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; Saskia Wortmann

doi:10.1186/s13023-018-0784-8

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

Department of Clinical Medicine

18 Citations (Scopus)

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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.

Original language	English
Article number	120
Journal	Orphanet Journal of Rare Diseases
Volume	13
Number of pages	10
ISSN	1750-1172
DOIs	https://doi.org/10.1186/s13023-018-0784-8
Publication status	Published - 19 Jul 2018

Keywords

Acidosis/genetics
Activities of Daily Living
Acyl-CoA Dehydrogenase/deficiency
Amino Acid Metabolism, Inborn Errors/genetics
Cardiomyopathy, Hypertrophic/genetics
Electron Transport Complex I/metabolism
Female
Humans
Male
Mitochondrial Diseases/genetics
Muscle Weakness/drug therapy
Prognosis
Riboflavin/therapeutic use

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Repp, B. M., Mastantuono, E., Alston, C. L., Schiff, M., Haack, T. B., Rötig, A., Ardissone, A., Lombès, A., Catarino, C. B., Diodato, D., Schottmann, G., Poulton, J., Burlina, A., Jonckheere, A., Munnich, A., Rolinski, B., Ghezzi, D., Rokicki, D., Wellesley, D., ... Wortmann, S. (2018). Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective? Orphanet Journal of Rare Diseases, 13, Article 120. https://doi.org/10.1186/s13023-018-0784-8

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

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

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.",

keywords = "Acidosis/genetics, Activities of Daily Living, Acyl-CoA Dehydrogenase/deficiency, Amino Acid Metabolism, Inborn Errors/genetics, Cardiomyopathy, Hypertrophic/genetics, Electron Transport Complex I/metabolism, Female, Humans, Male, Mitochondrial Diseases/genetics, Muscle Weakness/drug therapy, Prognosis, Riboflavin/therapeutic use",

author = "Repp, {Birgit M} and Elisa Mastantuono and Alston, {Charlotte L} and Manuel Schiff and Haack, {Tobias B} and Agnes R{\"o}tig and Anna Ardissone and Anne Lomb{\`e}s and Catarino, {Claudia B} and Daria Diodato and Gudrun Schottmann and Joanna Poulton and Alberto Burlina and An Jonckheere and Arnold Munnich and Boris Rolinski and Daniele Ghezzi and Dariusz Rokicki and Diana Wellesley and Diego Martinelli and Ding Wenhong and Eleonora Lamantea and Elsebet Ostergaard and Ewa Pronicka and Germaine Pierre and Smeets, {Hubert J M} and Ilka Wittig and Ingrid Scurr and {de Coo}, {Irenaeus F M} and Isabella Moroni and Jo{\'e}l Smet and Mayr, {Johannes A} and Lifang Dai and {de Meirleir}, Linda and Markus Schuelke and Massimo Zeviani and Morscher, {Raphael J} and Robert McFarland and Sara Seneca and Thomas Klopstock and Thomas Meitinger and Thomas Wieland and Strom, {Tim M} and Ulrike Herberg and Uwe Ahting and Wolfgang Sperl and Marie-Cecile Nassogne and Han Ling and Fang Fang and Peter Freisinger and {Van Coster}, Rudy and Valentina Strecker and Taylor, {Robert W} and Johannes H{\"a}berle and Jerry Vockley and Holger Prokisch and Saskia Wortmann",

year = "2018",

month = jul,

day = "19",

doi = "10.1186/s13023-018-0784-8",

language = "English",

volume = "13",

journal = "Orphanet Journal of Rare Diseases",

issn = "1750-1172",

publisher = "BioMed Central",

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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.

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

SN - 1750-1172

VL - 13

JO - Orphanet Journal of Rare Diseases

JF - Orphanet Journal of Rare Diseases

M1 - 120

ER -

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

Abstract

Keywords

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