Diagnosis of mitochondrial trifunctional protein deficiency in a blood spot from the newborn screening card by tandem mass spectrometry and DNA analysis

Trifunctional protein (TFP) plays a significant role in the mitochondrial b eta-oxidation of long-chain fatty acids. Its deficiency impairs the energy generating function of this pathway and causes hypoketotic hypoglycemia onc e hepatic glycogen stores are depleted. A Reye-Like syndrome, cardiomyopath y, and sudden death may follow. The diagnosis is based on demonstration of significantly decreased enzyme activity of at least two of the three involv ed enzymes in fibroblasts. The possibility of prospective diagnosis of TFP deficiency by newborn screening using tandem mass spectrometry (MS/MS) has not been evaluated. We report the postmortem diagnosis of a male newborn, w ho suffered sudden death at 2 wk of age, and his younger sister,who died of cardiomyopathy complicated by acute heart failure at the age of 6 mo, afte r she had acquired a common viral infection. Blood spots from the original newborn screening cards were the only remaining material from the patients. Analysis by MS/MS revealed acylcarnitine profiles consistent with either T FP or long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency. To prove the diagnosis, the alpha- and beta-subunit genes coding for TFP w ere examined. The patients were compound heterozygous for a 4-bp-deletion a nd an a --> g missense mutation, both in the same exon 3 donor consensus sp lice site. This is the first report of the diagnosis of TFP deficiency usin g blood spots obtained for newborn screening and suggests that TFP deficien cy may be detectable by prospective newborn screening using MS/MS.