Recessive Inheritance of a Rare Variant in the Nuclear Mitochondrial Gene for <i>AARS2</i> in Late-Onset Dilated Cardiomyopathy

Abstract

HomeCirculation: Genomic and Precision MedicineVol. 13, No. 5Recessive Inheritance of a Rare Variant in the Nuclear Mitochondrial Gene for AARS2 in Late-Onset Dilated Cardiomyopathy Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBRecessive Inheritance of a Rare Variant in the Nuclear Mitochondrial Gene for AARS2 in Late-Onset Dilated Cardiomyopathy Søren K. Nielsen, MD Frederikke Hansen, MS Henrik Daa Schrøder, MD, PhD Flemming Wibrand, PhD Finn Gustafsson, MD, PhD Jens MogensenMD, PhD Søren K. NielsenSøren K. Nielsen https://orcid.org/0000-0002-2231-3943 Department of Cardiology (S.K.N., F.H., J.M.), Odense University Hospital, Denmark. Department of Clinical Research, University of Southern Denmark, Odense (S.K.N., F.H., H.D.S., J.M.). , Frederikke HansenFrederikke Hansen Department of Cardiology (S.K.N., F.H., J.M.), Odense University Hospital, Denmark. Department of Clinical Research, University of Southern Denmark, Odense (S.K.N., F.H., H.D.S., J.M.). , Henrik Daa SchrøderHenrik Daa Schrøder Department of Pathology (H.D.S.), Odense University Hospital, Denmark. Department of Clinical Research, University of Southern Denmark, Odense (S.K.N., F.H., H.D.S., J.M.). , Flemming WibrandFlemming Wibrand Department of Clinical Genetics, Rigshospitalet (F.W.). , Finn GustafssonFinn Gustafsson Department of Cardiology, Rigshospitalet, University of Copenhagen, Denmark (F.G.). , Jens MogensenJens Mogensen Correspondence to: Jens Mogensen, MD, PhD, Department of Cardiology, Odense University Hospital, J.B. Winsløws Vej 4, Indgang 20, 4. Sal, 5000 Odense C, Denmark. Email E-mail Address: [email protected] https://orcid.org/0000-0002-8813-573X Department of Cardiology (S.K.N., F.H., J.M.), Odense University Hospital, Denmark. Department of Clinical Research, University of Southern Denmark, Odense (S.K.N., F.H., H.D.S., J.M.). Originally published16 Sep 2020https://doi.org/10.1161/CIRCGEN.120.003086Circulation: Genomic and Precision Medicine. 2020;13:560–562Rare DNA variants in the nuclear mitochondrial gene for AARS2 encoding mitochondrial alanyl-tRNA synthetase are recognized causes of fatal infantile cardiomyopathy and adult-onset progressive neurodegeneration.1This study presents the first case of a teenage female who developed dilated cardiomyopathy at the age of 15 due to a homozygous p.Arg592Trp variant in AARS2, which is a recognized founder mutation in Northern Europe and the only mutation linked to the development of cardiomyopathy. Different AARS2-mutations are associated with the development of isolated leukodystrophy.Clinical CaseThe patient is White and born as the second child of healthy nonconsanguineous parents. At the age of 2, she was referred for pediatric evaluation due to delayed motoric and cognitive development. During follow-up, a cardiac investigation was performed at the age 6, which showed a normal ECG and echocardiography. An ophthalmological examination was also performed which was entirely normal and did not explain her intermittent insecure walking ability.At the age of 14, she developed dyspnea and dizzy spells. Due to the dizzy spells, she underwent an otorhinolaryngologic examination, which was normal. Echocardiography revealed a dilated left ventricle end-diastolic diameter (LVED) of 50 mm (LVED indexed=29.4 mm/m2) and an LV ejection fraction of 50% (Figure [A]). Holter-monitoring demonstrated 2 episodes of nonsustained ventricular tachycardia with 3 consecutive ventricular beats having a frequency of 145/min. Her ECG showed a short PR-interval of 90 ms and inverted T waves (Figure [B]).Download figureDownload PowerPointFigure. Clinical and molecular characteristics of a female with dilated cardiomyopathy (DCM) due to a homozygous p.Arg592Trp variant in the AARS2 gene.A, Echocardiography performed at the age of 14 and 17 showed a progression in left ventricular (LV) dimensions from 50 to 80 mm at the parasternal long-axis view. B, ECG at the age of 15 showed a short PQ of 90 ms and inverted T waves in V4-V6. C, Cardiac magnetic resonance image with profound late gadolinium enhancement. D, The results of metabolic analyses of skeletal muscle homogenates revealed an isolated cytochrome c oxidase (complex IV) deficiency. E, Electron microscopy showed enlarged mitochondria (M) within the subsarcolemmal zone of which some had condensed cristae (arrows) in addition to increased amounts of extracellular collagen (C). F, Light-microscopy (Hematoxylin-Eosin) of myocardium from the explanted heart showed pronounced myocyte hypertrophy with abnormal nuclei in addition to cytoplasmatic vacuolization/clearing and loss of striation.At the age of 15, she had an LVED of 63 mm (LVED indexed=35 mm/m2) and LV ejection fraction of 40%. Cardiac magnetic resonance imaging demonstrated a normal density of the myocardium and profound late gadolinium enhancement (Figure [C]). Anticongestive therapy was initiated and included treatment with an angiotensin-converting enzyme 2-receptor blocker (ramipril 10 mg/d), a β-blocker (metoprolol 25 mg/d), and spironolactone (25 mg/d).At the age of 16, she underwent neurological examination including electroencephalogram and magnetic resonance imaging of the brain. Both examinations were normal.At the age of 17, her cardiac function deteriorated rapidly within a few months, and she was admitted to the intensive care unit in cardiogenic shock. Her LVED had enlarge to 80 mm (LVED indexed=47 mm/m2) with a LV ejection fraction of 10% (Figure [A]). At this stage, her pro-brain natriuretic peptide was 23508 ng/L which had increased from a value of 552 ng/L at the age