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 three (to six) 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, i.e. age 6 years. However, impact of dietary relaxation on long-term outcome is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations 1-3 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. This article is protected by copyright. All rights reserved.
| Original language | English |
|---|---|
| Pages (from-to) | 482-519 |
| Number of pages | 38 |
| Journal | Journal of Inherited Metabolic Disease |
| Volume | 46 |
| Issue number | 3 |
| Early online date | 11 Oct 2022 |
| DOIs | |
| Publication status | Published - May 2023 |
Bibliographical note
Funding Information:This third guideline revision was supported by the German Society of Paediatrics (Deutsche Gesellschaft für Kinder- und Jugendmedizin, DGKJ). We thank A. Boneh, A. P. Burlina, E. Christensen, M. Duran, M. Kyllermann, J. V. Leonard, E. Müller, E. R. Naughten and B. Wilcken for their contribution to the initial guideline development and first revision of guideline recommendations.48,50 Moreover, we thank D. M. Koeller, A. B. Burlina, M. Dixon, A. Garcia-Cazorla and C. R. Greenberg for their contribution to the second first revision of guideline recommendations.49 We additionally would like to express our sincere condolences, and also gratefulness, respect and appreciation to Stephen I. Goodman (†October 30, 2020), Section of Genetics and Metabolism, Department of Paediatrics, and Director of the Biochemical Genetics Laboratory at Children's Hospital Colorado, University of Colorado, USA, for his pioneer work in the field of GA1, including the discovery of the disease in 1974, followed by valuable contributions increasing knowledge on characterising, diagnosing and managing GA1 and many other inborn errors of metabolism. We are thankful for valuable discussions with Birgit Assmann (Heidelberg) and Laura Cif (Montpellier), that have been implemented as personal communications within the manuscript. Additionally, we thank Ms. Mirjam Kallmes as a representative of a support group for individuals with GA1 for her valuable input at the GDG meeting. Open Access funding enabled and organized by Projekt DEAL.
Publisher Copyright:
© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
