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CARDIAC VALVE INVOLVEMENT IN ADAR-RELATED TYPE I INTERFERONOPATHYYanick J Crow1,2, Nandaki Keshavan3,4*, J Patrick Barbet5, Geanina Bercu6, Vincent Bondet7, Charlotte Boussard8, Nathalie Dedieu9, Darragh Duffy7, Marie Hully10, Alessandro Giardini9, Cyril Gitiaux10, Gillian I Rice11, Luis Seabra1, Brigitte Bader-Meunier8,12, Shamima Rahman3,4Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes University, Sorbonne-Paris-Cité, INSERM UMR 1163, Institut Imagine, Paris, France Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, United KingdomMitochondrial Research Group, Genetics and Genomic Medicine, UCL Institute of Child Health, Guilford Street, London, UKMetabolic Unit, Great Ormond Street Hospital, London, UK Department of Paediatric Pathology, H?pital Necker-Enfants Malades, University Paris Descartes, Paris, France Paediatric Cardiac Surgery Department, Necker Hospital, APHP, Paris, France GBImmunobiology of Dendritic Cells, Institut Pasteur, 75015 Paris, France INSERM U1223, Paris, France Paediatric Hematology-Immunology and Rheumatology Department, H?pital Necker-Enfants Malades, AP-HP, Paris, France. Cardiology Department, Great Ormond Street Hospital, London, UK Paediatric Neurology Department, Necker Hospital, APHP, Paris, France Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK Reference Center for Rheumatic, Autoimmune and Systemic diseases in children (RAISE), Paris, France *Corresponding Author: Nandaki KeshavanMitochondrial Research Group, Genetics and Genomic Medicine, UCL Institute of Child Health, Guilford Street, London, UKMetabolic Unit, Great Ormond Street Hospital, London, UKLICENCE STATEMENTI, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance with the terms applicable for US Federal Government officers or employees acting as part of their official duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the Work in Journal of Medical Genetics and any other BMJ products and to exploit all rights, as set out in our?licence.The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to the Submitting Author unless you are acting as an employee on behalf of your employer or a postgraduate student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative Commons licence – details of these licences and which?Creative Commons?licence will apply to this Work are set out in our licence referred to above.I am one author signing on behalf of all co-authors of the Work.Nandaki KeshavanABSTRACTBackgroundADAR mutations cause a spectrum of neurological phenotypes ranging from severe encephalopathy (Aicardi-Goutières syndrome) to isolated spastic paraplegia and are associated with enhanced type I interferon signalling. Non-neurological involvement in the type I1 interferonopathies includes autoimmune and rheumatological phenomena, with calcifying cardiac valve disease only previously reported children in the context of MDA5 gain-of-function.ResultsWe describe three patients with biallelic ADAR mutations who developed calcifying cardiac valvular disease in late childhood (9.5-14 years). Echocardiography revealed progressive calcification of the valvular leaflets resulting in valvular stenosis and incompetence. Two patients became symptomatic with biventricular failure after 5- 6.5 years. In one case disease progressed to severe cardiac failure despite maximal medical management, with death occurring at 17 years. Another child received mechanical mitral and aortic valve replacement at 16 years with good postoperative outcome. Histological examination of the affected valves showed fibrosis and calcification.ConclusionsType I interferonopathies of differing genetic aetiology havedemonstrate an overlapping phenotypic spectrum which includes calcifying cardiac valvular disease. Cardiac valve calcification inIndividuals with ADAR-related type I1 interferonopathy may develop childhood-onset in childhood with insidious progression over several years to multivalvular stenosis and incompetence and which can progress insidiously to symptomatic, and ultimately fatal, cardiac failure which can be fatal. Regular surveillance echocardiograms are recommended to detect valvular disease early. Surgical valve replacement is an effective treatment although the long-term efficacy is currently unclear. 