of 16. Two weeks later, she underwent successful heart transplantation (HTx).The patient is now 18 years old and 6-month post-HTx. She remains well in New York Heart Association functional class I with normal renal and kidney function. Her motoric and intellectual deficits remain sparse, and she has a normal height of 170 cm and a body mass index of 22.Genetic InvestigationGenetic investigation was performed at the age of 15 in 96 genes related to dilated cardiomyopathy by next-generation sequencing.2 A recognized homozygous missense variant (p.Arg592Trp) in AARS2 was identified, which appears with an allele frequency of 1/2.500 in the European population.3 Her parents and 2 siblings were shown to be healthy heterozygous carriers of the variant.Morphological and Metabolic InvestigationsA skeletal muscle biopsy was obtained at the age of 15 and comprehensive metabolic analyses of skeletal muscle homogenates showed isolated cytochrome c oxidase deficiency (complex IV; Figure [D]).Findings by transmission electron microscopic of skeletal muscle tissue were consistent with a mitochondrial myopathy (Figure [E]). The explanted heart was dilated with an excessive weight of 568 g (body weight 62 kg/body surface area 1.7 m2). Light-microscopy showed myocyte hypertrophy and the presence of abnormal giant mitochondria (Figure [F]).Previously, 11 infants carrying the AARS2 p.Arg592 variant have been reported with fatal early-onset cardiomyopathy.1 Genetic investigations showed that 6 of these infants were homozygous carriers of the p.Arg592Trp while 5 were compound heterozygous and carried one additional variant in the same gene. One child was stillborn while the rest died of rapidly progressing cardio-respiratory failure before the age of 11 months (median: 2 months). The majority had findings consistent with hypertrophic cardiomyopathy in addition to systemic involvement with impaired function of both skeletal muscles and the central nervous system.Surprisingly, our patient survived childhood with only mild skeletal muscle and cognitive impairment. Her cardiac manifestations developed unusually late in life compared to the disease course in previously reported patients without any signs of HCM preceding the progressive development of heart failure.It is well known that patients with mitochondrial diseases may develop failure of various organs induced by metabolic stress factors, including fever-episodes, surgery, prolonged fasting, and medication. However, since our patient was fairly old at the onset of cardiac symptoms, she had already been exposed to many stress factors, which made it less likely that a single factor triggered the development of her cardiac condition. It is more likely that she received a diagnosis of mitochondrial disease due to the fact that the panel of genes investigated included the gene for AARS2. Interestingly, a previous study of heart failure patients with mitochondrial diseases receiving HTx reported that more than half of their study cohort were diagnosed with their condition post-HTx and that appropriate genetic investigations would have improved the diagnostic accuracy pre-HTx.4 Although HTx has the same outcome in patients with and without mitochondrial disease, it is of importance to be aware of the diagnosis since these patients are more vulnerable to the aforementioned metabolic stress factors. This should be taken into account in the overall risk assessment and strategies for post-HTx management.The diagnosis of mitochondrial disease in heart failure is often difficult and has important implications for counseling and management of patients. Genetic investigations in dilated cardiomyopathy are helpful to establish a firm diagnosis and should also include genes encoding mitochondrial diseases on a routine basis.Nonstandard Abbreviations and AcronymsDCMdilated cardiomyopathyHTxheart transplantationLVEDleft ventricle end-diastolic diameterAcknowledgmentsWe thank the participating family who made this study possible and MD, PhD, Bonnie Colville-Ebeling, Department of Pathology, Rigshospitalet, Copenhagen, who provided histology of the explanted heart.Sources of FundingNone.DisclosuresNone.FootnotesFor Sources of Funding and Disclosures, see page 561.Correspondence to: Jens Mogensen, MD, PhD, Department of Cardiology, Odense University Hospital, J.B. Winsløws Vej 4, Indgang 20, 4. Sal, 5000 Odense C, Denmark. Email jens.[email protected]dkReferences1. Euro L, Konovalova S, Asin-Cayuela J, Tulinius M, Griffin H, Horvath R, Taylor RW, Chinnery PF, Schara U, Thorburn DR, et al.. Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation.Front Genet. 2015; 6:21.CrossrefMedlineGoogle Scholar2. Health in Code. Dilated Cardiomyopathy panel.2020. https://www.healthincode.com/en/cardiovascular-genetics/cardiomyopathies/dilated/. Accessed May 29, 2020.Google Scholar3. Genome Aggregation Database (gnomAD).2020. https://gnomad.broadinstitute.org/variant/6-44272249-G-A?dataset=gnomad_r2_1. Accessed May 29, 2020.Google Scholar4. Parikh S, Karaa A, Goldstein A, Ng YS, Gorman G, Feigenbaum A, Christodoulou J, Haas R, Tarnopolsky M, Cohen BK, et al.. Solid organ transplantation in primary mitochondrial disease: proceed with caution.Mol Genet Metab. 2016; 118:178–184. doi: 10.1016/j.ymgme.2016.04.009CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails October 2020Vol 13, Issue 5Article InformationMetrics Download: 140 © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.120.003086PMID: 32938192 Originally publishedSeptember 16, 2020 Keywordsmitochondrial diseasesgenesmutationcardiomyopathiesheart failurePDF download SubjectsTransplantationCardiomyopathyHeart FailureGenetics

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