Fatal pitfalls in newborn screening for mitochondrial trifunctional protein (MTP)/long-chain 3-Hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.

BACKGROUND: Mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency are long-chain fatty acid oxidation disorders with particularly high morbidity and mortality. Outcome can be favorable if diagnosed in time, prompting the implementation in newborn screening programs. Sporadic cases missed by the initial screening sample have been reported. However, little is known on pitfalls during confirmatory testing resulting in fatal misconception of the diagnosis.

RESULTS: We report a series of three patients with MTP and LCHAD deficiency, in whom diagnosis was missed by newborn screening, resulting in life-threatening metabolic decompensations within the first half year of life. Two of the patients showed elevated concentrations of primary markers C16-OH and C18:1-OH but were missed by confirmatory testing performed by the maternity clinic. A metabolic center was not consulted. Confirmatory testing consisted of analyses of acylcarnitines in blood and organic acids in urine, the finding of normal excretion of organic acids led to rejection and underestimation of the diagnosis, respectively. The third patient, a preterm infant, was not identified in the initial screening sample due to only moderate elevations of C16-OH and C18:1-OH and normal secondary markers and analyte ratios.

CONCLUSION: Our observations highlight limitations of newborn screening for MTP/LCHAD deficiency. They confirm that analyses of acylcarnitines in blood and organic acids in urine alone are not suitable for confirmatory testing and molecular or functional analysis is crucial in diagnosing MTP/LCHAD deficiency. Mild elevations of primary biomarkers in premature infants need to trigger confirmatory testing. Our report underscores the essential role of specialized centers in confirming or ruling out diagnoses in suspicious screening results.