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

Birgit M. Repp,
Elisa Mastantuono,
Charlotte L. Alston,
Manuel Schiff,
Tobias B. 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 Wittig,
Ingrid Scurr,
Irenaeus F. M. de Coo,
Isabella Moroni,
Joél Smet,
Johannes A. Mayr,
Lifang Dai,
Linda de Meirleir,
Markus Schuelke,
Massimo Zeviani,
Raphael J. Morscher,
Robert McFarland,
Sara Seneca,
Thomas Klopstock,
Thomas Meitinger,
Thomas Wieland,
Tim M. Strom,
Ulrike Herberg,
Uwe Ahting,
Wolfgang Sperl,
Marie-Cecile Nassogne,
Han Ling,
Fang Fang,
Peter Freisinger,
Rudy Van Coster,
Valentina Strecker,
Robert W. Taylor,
Johannes Häberle,
Jerry Vockley,
Holger Prokisch and
Saskia WortmannEmail author

Orphanet Journal of Rare Diseases201813:120

https://doi.org/10.1186/s13023-018-0784-8

Received: 5 November 2017
Accepted: 9 March 2018
Published: 19 July 2018

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We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished.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.