3-Methylglutaconic aciduria—lessons from 50 genes and 977 patients

Saskia B Wortmann; Leo A J Kluijtmans; Richard J Rodenburg; Jörn Oliver Sass; Jessica Nouws; Edwin P van Kaauwen; Tjitske Kleefstra; Lisbeth Tranebjaerg; Maaike C de Vries; Pirjo Isohanni; Katharina Walter; Fowzan S Alkuraya; Izelle Smuts; Carolus J Reinecke; Francois H van der Westhuizen; David Thorburn; Jan A M Smeitink; Eva Morava; Ron A Wevers

doi:10.1007/s10545-012-9579-6

3-Methylglutaconic aciduria—lessons from 50 genes and 977 patients

Saskia B Wortmann, Leo A J Kluijtmans, Richard J Rodenburg, Jörn Oliver Sass, Jessica Nouws, Edwin P van Kaauwen, Tjitske Kleefstra, Lisbeth Tranebjaerg, Maaike C de Vries, Pirjo Isohanni, Katharina Walter, Fowzan S Alkuraya, Izelle Smuts, Carolus J Reinecke, Francois H van der Westhuizen, David Thorburn, Jan A M Smeitink, Eva Morava, Ron A Wevers

43 Citations (Scopus)

Abstract

Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic aciduria (e.g. organic acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.

Original language	English
Journal	Journal of Inherited Metabolic Disease
Volume	36
Issue number	6
Pages (from-to)	913-921
Number of pages	9
ISSN	0141-8955
DOIs	https://doi.org/10.1007/s10545-012-9579-6
Publication status	Published - Nov 2013

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Wortmann, S. B., Kluijtmans, L. A. J., Rodenburg, R. J., Sass, J. O., Nouws, J., van Kaauwen, E. P., Kleefstra, T., Tranebjaerg, L., de Vries, M. C., Isohanni, P., Walter, K., Alkuraya, F. S., Smuts, I., Reinecke, C. J., van der Westhuizen, F. H., Thorburn, D., Smeitink, J. A. M., Morava, E., & Wevers, R. A. (2013). 3-Methylglutaconic aciduria—lessons from 50 genes and 977 patients. Journal of Inherited Metabolic Disease, 36(6), 913-921. https://doi.org/10.1007/s10545-012-9579-6

Wortmann, SB, Kluijtmans, LAJ, Rodenburg, RJ, Sass, JO, Nouws, J, van Kaauwen, EP, Kleefstra, T, Tranebjaerg, L, de Vries, MC, Isohanni, P, Walter, K, Alkuraya, FS, Smuts, I, Reinecke, CJ, van der Westhuizen, FH, Thorburn, D, Smeitink, JAM, Morava, E & Wevers, RA 2013, '3-Methylglutaconic aciduria—lessons from 50 genes and 977 patients', Journal of Inherited Metabolic Disease, vol. 36, no. 6, pp. 913-921. https://doi.org/10.1007/s10545-012-9579-6

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title = "3-Methylglutaconic aciduria—lessons from 50 genes and 977 patients",

abstract = "Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic aciduria (e.g. organic acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.",

author = "Wortmann, {Saskia B} and Kluijtmans, {Leo A J} and Rodenburg, {Richard J} and Sass, {J{\"o}rn Oliver} and Jessica Nouws and {van Kaauwen}, {Edwin P} and Tjitske Kleefstra and Lisbeth Tranebjaerg and {de Vries}, {Maaike C} and Pirjo Isohanni and Katharina Walter and Alkuraya, {Fowzan S} and Izelle Smuts and Reinecke, {Carolus J} and {van der Westhuizen}, {Francois H} and David Thorburn and Smeitink, {Jan A M} and Eva Morava and Wevers, {Ron A}",

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doi = "10.1007/s10545-012-9579-6",

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AU - Wortmann, Saskia B

AU - Kluijtmans, Leo A J

AU - Rodenburg, Richard J

AU - Sass, Jörn Oliver

AU - Nouws, Jessica

AU - van Kaauwen, Edwin P

AU - Kleefstra, Tjitske

AU - Tranebjaerg, Lisbeth

AU - de Vries, Maaike C

AU - Isohanni, Pirjo

AU - Walter, Katharina

AU - Alkuraya, Fowzan S

AU - Smuts, Izelle

AU - Reinecke, Carolus J

AU - van der Westhuizen, Francois H

AU - Thorburn, David

AU - Smeitink, Jan A M

AU - Morava, Eva

AU - Wevers, Ron A

PY - 2013/11

Y1 - 2013/11

N2 - Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic aciduria (e.g. organic acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.

AB - Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic aciduria (e.g. organic acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.

U2 - 10.1007/s10545-012-9579-6

DO - 10.1007/s10545-012-9579-6

M3 - Journal article

C2 - 23355087

SN - 0141-8955

VL - 36

SP - 913

EP - 921

JO - Journal of Inherited Metabolic Disease

JF - Journal of Inherited Metabolic Disease

IS - 6

ER -

3-Methylglutaconic aciduria—lessons from 50 genes and 977 patients

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