All authors contributed to the article and approved the submitted version. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. doi: 10.1136/jmg.2005.035584, 15. IV-3 goes to a normal school, but special schooling is required for IV-6. National Center for Biotechnology Information. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Type IV collagen molecules attach to each other to form complex protein networks. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. COL4A1/A2-related disorders are dominant genetic disorders. Lanfranconi S, Markus HS. Am J Neuroradiol. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. (2014) 11:3612. Axenfeld-Rieger anomaly involves underdevelopment and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. government site. Ultrasound in utero from IV-6 (A). (2006) 354:148996. 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. 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. 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. This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network. Quincy, MA 02169 PS: wrote thi paper and performed the review of the literature under the supervision of GN. 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. Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. 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. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. To better define pathology caused by Col4a1 mutations, we characterized myopathy in two different Col4a1 mutant mouse strainsCol4a1 ex41 and Col4a1 G394V.We selected these strains from an allelic series of Col4a1 mutant mice because they showed the most severe myopathy according to NPN quantification in quadriceps while having different effects on [1(IV)] 2 2(IV) secretion. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. (2009) 73:187382. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). Neurology. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. 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). In addition to porencephaly there can be other forms of damage to the brain present at birth. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. 2012;21:R97-R110. We connect and coordinate our families with researchers and medical professionals to get our disease and management coordination into the medical realm. (1987) 8:4216. Curr Opin Neurol. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. doi: 10.1016/j.ejpn.2009.04.010, 27. 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. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. 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. Progressive cerebral atrophies in three children with COL4A1 mutations. 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). It affects mainly young adults, children and more typically neonates. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. He would separate the two halves of her brain by HANAC syndrome is caused by genetic changes in the COL4A1 gene. Disease Overview. Neurol. doi: 10.1056/NEJMoa071906, 14. Am J Med Genet A. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. eCollection 2022 Nov 8. 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. 2010;41:e513-518. Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. Clipboard, Search History, and several other advanced features are temporarily unavailable. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). It is not uncommon for an unaffected parent to have a severely affected child. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. 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. Federal government websites often end in .gov or .mil. 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. Other patients have been reported with cysts on the liver, irregular heartbeats (supraventricular arrhythmia), and Raynaud phenomenon, which is in which the fingers or toes become numb or have a prickly sensation in response to cold due to narrowing of blood vessels. Quincy, MA 02169 Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). 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. cuts under the microscope. In most cases, an affected person has one parent with the condition. N Engl J Med. doi: 10.1212/WNL.0b013e3181eee440, 28. COL4A1 mutations as a monogenic cause of cerebral Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Diseases Information Center National Center for Advancing Translational Sciences Browse by Disease About GARD Contact Us We recently launched the new GARD website and are still developing specific pages. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). Please note that NORD provides this information for the benefit of the rare disease community. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). N Engl J Med. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. Clin Genet. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. It is passed through families in a autosomal dominant fashion. CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. 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. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. doi: 10.1038/gim.2014.210, 3. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). J Perinatol. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. 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. Stroke is a leading cause of death and serious long-term disability in developed nations. Matrix Biol. HHS Vulnerability Disclosure, Help COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. These genes are the blueprints for two proteins that wind together like a long rope inside cells. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. In affected individuals, stroke is usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke), although either type can occur. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. NORD strives to open new assistance programs as funding allows. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. COL4A1-related brain small-vessel disease is a rare condition, although the exact prevalence is unknown. Teaching families how to advocate for their loved ones and access medical information. Recent findings: 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. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, For information about clinical trials sponsored by private sources, contact: Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al.