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. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. 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. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. The brain MRI of IV-6 disclosed a large right-sided frontoparietal cavity (Figure 3B) with communication to the lateral ventricle, isosignal to CFS. 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. eCollection 2021. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). Cephalic Disorders Fact Sheet. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. Unauthorized use of these marks is strictly prohibited. doi: 10.1212/WNL.0b013e3181c3fd12, 9. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. (2014) 11:3612. The number of genes implicated in epilepsy has grown rapidly in the past decade. Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. (2008) 23:17. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). doi: 10.1001/archophthalmol.2010.42, 10. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). doi: 10.1038/nmeth.2890, 22. Please note that NORD provides this information for the benefit of the rare disease community. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. 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. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. 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. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ultrasound in utero from IV-6 (A). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. NORD is a registered 501(c)(3) charity organization. COL4A1 Mutation in a Neonate With Intrauterine Stroke and Anterior Segment Dysgenesis. 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. Type IV collagen molecules attach to each other to form complex protein networks. For example, an individual may carry genetic variants elsewhere in their genome that confers protection or susceptibly to the mutation and environmental experiences (trauma, anticoagulant use, physical exertion etc.) HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Childhood presentation of COL4A1 mutations. Autosomal Dominant Familial Porencephaly Type I. official website and that any information you provide is encrypted (2010) 75:7479. HHS Vulnerability Disclosure, Help 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. Bethesda, MD 20894, Web Policies Clinical Testing and Workup 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. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. He would separate the two halves of her brain by Your support helps to ensure everyones free access to NORDs rare disease reports. 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). This is called genotype-phenotype correlation. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. There are 28 different types of collagen in your body and mutations in the genes that encode these proteins lead to multiple, highly diverse diseases. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. (2013) 73:4857. Children with the most severe brain malformations may have: Intellectual impairment Seizures Hydrocephalus Spasticity People who have a disorder of the corpus callosum typically have: (2008) 17:42433. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. HANAC syndrome is a rare condition, although the exact prevalence is unknown. Mutations in the COL4A1 gene cause HANAC syndrome. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). 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. The risk is the same for males and females. The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). These exceptions are nuanced and should be discussed with a genetic counselor. In the human genome, there are 46 chromosomes. 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. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. 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. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . Thats not to say Zeeva hasnt had to work hard since the surgery. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. After a normal neonatal period, those affected develop a rapidly progressive course involving irritability, hyperaesthesia, visual and hearing loss, severe cognitive and motor deterioration, and seizures. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Bennett RL, French KS, Resta RG, Doyle DL. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Am J Neuroradiol. Neurol. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Phone: 202-588-5700. doi: 10.1212/WNL.0000000000001309, 8. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Gould Syndrome is an ultra rare genetic, multi-system disorder. 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 Science. doi: 10.1111/j.1469-8749.2011.04198.x, 26. (2005) 308:116771. What are the different ways a genetic condition can be inherited? Contact a health care provider if you have questions about your health. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. Various muscles can be affected and muscle strength can become weakened. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. Before This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. 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. 11:827. doi: 10.3389/fneur.2020.00827. Clin Genet. 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. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. 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. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. All authors contributed to the article and approved the submitted version. Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. What are the different ways a genetic condition can be inherited? Stroke is a leading cause of death and serious long-term disability in developed nations. He smiled, caught it, and asked Zeeva if he could throw it back. 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. doi: 10.1038/gim.2015.30, 21. (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). NORD is a registered 501(c)(3) charity organization. doi: 10.1016/j.ejpn.2009.04.010, 27. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. 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. Autosomal Dominant Brain Small Vessel Disease. Molecular analysis in the father disclosed a heterozygous variant c.2228G>T (p.Gly743Val) in exon 30 of the COL4A1 gene that segregated with the phenotype. 30. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. It is important to discuss these concepts with a genetic counselor and understand their implications. Neurology. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. Staals J, Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 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. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 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.
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