197200/200 wordsINTRODUCTIONAdenosine deaminases acting on RNA (ADAR) catalyse the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA). Failure of this editing activity results in upregulation of interferon production, likely induced by unmodified endogenous nucleic acids signalling through the cytoplasmic dsRNA sensor MDA5.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BaG1hZDwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 1 Both loss-of-function mutations in ADAR and gain-of-function mutations in IFIH1 encoding MDA5 have been classified within the type I interferonopathy grouping, proposed to represent a novel set of inborn errors of immunity where an upregulation of type I interferon signalling is central to disease pathogenesis. ADDIN EN.CITE <EndNote><Cite><Author>Crow</Author><Year>2011</Year><RecNum>749</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>749</rec-number><foreign-keys><key app="EN" db-id="aws2zsrr4rrrfjertz1xs5ecr5xsvz29p5xv" timestamp="1562794254">749</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Crow, Y. J.</author></authors></contributors><auth-address>Genetic Medicine, University of Manchester, Manchester Academic Health Science Centre, Central Manchester Foundation Trust University Hospitals, United Kingdom. yanickcrow@</auth-address><titles><title>Type I interferonopathies: a novel set of inborn errors of immunity</title><secondary-title>Ann N Y Acad Sci</secondary-title></titles><periodical><full-title>Ann N Y Acad Sci</full-title></periodical><pages>91-8</pages><volume>1238</volume><edition>2011/12/02</edition><keywords><keyword>Autoimmune Diseases/genetics/immunology</keyword><keyword>Autoimmune Diseases of the Nervous System/genetics/immunology</keyword><keyword>Complement System Proteins/deficiency</keyword><keyword>Humans</keyword><keyword>Immunity</keyword><keyword>Immunologic Deficiency Syndromes/*genetics/*immunology/therapy</keyword><keyword>Interferon Type I/*genetics/immunology/metabolism</keyword><keyword>Lupus Erythematosus, Systemic/genetics/immunology</keyword><keyword>Nervous System Malformations/genetics/immunology</keyword><keyword>Osteochondrodysplasias/genetics/immunology</keyword><keyword>Up-Regulation</keyword></keywords><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1749-6632 (Electronic)
0077-8923 (Linking)</isbn><accession-num>22129056</accession-num><urls><related-urls><url> Such mutations are associated with a variety of phenotypes, ranging from the severe early-onset encephalopathy Aicardi-Goutières syndrome, through isolated spastic paraparesis to complete non-penetrance. ADDIN EN.CITE <EndNote><Cite><Author>Rodero</Author><Year>2016</Year><RecNum>750</RecNum><DisplayText><style face="superscript">3</style></DisplayText><record><rec-number>750</rec-number><foreign-keys><key app="EN" db-id="aws2zsrr4rrrfjertz1xs5ecr5xsvz29p5xv" timestamp="1562794275">750</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rodero, M. P.</author><author>Crow, Y. J.</author></authors></contributors><auth-address>INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, 75015 Paris, France.
INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, 75015 Paris, France yanickcrow@.
Paris Descartes University, Sorbonne-Paris-Cite, Institut Imagine, Hopital Necker, 75015 Paris, France.
