Summary
Acute encephalopathic crisis in glutaric aciduria type I results in an unfavourable disease course and poor outcome, dominated by dystonia, feeding problems, seizures and reduced life expectancy. A conditio sine qua non for the prevention of irreversible brain damage is timely diagnosis and start of therapy, i.e. before the onset of neurological disease. As there are no specific clinical signs or symptoms that allow a reliable detection of these patients before the manifestation of encephalopathic crises, neonatal screening programmes for glutaric aciduria type I have been established in some countries using analysis of glutarylcarnitine in dried blood spots by tandem mass spectrometry. This article summarizes recent strategies, pitfalls and shortcomings of mass screening for glutaric aciduria type I, focusing on the relevant risk of missing patients with a mild biochemical phenotype (i.e. low excretors). Furthermore, it evaluates a binary strategy – using glutarylcarnitine as primary variable and glutarylcarnitine/acylcarnitine ratios as secondary variable – to improve the diagnostic sensitivity and specificity of neonatal screening for glutaric aciduria type I. An optimization of diagnostic as well as therapeutic procedures must be achieved before screening for glutaric aciduria type I can be regarded as reliable and beneficial for all patients.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baric I, Wagner L, Feyh P, et al (1999) Sensitivity of free and total glutaric and 3-hydroxyglutaric acid measurement by stable isotope dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis 22: 867–882.
Bjugstad KB, Goodman SI, Freed CR (2000) Age at symptom onset predicts severity of motor impairment and clinical outcome of glutaric academia type 1. J Pediatr 137: 681–686.
Busquets C, Merinero B, Christensen E, et al (2000) Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically, and biochemically distinct. Pediatr Res 48: 315–322.
Chace DH, Kalas TA, Naylor EW (2002) The application of tandem mass spectrometry to neonatal screening for inherited disorders of intermediary metabolism. Annu Rev Genomics Hum Genet 3: 17–45.
Chace DH, Kalas TA, Naylor EW (2003) Use of tandem mass spectrometry for multi-analyte screening of dried blood specimens from newborns. Clin Chem 49: 1797–1817.
Christensen E (1993) A fibroblast glutaryl-CoA dehydrogenase assay using detritiation of 3H-labeled glutaryl-CoA: application in the genotyping of the glutaryl-CoA dehydrogenase locus. Clin Chim Acta 220: 71–80.
Christensen E, Ribes A, Merinero B, Zschocke J (2004) Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27: 861–868.
Donoho S, Rendell L (1998) Feature construction using fragmentary knowledge. In: Liu H, Motoda H, eds. Feature Extraction, Construction and Selection: A Data Mining Perspective. Norwell: Kluwer Academic Publishers, 273–288.
Gallagher RC, Cowan TM, Goodman SI, et al (2005) Glutaryl-CoA dehydrogenase deficiency and newborn screening: retrospective analysis of a low excretor provides further evidence that some cases may be missed. Mol Genet Metab 86: 417–420.
Goodman SI, Stein DE, Schlesinger S, et al (1998) Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): review and report of thirty novel mutations. Hum Mutat 12: 141–144.
Greenberg CR, Prasad AN, Dilling LA, et al (2002) Outcome of the first three years of a DNA-based neonatal screening program for glutaric acidemia type 1 in Manitoba and Northwestern Ontario, Canada. Mol Gen Metabol 75: 70–78.
Hoffmann GF, Athanassopoulos A, Burlina A, et al (1996) Clinical course, early diagnosis, treatment and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropediatrics 27: 115–123.
Johnson DW, Trinh MU (2004) Stability of malonylcarnitine and glutarylcarnitine in stored blood spots. J Inherit Metab Dis 27: 789–790.
Külker S, Greenberg CR, Müller E, Naughten ER, Hoffmann (2004a) Emergency treatment in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27: 893–902.
