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.

Outcome of three cases of untreated maternal glutaric aciduria type I

“…Blood spots are collected between the 3rd and 6th day of life, and amino acids and acylcarnitines are analyzed as butyl esters by tandem mass spectrometry (MS/ MS) using an API 2000 triple quadrupole tandem mass spectrometer (Applied Biosystems, Sciex). Glutarylcarnitine level and the glutarylcarnitine/acylcarnitine ratio are determined to improve the diagnostic sensitivity and specificity of GA I, as previously reported [12].…”

Brain MRI Findings as an Important Diagnostic Clue in Glutaric Aciduria Type 1

“…Glutarylcarnitine detection is the basis of newborn screening for GA-1 4 . The diagnosis is confirmed by enzyme assay and/or molecular analysis of the GCDH gene 5 . GA-1 is a disease with highly variable clinical manifestations.…”

“…A restrictive lysine and tryptophan diet, supplemented with L-carnitine and eventually, riboflavin, and a specific emergency treatment during intercurrent illness has significantly improved the outcome of pre-symptomatically diagnosed children [20][21][22] . Therefore, newborn screening for GA-1 has been implemented in some countries 5,7,23,24 . We describe two GA-1 patients illustrating the relevance of brain MRI for the diagnosis.…”

Decline of Acute Encephalopathic Crises in Children with Glutaryl-CoA Dehydrogenase Deficiency Identified by Newborn Screening in Germany

“…However, this discrepant experience most likely reflects the optimization process while establishing a novel screening method. We have recently demonstrated using data mining strategies that the sensitivity and specificity of MS/MS-based neonatal screening for GCDH deficiency can be increased by implementation of ratios (i.e., C5DC to palmitoylcarnitine or free carnitine) as second tier (28). Thus it is likely to assume that a second tier strategy would improve the identification of low excreting neonates with GCDH deficiency.…”