Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?
Authors
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 JM
Wittig, Ilka
Scurr, Ingrid
de Coo, Irenaeus FM
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
Publication Date
2018-07-19Journal Title
Orphanet J Rare Dis
ISSN
1750-1172
Publisher
Springer Science and Business Media LLC
Type
Journal Article
Metadata
Show full item recordCitation
Repp, B. M., Mastantuono, E., Alston, C. L., Schiff, M., Haack, T. B., Rötig, A., Ardissone, A., et al. (2018). Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?. [Journal Article]. https://doi.org/10.1186/s13023-018-0784-8
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 RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished.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. 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.
Sponsorship
Medical Research Council (MC_UP_1002/1)
European Commission Horizon 2020 (H2020) Societal Challenges (633974)
Medical Research Council (MC_UU_00015/8)
MRC (MC_UU_00015/8)
Identifiers
External DOI: https://doi.org/10.1186/s13023-018-0784-8
This record's DOI: https://doi.org/10.17863/CAM.25658
Rights
Rights Holder: The Author(s).
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