Faculty of Biology, Medicine, and Health, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester M13 9NT, England, UK.</auth-address><titles><title>Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview</title><secondary-title>J Exp Med</secondary-title></titles><periodical><full-title>J Exp Med</full-title></periodical><pages>2527-2538</pages><volume>213</volume><number>12</number><edition>2016/11/09</edition><keywords><keyword>Animals</keyword><keyword>Autoimmunity/immunology</keyword><keyword>Humans</keyword><keyword>Inflammation/*pathology/therapy</keyword><keyword>Interferon Type I/*metabolism</keyword><keyword>Models, Biological</keyword><keyword>Penetrance</keyword><keyword>Phenotype</keyword></keywords><dates><year>2016</year><pub-dates><date>Nov 14</date></pub-dates></dates><isbn>1540-9538 (Electronic)
0022-1007 (Linking)</isbn><accession-num>27821552</accession-num><urls><related-urls><url> Non-neurological features have also been recorded in the type I interferonopathy context, most frequently vasculitic chilblain-like lesions, glaucoma and a predisposition to autoimmune phenomena.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Dcm93PC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 6, 7 Here we report, for the first time, three children patients with biallelic ADAR mutations presenting with calcifying cardiac valve disease, further emphasising the phenotypic overlap across the type I interferonopathies.CASE REPORTSPatient 1The oldest child of healthy unrelated Polish parents, patient 1 was born after a normal pregnancy and delivery. The neonatal period and infancy were unremarkable, and he started to walk independently by 10 months. At one year of age he developed convulsions and ataxia after a febrile illness. An initial MRI brain was normal. Following the acute illness, he experienced a regression of motor skills and stopped walking for three months. By age 7 years he was mostly wheelchair dependent, although he could still take a few steps with a trolley at the age of 10 years. Other problems included feeding difficulties, gastro-oesophageal reflux, faltering growth, hypermetropia and hypothyroidism. Examination at age 9 years revealed freckles on his face and hands. He had a very soft systolic murmur, but cardiovascular examination was otherwise normal. There was no ptosis and there was a full range of eye movements without nystagmus. He had dysarthric speech. He had hypotonic arms with good muscle strength but symmetrically hypertonic legs with fixed flexion contractures at the knees. Reflexes were generally brisk, especially in the legs. Early blood investigations demonstrated intermittently elevated lactates with significant hyperalaninaemia, but at age 9 years blood lactate was repeatedly normal (1.1 - 1.3 mmol/L) with normal plasma amino acid profile, including normal alanine. Cerebrospinal fluid (CSF) investigations revealed normal glucose, protein, neurotransmitters and 5-methyltetrahydrofolate. Total CSF neopterin and dihydrobiopterin were elevated at 108 nmol/L (normal 7-65) and 23.3 nmol/L (0.4-13.9) respectively, with normal tetrahydrobiopterin at 33 nmol/L (9-39). MRI brain demonstrated symmetrically increased signal in the lenticular nuclei and posterior limbs of the internal capsules. Nerve conduction studies showed a demyelinating sensorimotor axonal neuropathy. The clinical features and MRI appearances led to suspicion of Leigh syndrome spectrumPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYWtlPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 10 whilst the canonical splice-site variant is not recorded in control databases ().Echocardiography at age 9.5 years demonstrated normal chamber dimensions, normal biventricular function but mild aortic valve dysplasia calcification and causing mild aortic valvular regurgitation and nowithout aortic stenosisincompetenc. Thise, which appeared to be static over several years. At 11 years of age he had bilateral femoral osteotomies with plate removal three years later in the absence of any perioperative problems. Aged 14 years, echocardiography showed normal chamber dimensions and ventricular function but mild aortic and mitral valve disease with trivial aortic and mild mitral incompetenceregurgitation. At 16.4 years of age his left atrium and ventricle appeared dilated (left ventricular end-diastolic dimension LVEDd 51.2 mm, Z-score +4.39)., hHe had normal ventricular function he hadbut worsening of the dysplastic valvular disease, with an echobright anterior mitral valve leaflet, restricted movement of the mitral valve leaflets, moderate mitral valve stenosis (mean inflow gradient 8.9 mmHg, HR 87) and, mild-to-moderate mitral regurgitation and. The left atrium and ventricle appeared dilated (left ventricular end-diastolic dimension LVEDd 51.2 mm, Z-score +4.39). Regurgitation and flow acceleration across the mild-to-moderate aortic regurgitation valve had also slightly worsened (peak velocity 3.1 m/sec). However, he had no cardiac symptoms and biventricular systolic function was satisfactory. At 17 years of age he presented with a two-month history of increasing cough especially at night, chest pain and pedal oedema. On examination he was tachypnoeic, especially when supine. He had low volume pulses and cardiac auscultation revealed