TY - JOUR

T1 - Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency

T2 - is riboflavin supplementation effective?

AU - Repp, Birgit M

AU - Mastantuono, Elisa

AU - Alston, Charlotte L

AU - Schiff, Manuel

AU - Haack, Tobias B

AU - Rötig, Agnes

AU - Ardissone, Anna

AU - Lombès, Anne

AU - Catarino, Claudia B

AU - Diodato, Daria

AU - Schottmann, Gudrun

AU - Poulton, Joanna

AU - Burlina, Alberto

AU - Jonckheere, An

AU - Munnich, Arnold

AU - Rolinski, Boris

AU - Ghezzi, Daniele

AU - Rokicki, Dariusz

AU - Wellesley, Diana

AU - Martinelli, Diego

AU - Wenhong, Ding

AU - Lamantea, Eleonora

AU - Ostergaard, Elsebet

AU - Pronicka, Ewa

AU - Pierre, Germaine

AU - Smeets, Hubert J M

AU - Wittig, Ilka

AU - Scurr, Ingrid

AU - de Coo, Irenaeus F M

AU - Moroni, Isabella

AU - Smet, Joél

AU - Mayr, Johannes A

AU - Dai, Lifang

AU - de Meirleir, Linda

AU - Schuelke, Markus

AU - Zeviani, Massimo

AU - Morscher, Raphael J

AU - McFarland, Robert

AU - Seneca, Sara

AU - Klopstock, Thomas

AU - Meitinger, Thomas

AU - Wieland, Thomas

AU - Strom, Tim M

AU - Herberg, Ulrike

AU - Ahting, Uwe

AU - Sperl, Wolfgang

AU - Nassogne, Marie-Cecile

AU - Ling, Han

AU - Fang, Fang

AU - Freisinger, Peter

AU - Van Coster, Rudy

AU - Strecker, Valentina

AU - Taylor, Robert W

AU - Häberle, Johannes

AU - Vockley, Jerry

AU - Prokisch, Holger

AU - Wortmann, Saskia

PY - 2018

Y1 - 2018

N2 - 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We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished.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.

AB - 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.

KW - Acidosis/genetics

KW - Activities of Daily Living

KW - Acyl-CoA Dehydrogenase/deficiency

KW - Amino Acid Metabolism, Inborn Errors/genetics

KW - Cardiomyopathy, Hypertrophic/genetics

KW - Electron Transport Complex I/metabolism

KW - Female

KW - Humans

KW - Male

KW - Mitochondrial Diseases/genetics

KW - Muscle Weakness/drug therapy

KW - Prognosis

KW - Riboflavin/therapeutic use

U2 - 10.1186/s13023-018-0784-8

DO - 10.1186/s13023-018-0784-8

M3 - Journal article

C2 - 30025539

VL - 13

JO - Orphanet Journal of Rare Diseases

JF - Orphanet Journal of Rare Diseases

SN - 1750-1172

M1 - 120

ER -