Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision

Nikolas Boy¹, Chris Mühlhausen², Esther M Maier³, Diana Ballhausen⁴, Matthias R Baumgartner⁵, Skadi Beblo⁶, Peter Burgard¹, Kimberly A Chapman⁷, Dries Dobbelaere⁸, Jana Heringer-Seifert¹, Sandra Fleissner³, Karina Grohmann-Held⁹, Gabriele Hahn¹⁰, Inga Harting¹¹, Georg F Hoffmann¹, Frank Jochum¹², Daniela Karall¹³, Vassiliki Konstantopoulous¹⁴, Michael B Krawinkel¹⁵, Martin Lindner¹⁶, E M Charlotte Märtner¹, Jean-Marc Nuoffer¹⁷, Jürgen G Okun¹, Barbara Plecko¹⁸, Roland Posset¹, Katja Sahm¹, Sabine Scholl-Bürgi¹², Eva Thimm¹⁹, Magdalena Walter¹, Monique Williams²⁰, Stephan Vom Dahl²¹, Athanasia Ziagaki²², Johannes Zschocke²³, Stefan Kölker¹

Affiliations

¹ Centre for Child and Adolescent Medicine, Department of General Paediatrics, Division of Neuropaediatrics and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany.
² Department of Paediatrics and Adolescent Medicine, University Medical Centre, Göttingen, Germany.
³ Dr von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, University of Munich Medical Centre, Munich, Germany.
⁴ Paediatric Metabolic Unit, Paediatrics, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Switzerland.
⁵ Division of Metabolism and Children's Research Centre, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁶ Department of Women and Child Health, Hospital for Children and Adolescents, Centre for Paediatric Research Leipzig (CPL), University Hospitals, University of Leipzig, Leipzig, Germany.
⁷ Rare Disease Institute, Children's National Health System, Washington, District of Columbia, USA.
⁸ Department of Paediatric Metabolism, Reference Centre of Inherited Metabolic Disorders, Jeanne de Flandre Hospital, Lille, France.
⁹ Centre for Child and Adolescent Medicine, University Hospital Greifswald, Greifswald, Germany.
¹⁰ Department of Radiological Diagnostics, UMC, University of Dresden, Dresden, Germany.
¹¹ Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany.
¹² Evangelisches Waldkrankenhaus Spandau, Berlin, Germany.
¹³ Clinic for Paediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.
¹⁴ Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
¹⁵ Institute of Nutritional Science, Justus Liebig University Giessen, Giessen, Germany.
¹⁶ Division of Metabolic Diseases, University Children's Hospital Frankfurt, Frankfurt, Germany.
¹⁷ University Institute of Clinical Chemistry, University of Bern, Bern, Switzerland.
¹⁸ Department of Paediatrics and Adolescent Medicine, Division of General Paediatrics, University Children's Hospital Graz, Medical University Graz, Graz, Austria.
¹⁹ Division of Experimental Paediatrics and Metabolism, Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
²⁰ Department of Paediatrics, Centre for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Centre, Rotterdam, The Netherlands.
²¹ Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, University of Düsseldorf, Düsseldorf, Germany.
²² Centre of Excellence for Rare Metabolic Diseases, Interdisciplinary Centre of Metabolism: Endocrinology, Diabetes and Metabolism, University-Medicine Berlin, Berlin, Germany.
²³ Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.

PMID: 36221165
DOI: 10.1002/jimd.12566

Free article

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision

Nikolas Boy et al. J Inherit Metab Dis. 2023 May.

Free article

. 2023 May;46(3):482-519.

doi: 10.1002/jimd.12566. Epub 2022 Nov 17.

Authors

Affiliations

¹ Centre for Child and Adolescent Medicine, Department of General Paediatrics, Division of Neuropaediatrics and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany.
² Department of Paediatrics and Adolescent Medicine, University Medical Centre, Göttingen, Germany.
³ Dr von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, University of Munich Medical Centre, Munich, Germany.
⁴ Paediatric Metabolic Unit, Paediatrics, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Switzerland.
⁵ Division of Metabolism and Children's Research Centre, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁶ Department of Women and Child Health, Hospital for Children and Adolescents, Centre for Paediatric Research Leipzig (CPL), University Hospitals, University of Leipzig, Leipzig, Germany.
⁷ Rare Disease Institute, Children's National Health System, Washington, District of Columbia, USA.
⁸ Department of Paediatric Metabolism, Reference Centre of Inherited Metabolic Disorders, Jeanne de Flandre Hospital, Lille, France.
⁹ Centre for Child and Adolescent Medicine, University Hospital Greifswald, Greifswald, Germany.
¹⁰ Department of Radiological Diagnostics, UMC, University of Dresden, Dresden, Germany.
¹¹ Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany.
¹² Evangelisches Waldkrankenhaus Spandau, Berlin, Germany.
¹³ Clinic for Paediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.
¹⁴ Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
¹⁵ Institute of Nutritional Science, Justus Liebig University Giessen, Giessen, Germany.
¹⁶ Division of Metabolic Diseases, University Children's Hospital Frankfurt, Frankfurt, Germany.
¹⁷ University Institute of Clinical Chemistry, University of Bern, Bern, Switzerland.
¹⁸ Department of Paediatrics and Adolescent Medicine, Division of General Paediatrics, University Children's Hospital Graz, Medical University Graz, Graz, Austria.
¹⁹ Division of Experimental Paediatrics and Metabolism, Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
²⁰ Department of Paediatrics, Centre for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Centre, Rotterdam, The Netherlands.
²¹ Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, University of Düsseldorf, Düsseldorf, Germany.
²² Centre of Excellence for Rare Metabolic Diseases, Interdisciplinary Centre of Metabolism: Endocrinology, Diabetes and Metabolism, University-Medicine Berlin, Berlin, Germany.
²³ Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.

PMID: 36221165
DOI: 10.1002/jimd.12566

Abstract

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes.

Keywords: glutaric aciduria type 1; glutaryl-CoA dehydrogenase; guideline; management; monitoring; newborn screening; therapy.

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References

REFERENCES

1. Boy N, Mengler K, Thimm E, et al. Newborn screening: a disease-changing intervention for glutaric aciduria type 1. Ann Neurol. 2018;83(5):970-979. doi:10.1002/ana.25233
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1. Lindner M, Kolker S, Schulze A, et al. Neonatal screening for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2004;27(6):851-859. doi:10.1023/B:BOLI.0000045769.96657.af
1. Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY. Inborn errors of metabolism identified via newborn screening: ten-year incidence data and costs of nutritional interventions for research agenda planning. Mol Genet Metab. 2014;113(1-2):14-26. doi:10.1016/j.ymgme.2014.07.009
1. Boy N, Mengler K, Heringer-Seifert J, Hoffmann GF, Garbade SF, Kölker S. Impact of newborn screening and quality of therapy on the neurological outcome in glutaric aciduria type 1: a meta-analysis. Genet Med. 2021;23:13-21. doi:10.1038/s41436-020-00971-4

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Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision

Affiliations

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision

Authors

Affiliations

Abstract

References

REFERENCES

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MeSH terms

Substances

Supplementary concepts

LinkOut - more resources

Full Text Sources

Medical