a loud second heart sound, an ejection systolic murmur at the upper left sternal edge, pansystolic and diastolic murmurs at the apex. He had decreased air entry bibasally and 3-4 cm hepatomegaly. Echocardiography showed large bilateral pleural effusions measuring about 10 cm in size and a small pericardial effusion around the left ventricle and right atrium. The inferior vena cava and hepatic veins were significantly dilated with no respiratory variation. There was severe left atrial (Z-score +19) and right atrial (Z-score +6.6) dilatation, There was no ventricular hypertrophy, but the left ventricle was dilated (LVEDd 56.8 mm, Z-score +7), with good ventricular systolic function (EF 65%). The most striking feature was the progression of the mitral and aortic valve calcification with extremely echobright appearances of the mitral and aortic annuli (Figure 1A, B). . There was ssevere mitral valve stenosis (mean pressure gradient 19 mmHg, HR 105) with severe mitral regurgitation, and moderate tricuspid regurgitation (peak velocity 4 m/sec) without tricuspid valve stenosis. There was no ventricular hypertrophy, but the left ventricle was dilated (LVEDd 56.8 mm, Z-score +7), with good ventricular systolic function (fractional shortening, FS 36%). There was moderatesignificant aortic stenosis with maximal aortic valve velocity of 3.9 m/sec, but no obvious aortic regurgitation. The most striking feature was the progression of the mitral and aortic valve calcification with extremely echobright appearances of the mitral and aortic annuli. There was mild pulmonary regurgitation (end-diastolic velocity 2.2 m/sec) and significant pulmonary hypertension. He received maximal medical management for heart failure and pulmonary hypertension and chest drains for the pleural effusions. Extensive multidisciplinary discussion concluded that there were no curative therapeutic options, and he received palliative care at home. He died a month later.Patient 2Patient 2, the younger sister of patient 1, had a normal birth and developed normally until age 9 months when she experienced an acute encephalopathy following a febrile illness, associated with cerebellar ataxia, dystonia and seizures. followed by delayed motor milestones. She crawled at 8 months of age but did not begin to walk until age 14 months. Investigations during early childhood revealed hyperalaninaemia, demyelinating sensorimotor neuropathy and bilateral basal ganglia signal hyperintensity consistent with Leigh syndrome on brain MRI. at 4 years of age. Examination at age 5.5 years revealed microcephaly, freckling of her hands and face and significant expressive speech delay. She had reduced mobility, (requiring support to walk or otherwise bottom-shuffling), and generalised hypertonia, proximal lower limb muscle weakness and brisk upper and lower limb tendon reflexes. Worsening neurodisability led to wheelchair dependence by 7 years of age. Exome sequencing subsequently revealed the same compound heterozygous pathogenic ADAR variants observed in her brother. Hip surgery for bilaterally dislocated hips at age 12 years was associated with an uneventful perioperative course. At 14 years she began to develop mild posture-dependent pedal oedema. Echocardiogram at 15 years of age showed normal chamber dimensions, FS 35% and LV EF 65%,normal ventricular function but mild focal calcification of the non-coronary cusp of the aortic valve with no other valvular abnormalities. Currently at 16 years of age she has a dystonic gait, reduced lower limb muscle strength and symmetrically brisk reflexes. her echocardiogram continues to show normal chamber dimensions and ventricular function but with calcification of the mitral valve, trivial mitral regurgitation and mild thickening of the non-coronary cusp of the aortic valve.She has no cardiac symptoms.Patient 3This female was born to unrelated parents of Caribbean origin after a normal pregnancy and delivery. The neonatal period and infancy were unremarkable, developing normally until age 2 years when she began to demonstrate progressive walking difficulties with lower limb spasticity, ataxia, dysarthria and nystagmus. T2 axial brain MRI revealed periventricular white matter high signal. At age 11 years she complained of myalgia and arthralgia. Two years later, a mild systolic murmur was noted and echocardiography demonstrated moderate aortic and mitral valve calcifications with mild mitral stenosis and mild mitral regurgitation. Examination at age 16 years revealed moderate psychomotor retardation, spastic tetraparesis and mitral and aortic valve murmurs. Transthoracic echocardiographEchocardiography y showed a LVEDd left ventricule with an end-diastolic diameter (EDD) ofat 40 mm, wall thickness at 8-9 mm (Z score + 2.3 DS) and good systolic function (LVEF 65%). The mitrale and aortic valves were severeily calcified (Figure 1C), with severe mitral stenosis (mean pressure gradient at? 11-12 mmHg, at HR 82/min) and moderate mitral regurgitation. The aortic stenosis was severe (mean pressure gradient at 65 mmHg) with mild aortic regurgitation. Computed tomography (CT) of the heart confirmed mitral and aortic leaflets and annular calcifications (Figure 1D).?Echocardiography showed significant aortic and mitral valve dysplasia with calcifications, severe