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 MartinelliDing 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, Saskia Wortmann

Research output: Contribution to journalArticle

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RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished.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

Original languageEnglish
Pages (from-to)120
JournalOrphanet Journal of Rare Diseases
Volume13
Issue number1
DOIs
Publication statusPublished - Jul 19 2018

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Riboflavin Deficiency
Acyl-CoA Dehydrogenase
Molecular Biology
Riboflavin
Cardiomyopathies
Survival
Electron Transport Complex I
Lactic Acidosis
Muscle Weakness
Genetic Association Studies
Activities of Daily Living
Electron Transport

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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.

In: Orphanet Journal of Rare Diseases, Vol. 13, No. 1, 19.07.2018, p. 120.

Research output: Contribution to journalArticle

Repp, BM, Mastantuono, E, Alston, CL, Schiff, M, Haack, TB, Rötig, A, Ardissone, A, Lombès, A, Catarino, CB, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Wenhong, D, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, HJM, Wittig, I, Scurr, I, de Coo, IFM, Moroni, I, Smet, J, Mayr, JA, Dai, L, de Meirleir, L, Schuelke, M, Zeviani, M, Morscher, RJ, McFarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, TM, Herberg, U, Ahting, U, Sperl, W, Nassogne, M-C, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, RW, Häberle, J, Vockley, J, Prokisch, H & Wortmann, S 2018, 'Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?', Orphanet Journal of Rare Diseases, vol. 13, no. 1, pp. 120. https://doi.org/10.1186/s13023-018-0784-8
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. / Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency : is riboflavin supplementation effective?. In: Orphanet Journal of Rare Diseases. 2018 ; Vol. 13, No. 1. pp. 120.
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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.",
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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 - 2018/7/19

Y1 - 2018/7/19

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.

U2 - 10.1186/s13023-018-0784-8

DO - 10.1186/s13023-018-0784-8

M3 - Article

C2 - 30025539

VL - 13

SP - 120

JO - Orphanet Journal of Rare Diseases

JF - Orphanet Journal of Rare Diseases

SN - 1750-1172

IS - 1

ER -