Külker S, Greenberg CR, Leonard JV, et al (2004b). International cross-sectional study on outcome and therapeutic efficacy in glutaric aciduria type I (GA-I) (abstract). J Inherit Metab Dis 27(Supplement 1): 70.
Kyllerman M, Steen G (1980) Glutaric aciduria. A ‘common’ metabolic disorder? Arch Fr Pediatr 37: 279.
Kyllerman M, Skjeldal O, Christensen E, et al (2004) Long-term follow-up, neurological outcome and survival rate in 28 Nordic patients with glutaric aciduria type 1. Eur J Paediatr Neurol 8: 121–129.
Lindner M, Külker S, Schulze A, Christensen E, Greenberg CR, Hoffmann GF (2004) Neonatal screening for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27: 851–859.
Mühlhausen C, Christensen E, Schwartz N, Muschol K, Ullrich Z (2003) Severe phenotype despite high residual glutaryl-CoA dehydrogenase activity: a novel mutation in a Turkish patient with glutaric aciduria type I. J Inherit Metab Dis 26: 713–714.
Naughten ER, Mayne PD, Monavari AA, Goodman SI, Sulaiman G, Croke DT (2004) Glutaric aciduria type I, outcome in the Republic of Ireland. J Inherit Metab Dis 27: 917–920.
Napolitano N, Wiley V, Pitt JJ (2004) Pseudo-glutarylcarnitinaemia in medium-chain acyl-CoA dehydrogenase deficiency detected by tandem mass spectrometry newborn screening. J Inherit Metab Dis 27: 465–471.
Naylor EW, Chace DW (1999) Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid and amino acid metabolism. J Child Neurol 14(Supplement 1): S4–8.
Roscher AA, Fingerhut R, Liebl B, Olgemüller B (2001) Erweiterung des Neugeborenenscreenings durch Tandemmassenspektrometrie. Monatsschr Kinderheilkd 149: 1297–1303.
Schulze A, Lindner M, Kohlmüller D, Olgemüller K, Mayatepek E, Hoffmann GF (2003) Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics 111: 1399–1406.
Smith WE, Millington DS, Koeberl DK, Lesser PS (2001) Glutaric acidemia, type I, missed by newborn screening in an infant with dystonia following promethazine administration. Pediatrics 107: 1184–1187.
Strauss KA, Puffenberg EG, Robinson DL, Morton DH (2003) Type I glutaric aciduria, part 1: Natural history of 77 patients. Am J Med Genet C Semin Med Genet 121: 38–52.
Treacy EP, Lee-Chong A, Roche G, Lynch B, Ryan S, Goodman SI (2003) Profound neurological presentation resulting from homozygosity for a mild glutaryl-CoA dehydrogenase mutation with a minimal biochemical phenotype. J Inherit Metab Dis 26: 72–74.
Wilcken B, Wiley V, Hammond J, Carpenter K (2003) Screening newborns for inborn errors of metabolism by tandem mass spectrometry. N Engl J Med 348: 2304–2312.
Wiley V, Carpenter K, Wilcken B (1999) Newborn screening with tandem mass spectrometry: 12 months' experience in NSW Australia. Acta Paediatr Suppl 88: 48–51.
Zschocke J, Baric I, Merinero B, et al (1997) Wertigkeit der Acylcarnitinanalyse für die Diagnose der Glutarazidurie Typ I. Monatsschr Kinderheilkd 145: 432.
Zytkovicz TH, Fitzgerald EF, Marsden D, et al (2001) Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program. Clin Chem 47: 1945–1955.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicating editor: Jean-Marie Saudubray
Ethics approval was not required since all data were taken from routine neonatal screening and were anonymized
Competing interests: None declared
Rights and permissions
About this article
Cite this article
Lindner, M., Ho, S., Fang-Hoffmann, J. et al. Neonatal screening for glutaric aciduria type I: Strategies to proceed. J Inherit Metab Dis 29, 378–382 (2006). https://doi.org/10.1007/s10545-006-0284-1
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10545-006-0284-1