aortic and mitral valve stenosis and incompetence. Computed tomography (CT) of the heart revealed mitral and aortic valve calcification (Figure 1). The left ventricle was moderately dilated, with good ventricular systolic function (FS 65%). T2 axial brain MRI brain demonstrated periventricular white matter high signal, and calcifications were seen in the basal ganglia, dentate nuclei, thalami and right caudate on brain CT. Nerve conduction studies revealed a progressive sensorimotor axonal neuropathy involving large and small fibres. Normal investigations included full blood count, renal and liver function, creatine kinase, erythrocyte sedimentation rate and C-reactive protein. Immunological studies showed positive antinuclear antibody (ANA) (1:200) without anti-DNA antibodies. There was an upregulation of interferon stimulated gene transcripts in blood (interferon score = 7.4: normal < 2.4), and serum interferon alpha, measured using digital ELISA technology, ranged from normal (10 fg/mL; normal <10 fg/mL) to moderately elevated levels (35 fg/mL). CSF interferon alpha protein was elevated (103 fg/mL). Sequencing of genes related to known type I interferonopathies identified two ADAR variants, c.518A>G;p.Asn173Ser and c.1552dup;p.Thr518Asnfs*31. The p.Asn173Ser substitution, although present in gnomAD (144 of 282,856 alleles) was previously observed in another child with ADAR-related diseasePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXZpbmdzdG9uPC9BdXRob3I+PFllYXI+MjAxNDwvWWVh
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ADDIN EN.CITE.DATA 11 whilst the second (novel) variant results in a frameshift and truncated protein. Parental testing confirmed biallelic inheritance. Owing to the severity of heart disease, the patient underwent mechanical mitral and aortic valve replacements. Pathological studies of the aortic valve demonstrated fibrosis and calcification (Figure 2A-C). EEchocardiography 6 months after surgery showed no left ventricular hypertrophy, good left ventricular function (EF 65%) and prosthetic valves working well. chocardiography 6 months after surgery showed no ventricular hypertrophy, with moderate left ventricular dilation (LVEDd 38 mm), good systolic function (FS 65%) and prosthetic valves working well.DISCUSSIONThe type I interferonopathies are grouped on the premise of shared pathogenic upregulation of type I interferon signalling. One argument in favour of the type I interferon hypothesis is an overlap of clinical features across genotypes, with intracranial calcification, vasculitic skin lesions and glaucoma being particularly frequent associations. However, genotype-specific differences have also been noted, including cerebral vasculopathy in SAMHD1 disease, and bilateral striatal necrosis with ADAR dysfunction.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Dcm93PC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 4 SMS was previously considered a distinct disorder, but the recent clarification of its molecular basis has revealed that this phenotype represents part of a broader spectrum associated with MDA5 gain-of-function. DA specific heterozygousominant mutations in ADAR (p.Gly1007Arg), acting as a dominant-negative, have been linked to a mildercan variably cause both syndrome ofskin lesions consistent with dDyschromatosis sSymmetrica hHereditaria (DSH) and a neurological phenotype. Adult-onsetInterestingly, Significant dystonia was reported in a dominant DSHone such pedigree, which includeding an adult male who died at age 38 years of cardiac failure caused bydue to aortic valve calcification and stenosishas been described in a single male who whose daughter received a diagnosis of autosomal dominant inherited Dyschromatosis Symmetrica Hereditaria secondary to ADAR deficiencyPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ub2pvPC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 12. However, the father was never tested for a mutation in ADAR or for elevated interferon signalling so a link between valvular disease and ADAR-related interferonopathy could not be established. Here, we provide further evidence of clinical overlap across the interferonopathy genotypes, demonstrating that life-threatening cardiac valve dysfunction with calcification can occur in the context of both IFIH1 and ADAR mutations. The clinical and MRI features observed in Patients 1 and 2 initially led to suspicion of a mitochondrial disorder in the Leigh syndrome spectrum. Although ADAR mutations are a recognised cause of Leigh syndrome, there are now more than 89 different monogenic causes of this syndrome,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYWhtYW48L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 13 and a specific genetic diagnosis is frequently only made after genome-wide next generation sequencing. ADDIN EN.CITE <EndNote><Cite><Author>Rahman</Author><Year>2018</Year><RecNum>486</RecNum><DisplayText><style face="superscript">14</style></DisplayText><record><rec-number>486</rec-number><foreign-keys><key app="EN" db-id="aws2zsrr4rrrfjertz1xs5ecr5xsvz29p5xv" timestamp="1546386692">486</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rahman, J.</author><author>Rahman, S.</author></authors></contributors><auth-address>Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK.
Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK; Metabolic Unit, Great Ormond Street Hospital NHS Foundation Trust, London, UK. Electronic address: shamima.rahman@ucl.ac.uk.</auth-address><titles><title>Mitochondrial medicine in the omics era</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>2560-2574</pages><volume>391</volume><number>10139</number><edition>2018/06/16</edition><keywords><keyword>Genetic Therapy</keyword><keyword>Genomics</keyword><keyword>Humans</keyword><keyword>Metabolomics</keyword><keyword>Mitochondria/*metabolism</keyword><keyword>Mitochondrial Diseases/etiology/*metabolism</keyword><keyword>Mutation</keyword><keyword>Proteomics</keyword></keywords><dates><year>2018</year><pub-dates><date>Jun 23</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>29903433</accession-num><urls><related-urls><url>(18)30727-X</electronic-resource-num></record></Cite></EndNote>14 The presence of skin freckles and cardiac valve dysplasia calcification may facilitate clinical recognition of ADAR deficiency in a child with suspected Leigh syndrome. Cardiac valvular disease is extremely uncommon in primary mitochondrial disorders and the few reported cases include two siblings with defective biosynthesis of coenzyme Q10 caused by biallelic mutations in PDSS1.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xsZXQ8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 16, our findings highlight the need to monitor cardio-pulmonary status with regular echocardiograms to detect valvular disease early in the type I interferonopathy context, and further emphasise a likely shared pathogenesis. The favourable postoperative course in Patient 3 suggests that early surgical intervention with cardiac valve replacement may be indicated where medical management has failed in interferonopathy-related valvular cardiac disease. Other potential therapeutic options that might be considered include JAK 1/2 blockade using ruxolitinib, which has shown beneficial effects in patients with MDA5 gain-of-function mutationsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3RodXI8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 17, 18. However, further studies are needed to test the hypothesis that valvular disease is a direct effect of an interferon-driven inflammatory process, and therefore determine whether anti-interferon therapies might be an effective disease modifying treatment.20002019/2000 wordsREFERENCES ADDIN EN.REFLIST 1.Ahmad S, Mu X, Yang F, Greenwald E, Park JW, Jacob E, Zhang CZ and Hur S. Breaching Self-Tolerance to Alu Duplex RNA Underlies MDA5-Mediated Inflammation. Cell. 2018;172:797-810 e13.2.Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci. 2011;1238:91-8.3.Rodero MP and Crow YJ. Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview. J Exp Med. 2016;213:2527-2538.4.Crow YJ, Chase DS, Lowenstein Schmidt J, Szynkiewicz M, Forte GM, Gornall HL, Oojageer A, Anderson B, Pizzino A, Helman G, Abdel-Hamid MS, Abdel-Salam GM, Ackroyd S, Aeby A, Agosta G, Albin C, Allon-Shalev S, Arellano M, Ariaudo G, Aswani V, Babul-Hirji R, Baildam EM, Bahi-Buisson N, Bailey KM, Barnerias C, Barth M, Battini R, Beresford MW, Bernard G, Bianchi M, Billette de Villemeur T, Blair EM, Bloom M, Burlina