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Clinical, Biochemical and Genetic Spectrum of 70 Patients with ACAD9

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Clinical, Biochemical and Genetic Spectrum of 70 Patients with ACAD9 Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency is riboflavin supplementation effective? Repp, Birgit M; Mastantuono, Elisa; Alston, Charlotte L; Schiff, Manuel; Haack, Tobias B; Rötig, Agnes; Ardissone, Anna; Lombès, Anne; Catarino, Claudia B; Diodato, Daria; Schottmann, Gudrun; Poulton, Joanna; Burlina, Alberto; Jonckheere, An; Munnich, Arnold; Rolinski, Boris; Ghezzi, Daniele; Rokicki, Dariusz; Wellesley, Diana; Martinelli, Diego; Wenhong, Ding; Lamantea, Eleonora; Ostergaard, Elsebet; Pronicka, Ewa; Pierre, Germaine; Smeets, Hubert J M; Wittig, Ilka; Scurr, Ingrid; de Coo, Irenaeus F M; Moroni, Isabella; Smet, Joél; Mayr, Johannes A; Dai, Lifang; de Meirleir, Linda; Schuelke, Markus; Zeviani, Massimo; Morscher, Raphael J; McFarland, Robert; Seneca, Sara; Klopstock, Thomas; Meitinger, Thomas; Wieland, Thomas; Strom, Tim M; Herberg, Ulrike; Ahting, Uwe; Sperl, Wolfgang; Nassogne, Marie-Cecile; Ling, Han; Fang, Fang; Freisinger, Peter; Van Coster, Rudy; Strecker, Valentina; Taylor, Robert W; Häberle, Johannes; Vockley, Jerry; Prokisch, Holger; Wortmann, Saskia Published in: Orphanet Journal of Rare Diseases DOI: 10.1186/s13023-018-0784-8 Publication date: 2018 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Repp, B. M., Mastantuono, E., Alston, C. L., Schiff, M., Haack, T. B., Rötig, A., Ardissone, A., Lombès, A., Catarino, C. B., Diodato, D., Schottmann, G., Poulton, J., Burlina, A., Jonckheere, A., Munnich, A., Rolinski, B., Ghezzi, D., Rokicki, D., Wellesley, D., ... Wortmann, S. (2018). Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective? Orphanet Journal of Rare Diseases, 13, [120]. https://doi.org/10.1186/s13023-018-0784-8 Download date: 28. sep.. 2021 Repp et al. Orphanet Journal of Rare Diseases (2018) 13:120 https://doi.org/10.1186/s13023-018-0784-8 RESEARCH Open Access Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective? Birgit M. Repp1,2, Elisa Mastantuono1,2, Charlotte L. Alston3, Manuel Schiff4,5, Tobias B. Haack1,46, Agnes Rötig6, Anna Ardissone7,8,9, Anne Lombès10, Claudia B. Catarino11, Daria Diodato12, Gudrun Schottmann13, Joanna Poulton14, Alberto Burlina15, An Jonckheere16, Arnold Munnich6, Boris Rolinski17, Daniele Ghezzi7,18, Dariusz Rokicki19, Diana Wellesley20, Diego Martinelli21, Ding Wenhong22, Eleonora Lamantea7, Elsebet Ostergaard23, Ewa Pronicka19, Germaine Pierre24, Hubert J. M. Smeets25, Ilka Wittig26, Ingrid Scurr27, Irenaeus F. M. de Coo28,29, Isabella Moroni8, Joél Smet30, Johannes A. Mayr31, Lifang Dai32, Linda de Meirleir33,34, Markus Schuelke13, Massimo Zeviani35, Raphael J. Morscher31,36, Robert McFarland3, Sara Seneca37, Thomas Klopstock11,38,39, Thomas Meitinger1,2,39,40, Thomas Wieland2, Tim M. Strom1,2, Ulrike Herberg41, Uwe Ahting1, Wolfgang Sperl31, Marie-Cecile Nassogne42, Han Ling22, Fang Fang32, Peter Freisinger43, Rudy Van Coster30, Valentina Strecker26, Robert W. Taylor3, Johannes Häberle44, Jerry Vockley45, Holger Prokisch1,2 and Saskia Wortmann1,2,31* Abstract Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. (Continued on next page) * Correspondence: [email protected] Birgit M. Repp and Elisa Mastantuono are equal first authors. Charlotte L. Alston, Manuel Schiff and Tobias B. Haack are equal co-authors. Holger Prokisch and Saskia Wortmann jointly supervised this work. 1Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675 Munich, Germany 2Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Repp