Neonatal screening for glutaric aciduria type I: Strategies to proceed

Abstract

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.