AB, Carpanelli ML, Carvalho DR, Castro-Gago M, Cavallini A, Cereda C, Chandler KE, Chitayat DA, Collins AE, Sierra Corcoles C, Cordeiro NJ, Crichiutti G, Dabydeen L, Dale RC, D'Arrigo S, De Goede CG, De Laet C, De Waele LM, Denzler I, Desguerre I, Devriendt K, Di Rocco M, Fahey MC, Fazzi E, Ferrie CD, Figueiredo A, Gener B, Goizet C, Gowrinathan NR, Gowrishankar K, Hanrahan D, Isidor B, Kara B, Khan N, King MD, Kirk EP, Kumar R, Lagae L, Landrieu P, Lauffer H, Laugel V, La Piana R, Lim MJ, Lin JP, Linnankivi T, Mackay MT, Marom DR, Marques Lourenco C, McKee SA, Moroni I, Morton JE, Moutard ML, Murray K, Nabbout R, Nampoothiri S, Nunez-Enamorado N, Oades PJ, Olivieri I, Ostergaard JR, Perez-Duenas B, Prendiville JS, Ramesh V, Rasmussen M, Regal L, Ricci F, Rio M, Rodriguez D, Roubertie A, Salvatici E, Segers KA, Sinha GP, Soler D, Spiegel R, Stodberg TI, Straussberg R, Swoboda KJ, Suri M, Tacke U, Tan TY, te Water Naude J, Wee Teik K, Thomas MM, Till M, Tonduti D, Valente EM, Van Coster RN, van der Knaap MS, Vassallo G, Vijzelaar R, Vogt J, Wallace GB, Wassmer E, Webb HJ, Whitehouse WP, Whitney RN, Zaki MS, Zuberi SM, Livingston JH, Rozenberg F, Lebon P, Vanderver A, Orcesi S and Rice GI. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A. 2015;167A:296-312.5.Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, Rice GI, Erlandsen H, Kehl HG, Thiele H, Nurnberg P, Hohne W, Crow YJ, Feigenbaum A and Hennekam RC. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015;96:275-82.6.de Carvalho LM, Ngoumou G, Park JW, Ehmke N, Deigendesch N, Kitabayashi N, Melki I, Souza FFL, Tzschach A, Nogueira-Barbosa MH, Ferriani V, Louzada-Junior P, Marques W, Jr., Lourenco CM, Horn D, Kallinich T, Stenzel W, Hur S, Rice GI and Crow YJ. Musculoskeletal Disease in MDA5-Related Type I Interferonopathy: A Mendelian Mimic of Jaccoud's Arthropathy. Arthritis Rheumatol. 2017;69:2081-2091.7.Buers I, Rice GI, Crow YJ and Rutsch F. MDA5-Associated Neuroinflammation and the Singleton-Merten Syndrome: Two Faces of the Same Type I Interferonopathy Spectrum. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 2017;37:214-219.8.Lake NJ, Compton AG, Rahman S and Thorburn DR. Leigh Syndrome: One disorder, more than 75 monogenic causes. AnnNeurol. 2015.9.Pronicka E, Piekutowska-Abramczuk D, Ciara E, Trubicka J, Rokicki D, Karkucinska-Wieckowska A, Pajdowska M, Jurkiewicz E, Halat P, Kosinska J, Pollak A, Rydzanicz M, Stawinski P, Pronicki M, Krajewska-Walasek M and Ploski R. New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre. Journal of translational medicine. 2016;14:174.10.Rice GI, Kitabayashi N, Barth M, Briggs TA, Burton ACE, Carpanelli ML, Cerisola AM, Colson C, Dale RC, Danti FR, Darin N, De Azua B, De Giorgis V, De Goede CGL, Desguerre I, De Laet C, Eslahi A, Fahey MC, Fallon P, Fay A, Fazzi E, Gorman MP, Gowrinathan NR, Hully M, Kurian MA, Leboucq N, Lin JS, Lines MA, Mar SS, Maroofian R, Marti-Sanchez L, McCullagh G, Mojarrad M, Narayanan V, Orcesi S, Ortigoza-Escobar JD, Perez-Duenas B, Petit F, Ramsey KM, Rasmussen M, Rivier F, Rodriguez-Pombo P, Roubertie A, Stodberg TI, Toosi MB, Toutain A, Uettwiller F, Ulrick N, Vanderver A, Waldman A, Livingston JH and Crow YJ. Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease. Neuropediatrics. 