et al. Orphanet Journal of Rare Diseases (2018) 13:120 Page 2 of 10 (Continued from previous page) Conclusions: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin. Keywords: Complex I, Cardiomyopathy, Heart transplantation, Mitochondrial disorder, Lactic acidosis, Treatment, Prognosis, Neonatal, Vitamin, Activities of daily living Background long chain (ACADVL) deficiencies in whom no im- Complex I of the mammalian mitochondrial respiratory provement could be detected [11]. chain is a large multimeric complex composed of 44 In this study, we provide a comprehensive overview of subunits encoded by the mitochondrial and nuclear gen- the clinical, biochemical and genetic spectrum of 70 ome. Beside the structural subunits, at least 19 complex ACAD9 deficient individuals, of whom 29 are unpub- I specific assembly factors are required to obtain fully lished. We further evaluate the effect of riboflavin in pa- assembled complex I [1]. tients and the effect of riboflavin and bezafibrate One assembly factor is ACAD9. Beside its role in the supplementation in patient-derived fibroblast cell lines. proper assembly of complex I, ACAD9 exhibits acyl- CoA dehydrogenase (ACAD) activity [2, 3]. ACADs be- Methods long to a family of flavoenzymes involved in the ß-oxida- Individuals tion of acyl-CoA and amino acid catabolism. ACAD9 is All procedures followed were in accordance with the most homologous (47% amino acid identity, 65% amino ethical standards of the responsible committee on acid similarity) to very long-chain acyl-CoA dehydrogen- human experimentation (institutional and national) and ase (VLCAD). Both ACAD9 and VLCAD function as with the Helsinki Declaration of 1975, as revised in homodimers associated with the inner mitochondrial 2000. Written informed consent was obtained from all membrane and catalyze the initial step of the fatty acid individuals or caregivers. The clinical data were collected oxidation (FAO) cycle [4]. via an online survey completed by the respective phys- Mutations in ACAD9 have been related to human dis- ician. The online survey included 93 questions regarding ease [5–7]. The clinical presentation of ACAD9 deficiency age at presentation, current age or age at death, signs is dominated by cardiomyopathy. Other features are lactic and symptoms during the fetal and neonatal period, at acidosis, myopathy and developmental delay. Age of onset, the beginning and during the course of disease, circum- severity of symptoms and progression are variable. We stances of death etc.. A special emphasis lay on the car- have shown that residual ACAD9 enzyme activity, and not diac and neurological phenotype, daily life activities and complex I activity, correlates with the severity of clinical the use of cardiac medication as well as vitmains and symptoms in ACAD9 deficient patients [3]. co-factors (e.g. riboflavin). In anecdotal reports of patients with a predominance Kaplan Meier curves were created using the R project of myopathic features, alleviation of symptoms under for statistical computing (survival package, https://www. riboflavin treatment has been reported [5, 7, 8]. Ribofla- r-project.org/). vin is the precursor of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), which are cofactors Molecular genetic investigations for complex I and numerous dehydrogenases involved in Exome sequencing, panel sequencing and Sanger sequen- FAO. The mode of action is unclear, previous studies cing was performed as described previously [7, 12–22]. suggested that riboflavin increases the mitochondrial FAD concentration thereby
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