Detection of urinary hexanoylglycine in the diagnosis of MCAD deficiency from newborn screening.

We strongly support Piero Rinaldo_s and Kevin Carpenter_s comments regarding the importance of accurate and reliable identification of urinary hexanoylglycine (HG) as a definitive diagnostic factor for MCAD deficiency (J Inherit Metab Dis 2008;31: 142–145, Notes and Queries in Metab-L). Qualitative organic acid analysis should detect the near normal concentrations of HG seen in some Fnon-crisis_ MCADD (both c.985A>G homozygotes and mild variants) samples. However, data from the ERNDIM EQA scheme with >70 participants demonstrate failure to detect HG around 8 2mol/mmol creatinine in 10–30% of samples. When the UK embarked on pilot screening for MCADD in 2004 the six UKCSNS-MCADD screening centres (Shortland et al 2006) agreed that, after qualitative organic acid assessment of trimethylsilyl derivatives by individual laboratories, all follow-up urine samples from presumptive positive cases (day 5 blood spot octanoylcarnitine >0.5 2mol/L) would have HG quantified by a central laboratory using GC-MS stable-isotope dilution analysis (SID) of methyl esters. To our knowledge, quantitative HG data have not been available in other studies of newborn screening for MCADD. In the two-year pilot period, HG concentrations (2mol/mmol creatinine) were available in 93/105 cases: 6 but in only 1/13 samples below the upper limit of normal (<1.1). Detection of HG failed in 4 samples with concentrations above the normal range (values 1.2, 5.0, 5.5 and 5.9). In view of these findings, for implementation of MCADD screening in the UK (completion due April 2009) the UKCSNS-MCADD recommended that follow up urine samples where HG is not detected on qualitative analysis should have HG quantified by GCMS-SID.