IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects). Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Danbury, CT 06810 1A-B). This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: The risk is the same for males and females. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. Pediatr Neurol. 1779 Massachusetts Avenue Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Phone: 617-249-7300, Danbury, CT office 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. People listened to us and to Zeeva in a very different and proactive way. NORD is a registered 501(c)(3) charity organization. 10.2174/092986710790936293. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. 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 Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). The https:// ensures that you are connecting to the The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. This group rarely survives beyond 2 years. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Neurology. What does it mean if a disorder seems to run in my family? The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. 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: The first time he came to meet us, Zeeva threw a sock at him. Resource(s) for Medical Professionals and Scientists on This Disease: Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Suite 310 Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, 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. HANAC syndrome is a rare condition, although the exact prevalence is unknown. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. NORD is a registered 501(c)(3) charity organization. Phone: 202-588-5700. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. 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). 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Epub 2010 Jun 17. Plaisier E, Ronco P. COL4A1-Related Disorders. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. government site. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Gould Syndrome is an ultra rare genetic, multi-system disorder. (2012) 54:56974. Probands' father had severe hypermetropia and bilateral cataracts. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. She, then, developed seizures which were controlled by valproic acid. Neurology. There are no standardized treatment protocols or guidelines for affected individuals. He was confident this would reduce or stop the The surgery A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. In most people, small vessel disease in the brain does not cause symptoms. Recent findings: 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. Gould Syndrome is a rare, genetic, multi-system disorder. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. BMC Med Genet. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. Fax: 203-263-9938, Washington, DC Office doi: 10.1001/archophthalmol.2010.42, 10. 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. (19). No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. When we didnt feel we had any options left for treatment, In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). Prenatal clinical manifestations in individuals with COL4A1/2 variants. J Neurol Sci. doi: 10.1038/jp.2013.135, 29. To use the sharing features on this page, please enable JavaScript. In addition to porencephaly there can be other forms of damage to the brain present at birth. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. 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. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. ClinVar; [VCV000389182.3]. 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 (2015) 84:91826. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, (1982) 40:5679. Figure 3. Summary. Individuals with HANAC syndrome also experience a variety of eye problems. 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. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. He would separate the two halves of her brain by (2002) 112:198202. (2006) 354:148996. eCollection 2021. 30. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). Your support helps to ensure everyones free access to NORDs rare disease reports. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. 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. When these ropes are secreted, they assemble into net-like structures outside the cells. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. (2014) 252:178994. eCollection 2022 Nov 8. Years published: 2019. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. 55 Kenosia Avenue The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. (2018) 91:e207888. Contact a health care provider if you have questions about your health. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients even among members of a family who carry the same gene mutation. (2011) 42:13. Ann The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. (2014) 34:757. eCollection 2022. Curr Opin Neurol. sharing sensitive information, make sure youre on a federal It is not uncommon for an unaffected parent to have a severely affected child. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. 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. Matrix Biol. Muscle cramps can be spontaneous or triggered by exercise. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. PS: wrote thi paper and performed the review of the literature under the supervision of GN. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: Ophthalmological features associated with COL4A1 mutations. Neuropsychological tests disclosed language delay and learning difficulties requiring speech therapy at the age of 9 years. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. Lanfranconi S, Markus HS. INTERNET The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Stroke. If either parent also carries the mutation, it is considered inherited. Washington, DC 20036 55 Kenosia Avenue 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. Phone: 203-263-9938 Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. 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. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. 2009 Jun 25 [updated 2016 Jul 7]. Phone: 203-263-9938 Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 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%). (2004) 62:16135. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. 2010 Aug;41(8):e513-8. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Pathology. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. 2018;91:e2078-e2088. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 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: 1779 Massachusetts Avenue Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. It looks like nothing was found at this location. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. Suite 500 Various treatments have been reported in the medical literature as part of single case reports or small series of patients. The retina is the light-sensitive membrane that lines the inside of the eyes. Maybe try a search? Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 doi: 10.1212/WNL.0b013e3181c3fd12, 9. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. Type IV collagen molecules attach to each other to form complex protein networks. 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. If we dont have a program for you now, please continue to check back with us. Our review highlights that COL4A1 mutations can present for the first time in adult life with features of cerebral SVD, including subcortical hemorrhage and ischemic stroke, . Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . Please note that NORD provides this information for the benefit of the rare disease community. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. doi: 10.1056/NEJMoa053727, 7. my mom suggested we call Boston Childrens Hospital. Fetal intracerebral hemorrhage and cataract: think COL4A1. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Childhood presentation of COL4A1 mutations. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. This site needs JavaScript to work properly. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. 10.1161/STROKEAHA.110.581918. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. 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. Brain magnetic resonance imaging (MRI) scans were carried out on a three Tesla Brain MRI (Achieva, Ingenia; Philips Healthcare, Best, The Netherlands). Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role 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.) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Six alpha chains of type IV. The number of genes implicated in epilepsy has grown rapidly in the past decade. 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. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. 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. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. 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. Contact a health care provider if you have questions about your health. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. 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. Cereb Circ Cogn Behav. 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. J Med Genet. Surgery may be necessary for individuals with severe cataracts. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Neurol. Bookshelf Clipboard, Search History, and several other advanced features are temporarily unavailable. for the triple helical CB3[IV] domain. Berg R, Aleck A, Kaplan A. Familial porencephaly. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. 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). 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. Arch Neurol. 2011 With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. However, there are exceptions that depend on precisely when and where the mutation arose. It is ubiquitously expressed in many tissues and cell types. Unable to load your collection due to an error, Unable to load your delegates due to an error. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Treatment can also contribute. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. Rarely, affected individuals will have a condition called Raynaud phenomenon in which the blood vessels in the fingers and toes temporarily narrow, restricting blood flow to the fingertips and the ends of the toes. Neurol. Jeanne M, Gould DB. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). 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. 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/. Front. He also wanted to remove a shunt that was implanted in 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. Congenital Cephalic Disorders In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. This condition causes mutations in genes that produce a specific type of collagen. The disorder causes many symptoms, not the least of which are strokes and epilepsy. 8600 Rockville Pike For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. Cephalic Disorders Fact Sheet. 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). 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. Seattle, WA: University of Washington, Seattle; 1993-. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. Hereditary cerebral small vessel diseases: a review. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. IV-3 goes to a normal school, but special schooling is required for IV-6. Clinical Testing and Workup COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance.
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