2017;48:166-184.11.Livingston JH, Lin JP, Dale RC, Gill D, Brogan P, Munnich A, Kurian MA, Gonzalez-Martinez V, De Goede CG, Falconer A, Forte G, Jenkinson EM, Kasher PR, Szynkiewicz M, Rice GI and Crow YJ. A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J Med Genet. 2014;51:76-82.12.Tojo K, Sekijima Y, Suzuki T, Suzuki N, Tomita Y, Yoshida K, Hashimoto T and Ikeda S. Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation. Mov Disord. 2006;21:1510-3.13.Rahman J, Noronha A, Thiele I and Rahman S. Leigh map: A novel computational diagnostic resource for mitochondrial disease. Ann Neurol. 2017;81:9-16.14.Rahman J and Rahman S. Mitochondrial medicine in the omics era. Lancet. 2018;391:2560-2574.15.Mollet J, Giurgea I, Schlemmer D, Dallner G, Chretien D, Delahodde A, Bacq D, de LP, Munnich A and Rotig A. Prenyldiphosphate synthase, subunit 1 (PDSS1) and OH-benzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders. JClinInvest. 2007;117:765-772.16.Adang LA, Frank DB, Gilani A, Takanohashi A, Ulrick N, Collins A, Cross Z, Galambos C, Helman G, Kanaan U, Keller S, Simon D, Sherbini O, Hanna BD and Vanderver AL. Aicardi goutieres syndrome is associated with pulmonary hypertension. Mol Genet Metab. 2018;125:351-358.17.Kothur K, Bandodkar S, Chu S, Wienholt L, Johnson A, Barclay P, Brogan PA, Rice GI, Crow YJ and Dale RC. An open-label trial of JAK 1/2 blockade in progressive IFIH1-associated neuroinflammation. Neurology. 2018;90:289-291.18.McLellan KE, Martin N, Davidson JE, Cordeiro N, Oates BD, Neven B, Rice GI and Crow YJ. JAK 1/2 Blockade in MDA5 Gain-of-Function. J Clin Immunol. 2018;38:844-846.CONTRIBUTORSHIP STATEMENTConceptualisation: YJC, BBM, SRClinical data collection: BBM, CB, MH, CG, SR, NKImmunological data collection: VB, DDCardiac data collection: GB, ND, AGGenetic data collection: SR, GIR, LS, YJCManuscript drafting: YJC, SR, NKImages: BBM, JPBCritical review of manuscript: all authorsPATIENT CONSENTConsent from both families has been obtained for publicationFUNDINGYJC acknowledges funding from the European Research Council (GA 309449: Fellowship to YJC and a state subsidy managed by the National Research Agency (ANR, France) under the “Investments for the Future” (ANR-10-IAHU-01).SR acknowledges funding from the Great Ormond Street Hospital Children’s Charity, the NIHR Great Ormond Street Hospital Biomedical Research Centre and the Lily Foundation. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of PETING INTERESTSNo competing interests are declaredACKNOWLEDGEMENTSNone declaredFIGURE LEGENDSFigure 1. A, B Cardiac valve calcification as demonstrated by echocardiography of patient 1Cardiac valve calcification as demonstrated by Computed tomography (CT) of patient 3 C Cardiac valve calcification as demonstrated by echocardiography of patient 3D Cardiac valve calcification as demonstrated by Computed tomography (CT) of patient 3 Figure 2 Histological findings of explanted mitral valve from patient 3A, B: Fibrosis and calcification of the valve valvular tissue remodeledremodelled by the presence of fibrous nodules and areas of microcalcifications. C: Ossification of the valve ................
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