Diagnosis of very long chain acyl-dehydrogenase deficiency from an infant's newborn screening card

Very long chain fatty acid dehydrogenase (VLCAD) deficiency is a rare but t reatable cause of cardiomyopathy, fatty liver, skeletal myopathy, pericardi al effusions, ventricular arrhythmias, and sudden death. Unrecognized, VLCA D deficiency may be rapidly progressive and fatal, secondary to its cardiac involvement. Because early diagnosis improves outcome, we present a neonat e with VLCAD deficiency in whom retrospective analysis of the newborn scree ning card revealed that a correct diagnosis could have been made by newborn screening using tandem mass spectrometry. Our patient demonstrated a classic neonatal course with transient hypoglyce mia at birth, interpreted as culture-negative sepsis, followed by a quiesce nt period notable only for hypotonia and poor feeding. At 3 months, he pres ented with cardiorespiratory failure and pericardial effusions, requiring p ericardiocentesis, tracheostomy, and prolonged mechanical ventilation. Plas ma free-fatty acid and acylcarnitine profiles demonstrated small but signif icant elevations of C14:2, C14:1, C16, and C18:1 acylcarnitine species, fin dings consistent with a biochemical diagnosis of VLCAD deficiency. Enteral feeds were changed to Portagen formula with marked improvement in cardiac s ymptoms over several weeks. To confirm the biochemical diagnosis, molecular analysis was performed by a nalysis of genomic DNA on a blood sample of the patient. Sequencing analysi s and delineation of VLCAD mutations were performed using polymerase chain reaction and genomic sequencing. The patient was heterozygous for 2 differe nt disease-causing mutations at the VLCAD locus. The maternal mutation was a deletion of bp 842-3 in exon 8, causing a shift in the reading frame. The paternal mutation was G+1A in the consensus donor splice site after exon 1 ; this splice-site mutation would likely result in decreased mRNA. The like ly consequence of these mutations is essentially a null phenotype. To determine whether this case could have been picked up by tandem mass spe ctrometry analysis at birth when the patient was asymptomatic, acylcarnitin e analysis was performed on the patient's original newborn card (after obta ining parental consent, the original specimen was provided courtesy of Dr K enneth Pass, Director, New York State Newborn Screening Program). The blood sample had been obtained at 1 week of age and stored at room temperature f or 6 months and at 70 degreesC thereafter for 18 months. Electrospray tande m mass spectrometry used a LC-MS/MS API 2000 operated in ion evaporation mo de with the TurboIonSpray ionization probe source. The acylcarnitine profile obtained from the patient's original newborn card was analyzed 2 years after it was obtained. In comparison with a normal co ntrol, there was a significant accumulation of long chain acylcarnitine spe cies, with a prominent peak of tetradecenoylcarnitine (C14: 1), the most ch aracteristic metabolic marker of VLCAD deficiency. This profile would have likely been even more significant if it had been analyzed at the time of co llection, yet 2 years later is sufficient to provide strong biochemical evi dence of the underlying disorder. Discussion. VLCAD was first discovered in 1992, and clinical experience wit h VLCAD deficiency has been accumulating rapidly. Indeed, the patients orig inally diagnosed with long chain acyl-CoA deficiency suffer instead from VL CAD deficiency. The phenotype of VLCAD deficiency is heterogeneous, ranging from catastrophic metabolic and cardiac failure in infancy to mild hypoket otic, hypoglycemia, and exertional rhabdomyolysis in adults. This case demo nstrates that VLCAD deficiency could have been detected from the patient's own neonatal heel-stick sample. Most likely, a presymptomatic diagnosis wou ld have avoided at least part of a lengthy and intensive prediagnosis hospi talization that had an estimated cost of $400 000. Although VLCAD is relatively rare, timely and correct diagnosis leads to dr amatic recovery, so that detection by newborn screening could prevent the o nset of arrhythmias, heart failure, metabolic insufficiency, and death. Fat ty acid oxidation defects, including VLCAD deficiency, may account for as m any as 5% of sudden infant death patients. Recent instrumentation advances have made automated tandem mass spectrometry of routine neonatal heel-stick samples technically feasible. Pilot studies have demonstrated an incidence of fatty acid oxidation defects, including short chain, medium chain, and very long chain acyl-CoA dehydrogenase deficiencies, of approximately 1/12 000. As a result, cost-benefit ratios for this approach should be systemati cally examined.