There are no standardized treatment protocols or guidelines for affected individuals. All authors contributed to the article and approved the submitted version. 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). The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. doi: 10.1038/gim.2015.30, 21. COL4A1 Syndrome CADASIL (2015) 17:40524. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Hereditary angiopathy with nephropathy, aneurysms, and - MedlinePlus COL4A1/A2-related disorders are dominant genetic disorders. 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 Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. National Institute of Neurological Disorders and Stroke. 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 type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). 1900 Crown Colony Drive The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. mutations: a novel genetic multisystem disease. 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. Clin Neurol Neurosurg. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Role of COL4A1 in Small-Vessel Disease and Hemorrhagic Stroke doi: 10.1038/gim.2014.210, 3. 55 Kenosia Avenue https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Lenses corrected for hypermetropia. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Type IV collagen networks play an important role in the basement membranes in virtually all tissues throughout the body, particularly the basement membranes surrounding the body's blood vessels (vasculature). The size and location of cerebral cavities contributes to clinical variability. the basement membranes surrounding the body's blood vessels, National Organization for Rare Disorders (NORD), BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES. Type IV collagen molecules attach to each other to form complex protein networks. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. (2014) 252:178994. Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. 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 information on this site should not be used as a substitute for professional medical care or advice. National Library of Medicine Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. doi: 10.1111/cge.12379, 13. Compared to other COL4A1-related disorders, the brain is only mildly affected in HANAC syndrome. Neurology. Clinical Testing and Workup In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. Bethesda, MD 20894, Web Policies Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. 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. This group rarely survives beyond 2 years. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Role of COL4A1 in small-vessel disease and hemorrhagic stroke. U.S. Department of Health and Human Services, Autosomal dominant familial hematuria, retinal arteriolar tortuosity, contractures, Hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome. doi: 10.1056/NEJMoa071906, 14. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. 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%). Purpose of review: He was confident this would reduce or stop the Unable to load your collection due to an error, Unable to load your delegates due to an error. Congenital Cephalic Disorders All individuals with this condition have arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eyes (arterial retinal tortuosity). Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. COL4A1-related brain small-vessel disease - MedlinePlus (2014) 83:122834. In addition to porencephaly there can be other forms of damage to the brain present at birth. Maybe try a search? The COL4A1 and COL4A2 genes were screened in proband IV-6. 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. In the human genome, there are 46 chromosomes. 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. (2011) 42:13. 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. (2005) 308:116771. Genet Med. Phone: 203-263-9938 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/. He also wanted to remove a shunt that was implanted in Gould Syndrome is an ultra rare genetic, multi-system disorder. cutting tissue called the corpus callosum, then make some additional delicate Last updated: Cesarean delivery for pregnancies with fetus at risk for a COL4A1-related disorder is recommended to prevent brain vascular injury attributable to birth trauma during delivery (6). 2010;17(13):1317-24. doi: Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. 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. Zeevas brain to treat a cyst in her brain caused by porencephaly. HANAC syndrome is caused by genetic changes in the COL4A1 gene. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Internet. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). doi: 10.1056/NEJMoa053727, 7. Neurol. Phone: 202-588-5700. Phone: 202-588-5700. 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, . 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. 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. Gould Syndrome is a rare, genetic, multi-system disorder. TTY: (866) 411-1010 (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). The first time he came to meet us, Zeeva threw a sock at him. 10.1161/STROKEAHA.110.581918. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Clin Genet. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. What are the different ways a genetic condition can be inherited? Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. The surgery How are genetic conditions treated or managed? 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. Washington, DC 20036 Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. The COL4A1 stroke syndrome. Written informed consent was obtained from the patient and the patient's parents for publication of this case report. PS: wrote thi paper and performed the review of the literature under the supervision of GN. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. 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 . 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. 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. Arch Ophthalmol. doi: 10.2214/ajr.149.2.351, 19. However, in people with HANAC syndrome, these aneurysms typically do not burst. Fax: 203-263-9938, Washington, DC Office Dev Med Child Neurol. 8600 Rockville Pike 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. INTERNET The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Stroke. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. The .gov means its official. Zagaglia Selch C, Nisevic JR, et al. 1A-B). These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps Treatment When these ropes are secreted, they assemble into net-like structures outside the cells. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Ultrasound in utero from IV-6 (A). More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Phone: 203-263-9938 Other eye problems experienced by people with COL4A1-related brain small-vessel disease include clouding of the lens of the eye (cataract) and the presence of arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eye (arterial retinal tortuosity). 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. Resource(s) for Medical Professionals and Scientists on This Disease: Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. doi: 10.1212/WNL.0b013e3181eee440, 28. Autosomal Dominant Brain Small Vessel Disease. If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. It is important to discuss these concepts with a genetic counselor and understand their implications. COL4A1 -Related Disorders - PubMed Disclaimer. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. 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. 2010 Aug;41(8):e513-8. What does it mean to have a COL4A1 - Little Braveheart | Facebook 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. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. 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. 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. While there are other explanations, parental mosaicism should be considered. Neuropediatrics. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. functional hemispherectomy. Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel. How can gene variants affect health and development? Contact a health care provider if you have questions about your health. Acute urinary retention due to a novel collagen COL4A1 mutation. Collagen type IV alpha 1 (COL4A1) silence hampers the invasion, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cells through blocking Hedgehog signaling pathway. percent confident in Dr. Madsen and the epilepsy team. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. Epub 2016 Apr 24. Stroke is a leading cause of death and serious long-term disability in developed nations. National Center for Biotechnology Information. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Matrix Biol. When this enzyme is elevated, it is a sign of muscle damage. doi: 10.1038/jp.2013.135, 29. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. COL4A1 mutations in patients with sporadic late-onset intracerebral IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. To use the sharing features on this page, please enable JavaScript. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. Firstly, it segregates within the family with the phenotype. Bookshelf Summary. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. (2004) 62:16135. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. 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. Federal government websites often end in .gov or .mil. Standardized (15) familiar pedigree is showed in Figure 1. 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. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Neurology. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. Am J Neuroradiol. His bedside manner was incredible. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. 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 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. Cavalin M, Mine M, Philbert M, et al. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. We provide education, advocacy, and resources for families and individuals affected. These exceptions are nuanced and should be discussed with a genetic counselor. Prenatal clinical manifestations in individuals with COL4A1/2 variants. 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. 55 Kenosia Avenue NORD is a registered 501(c)(3) charity organization. Fetal intracerebral hemorrhage and cataract: think COL4A1. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. The number of genes implicated in epilepsy has grown rapidly in the past decade. Accessibility IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. 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. doi: 10.1056/NEJMoa1707914, 6. 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. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. (2008) 23:17. Changing lives of those with rare disease. 1 Survivors often have a severely diminished quality of life, require long-term care, and are at high risk . Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 Am J Med Genet. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Disease Overview. Dr. Madsen suggested Zeeva have an operation called a Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. 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 the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. Seattle, WA: University of Washington, Seattle; 1993-. The severity of the condition varies greatly among affected individuals. MeSH Would you like email updates of new search results? 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. Vilain C, Van Regemorter N, Verloes A, David P, Van Bogaert P. Neuroimaging fails to identify asymptomatic carriers of familial porencephaly.
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