50 individuals with this condition have been described in the scientific literature. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Clin Genet. Epub 2014 Jan 5. eCollection 2022. IV-3 was diagnosed with ventriculomegaly in utero. 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. COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel - Stroke U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. can also contribute. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Summary. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). 2012;21:R97-R110. All authors contributed to the article and approved the submitted version. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. doi: 10.1212/WNL.0b013e3181c3fd12, 9. (2006) 354:148996. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. doi: 10.1111/j.1469-8749.2011.04198.x, 26. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. COL4A1-related brain small-vessel disease - MedlinePlus What does it mean to have a COL4A1 gene mutation: The COL4A1 gene provides instructions for making one component of type IV collagen, which is a flexible protein important in the structure of many. Bone. Stroke. doi: 10.1038/gim.2015.30, 21. 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. Agenesis of the Corpus Callosum | National Institute of Neurological small vessel disease: a systematic review. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. J Neurol Sci. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. The signs and symptoms can manifest at almost any age from before birth to old age. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps Col4a1 mutation generates vascular abnormalities correlated with Summary: Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. 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. Affected individuals may have no observable symptoms or only isolated migraines with aura. doi: 10.1111/cge.12379, 13. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Neurol. Neurology. 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). Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. N Engl J Med. doi: 10.1056/NEJMoa071906, 14. It affects mainly young adults, children and more typically neonates. Epub 2016 Apr 24. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. Fetal intracerebral hemorrhage and cataract: think COL4A1. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. 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. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Epilepsy and related challenges in children with COL4A1 and - PubMed See our, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome, URL of this page: https://medlineplus.gov/genetics/condition/hereditary-angiopathy-with-nephropathy-aneurysms-and-muscle-cramps-syndrome/. Changing lives of those with rare disease. 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. J Genet Couns. Phone: 203-263-9938 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. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. (2012) 54:56974. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. However, there are exceptions that depend on precisely when and where the mutation arose. 1A-B). Danbury, CT 06810 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. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. doi: 10.1212/WNL.0000000000000837, 20. No use, distribution or reproduction is permitted which does not comply with these terms. mutations: a novel genetic multisystem disease. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. 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. N Engl J Med. In the human genome, there are 46 chromosomes. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Nearly half of these participants were diagnosed with infantile spasms. 2018;61:765-772. Ann Neurol. These genes are the blueprints for two proteins that wind together like a long rope inside cells. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Painful muscle cramps can occur and can develop before three years of age. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. However, in people with HANAC syndrome, these aneurysms typically do not burst. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. doi: 10.1136/jmg.2005.035584, 15. Neurology. 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). 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. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. (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). Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). 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%). Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. 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. He smiled, caught it, and asked Zeeva if he could throw it back.