The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. (2015) 84:91826. National Center for Biotechnology Information. (2005) 308:116771. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. N Engl J Med. Stroke. Surgery may be necessary for individuals with severe cataracts. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). It affects mainly young adults, children and more typically neonates. COL4A1 mutations as a monogenic cause of cerebral Teaching families how to advocate for their loved ones and access medical information. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. doi: 10.1136/jmg.2005.035584, 15. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. This site needs JavaScript to work properly. (No doctor had ever taken a call on their lunch break to speak with me). The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories. Bethesda, MD 20894, Web Policies Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Recent findings: doi: 10.1001/archophthalmol.2010.42, 10. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. doi: 10.1007/s00417-014-2800-6, 12. Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. 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. 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. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). 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 Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Mutations in the COL4A1 gene cause HANAC syndrome. 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. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. The disorder causes many symptoms, not the least of which are strokes and epilepsy. doi: 10.1186/s12881-014-0097-2, 11. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. In addition to porencephaly there can be other forms of damage to the brain present at birth. Disclaimer. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. 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. In the human genome, there are 46 chromosomes. 2010;17(13):1317-24. doi: While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. (2020). Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. 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. 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. eCollection 2022 Nov 8. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Jeanne M, Gould DB. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. 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. A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium). Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. Cavalin M, Mine M, Philbert M, et al. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, So far, it appears as though mutations in COL4A1 and COL4A2 lead to identical disease, however, for reasons that are not yet understood, mutations in COL4A2 are much less frequent than those in COL4A1. NORD strives to open new assistance programs as funding allows. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Understanding what it has taken to get her to this point, though, is close to unimaginable. 2009 Jun 25 [Updated 2016 Jul 7]. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. What is Gould Syndrome? - Gould Syndrome Foundation Your support helps to ensure everyones free access to NORDs rare disease reports. 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. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. 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. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. The first time he came to meet us, Zeeva threw a sock at him. (2004) 62:16135. Changing lives of those with rare disease. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. An official website of the United States government. Progressive cerebral atrophies in three children with COL4A1 mutations. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. 10.2174/092986710790936293. (2012) 54:56974. J Perinatol. FOIA 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. He also wanted to remove a shunt that was implanted in What is the prognosis of a genetic condition? Front. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Am J Neuroradiol. Firstly, it segregates within the family with the phenotype. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. This page is currently unavailable. (2015) 17:40524. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. 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. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). doi: 10.2214/ajr.149.2.351, 19. Phone: 617-249-7300, Danbury, CT office 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. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. percent confident in Dr. Madsen and the epilepsy team. This is called genotype-phenotype correlation. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, et al. 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. Summary. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. Gould Syndrome is an ultra rare genetic, multi-system disorder. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance. How can gene variants affect health and development? 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. The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. 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). TTY: (866) 411-1010 Neurology. For the nucleotide numbering, the HVGS terms (www.hgvs.org) were applied with the nucleotide A of the ATG startcodon = c.1. Please note that NORD provides this information for the benefit of the rare disease community. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Hum Mol Genet. Autosomal Dominant Brain Small Vessel Disease. Graefe's Arch Clin Exp Ophthalmol. (2015) 88:46873. 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 . Dr. Madsen suggested Zeeva have an operation called a Purpose of review: She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature She also showed severe hypermetropia. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease.
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