Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency : is riboflavin supplementation effective?

  • 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 Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished.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. 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.
Metadaten
Author:Birgit M. Repp, Elisa Mastantuono, Charlotte Alston, Manuel Schiff, Tobias Haack, Agnes Rötig, Anna Ardissone, Anne Lombès, Claudia B. Catarino, Daria Diodato, Gudrun Schottmann, Joanna Poulton, Alberto Burlina, An Jonckheere, Arnold Munnich, Boris Rolinski, Daniele Ghezzi, Dariusz Rokicki, Diana Wellesley, Diego Martinelli, Ding Wenhong, Eleonora Lamantea, Elsebet Ostergaard, Ewa Pronicka, Germaine Pierre, Hubert J. M. Smeets, Ilka WittigORCiD, Ingrid Scurr, Irenaeus F. M. De Coo, Isabella Moroni, Joél Smet, Johannes A. Mayr, Lifang Dai, Linda de Meirleir, Markus Schülke-GerstenfeldGND, Massimo Zeviani, Raphael J. Morscher, Robert McFarland, Sara Seneca, Thomas Klopstock, Thomas Meitinger, Thomas WielandORCiDGND, Tim-Matthias Strom, Ulrike Herberg, Uwe Ahting, Wolfgang Sperl, Marie-Cécile Nassogne, Han Ling, Fang Fang, Peter Freisinger, Rudy van Coster, Valentina Strecker, Robert W. Taylor, Johannes Häberle, Jerry Vockley, Holger ProkischORCiDGND, Saskia Wortmann
URN:urn:nbn:de:hebis:30:3-471666
DOI:https://doi.org/10.1186/s13023-018-0784-8
ISSN:1750-1172
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30025539
Parent Title (English):Orphanet journal of rare diseases
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/07/19
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/09/04
Tag:Activities of daily living; Cardiomyopathy; Complex I; Heart transplantation; Lactic acidosis; Mitochondrial disorder; Neonatal; Prognosis; Treatment; Vitamin
Volume:13
Issue:1, Art. 120
Page Number:10
First Page:1
Last Page:10
Note:
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.
HeBIS-PPN:437862194
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0