Here, we report a patient with schizencephaly, detected by fetal ultrasonography and fetal magnetic resonance imaging, with a de novo novel mutation in COL4A1 (c.2645_2646delinsAA, p.Gly882Glu). Prenatal clinical manifestations in individuals with COL4A1/2 variants. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. 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). COL4A1 mutations as a monogenic cause of cerebral 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. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Neuropediatrics. Migraines can occur with or without aura. eCollection 2022. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. government site. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. The first reports of human COL4A1 mutations were in patients with autosomal dominant porencephaly and a more recent study found that COL4A1 mutations were found in ~16% of patients with porencephaly. doi: 10.1016/j.ejpn.2009.04.010, 27. 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. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies, https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, https://www.ncbi.nlm.nih.gov/pubmed/28254515, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, https://www.nature.com/articles/gim2014210, https://www.ncbi.nlm.nih.gov/pubmed/23225343, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, https://www.ncbi.nlm.nih.gov/pubmed/22868088, https://www.ncbi.nlm.nih.gov/pubmed/22574627, https://www.ncbi.nlm.nih.gov/pubmed/20558831, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, https://www.ncbi.nlm.nih.gov/pubmed/26610912, https://www.ncbi.nlm.nih.gov/books/NBK7046/, https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet, https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/, https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/, https://rarediseases.org/patient-assistance-programs/caregiver-respite/, Learn more about Patient Assistance Programs >, Arginine: Glycine Amidinotransferase Deficiency, https://rarediseases.org/non-member-patient/epilepsy-foundation/, Gould Syndrome Foundation (COL4a1/COL4A2), https://rarediseases.org/non-member-patient/gould-syndrome-foundation-col4a1-col4a2/, https://rarediseases.org/non-member-patient/national-kidney-foundation/, https://rarediseases.org/non-member-patient/nih-national-eye-institute/, NIH/National Institute of Neurological Disorders and Stroke, Aromatic L-Amino Acid Decarboxylase Deficiency, https://rarediseases.org/non-member-patient/nih-national-institute-of-neurological-disorders-and-stroke/, https://rarediseases.org/non-member-patient/the-arc/, Learn more about Patient Organization & Membership >, HANAC: hereditary angiopathy, nephropathy and cramps syndrome (OMIM #611773), POREN1: autosomal dominant type 1 porencephaly; porencephaly with infantile hemiplegia (OMIM #175780, RATOR: retinal arterial tortuosity (OMIM #180000), BSVD: brain small vessel disease with or without ocular anomalies (OMIM #607595), ICH: susceptibility to intracerebral hemorrhage (OMIM #614519). COL4A1 is an essential component for basal membrane stability. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. The retina is the light-sensitive membrane that lines the inside of the eyes. Bookshelf This raises questions about what tests Liliane has a lot to be grateful for this holiday season. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. No microbleeds or cystic cavities were found. 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). 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. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. (2006) 354:148996. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Neurology. Phone: 202-588-5700. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Washington, DC 20036 Eur J Med Genet. 1900 Crown Colony Drive We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. National Library of Medicine People listened to us and to Zeeva in a very different and proactive way. 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). doi: 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Genet Med. It is important to discuss these concepts with a genetic counselor and understand their implications. Another limitation is the systemic work-up based on described phenotypes and supposed affected organs. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. 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. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). The disorder causes many symptoms, not the least of which are strokes and epilepsy. Cephalic Disorders Fact Sheet. cuts under the microscope. (2017) 377:111931. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) This group rarely survives beyond 2 years. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. This condition causes mutations in genes that produce a specific type of collagen. 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). Please note that NORD provides this information for the benefit of the rare disease community. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Fax: 203-263-9938, Washington, DC Office HHS Vulnerability Disclosure, Help To use the sharing features on this page, please enable JavaScript. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Surgery may be necessary for individuals with severe cataracts. Doctors and researchers to bring research and medical therapeutic options to those affected. (2010) 75:7479. doi: 10.1056/NEJMoa053727, 7. Hereditary cerebral small vessel diseases: a review. 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. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Accessibility Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot. He would separate the two halves of her brain by A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Childhood presentation of COL4A1 mutations. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. doi: 10.1038/gim.2014.210, 3. 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). Graefe's Arch Clin Exp Ophthalmol. 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. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Arch Ophthalmol. seizure activity. Full ophthalmological evaluations including slit lamp and fundoscopy were realized and disclosed for bilateral hypermetropia in IV-3 [15 dioptre (D)], IV-6 (8.5 D), IV-5 (10 D), and III-3 (7 D). Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Hum Mol Genet. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. 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. Bull Acad Natl Med. Further refinement of COL4A1 and COL4A2 related cortical malformations. Pediatr Neurol. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. Ultrasound in utero from IV-6 (A). Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. We provide education, advocacy, and resources for families and individuals affected. A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. Ann Neurol. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. ACS Omega. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. (2008) 23:17. What does it mean if a disorder seems to run in my family? MedlinePlus also links to health information from non-government Web sites. The disorder causes many symptoms, not the least of which are strokes and epilepsy. 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: Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. The information on this site should not be used as a substitute for professional medical care or advice. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. 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. 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). Dev Med Child Neurol. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. 2011 People with COL4A1-related brain small vessel disease also have leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI). 2011 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. Ophthalmological features associated with COL4A1 mutations. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. Standardized (15) familiar pedigree is showed in Figure 1. 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. my mom suggested we call Boston Childrens Hospital. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: All authors contributed to the article and approved the submitted version. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. doi: 10.1136/jmg.2005.035584, 15. Neurology. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 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. 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 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. doi: 10.1212/WNL.0000000000001309, 8. (2007) 357:268795. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. The signs and symptoms can manifest at almost any age from before birth to old age. No use, distribution or reproduction is permitted which does not comply with these terms. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. and transmitted securely. 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/. COL4A1 Syndrome CADASIL We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. PMC Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). BMC Med Genet. 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. 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. 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 J Med Genet. 2009 Jun 25 [updated 2016 Jul 7]. The COL4A2 test was negative. mutations: a novel genetic multisystem disease. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Cavalin M, Mine M, Philbert M, et al. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. ClinVar; [VCV000389182.3]. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain.
Jobs At Allegiant Stadium, Used Rottler Seat And Guide Machine For Sale, Mount Kellett Capital Management Fortress, Sagittarius Woman And Aries Man Break Up, David Attenborough: A Life On Our Planet Answer Key, Articles C