Matern, Dietrich

COASY-related disorders (CRDs) are a spectrum of autosomal recessive conditions caused by the dysfunction of CoA synthase, an enzyme responsible for the final steps of CoA synthesis. Clinical manifestations of CRDs are highly variable, ranging from perinatal lethal pontocerebellar hypoplasia to childhood-onset neurodegenerative brain iron accumulation, which is often recognized after clinical regression. Recent reports have described a few individuals with CRD who screened positive for carnitine palmitoyltransferase-I deficiency by newborn screening (NBS). However, heterogeneous clinical presentations, conflicting biochemical/molecular sequencing of CPT1A, and a lack of metabolic characterization have led to lengthy, costly diagnostic journeys. To address some of these aspects, this investigation retrospectively evaluated NBS acylcarnitine patterns in five CRD cases using Collaborative Laboratory Integrated Reports (CLIR). A total of 25 metabolites/ratios were identified to deviate significantly from reference ranges and were primarily composed of elevated free carnitine and reduced long-chain acylcarnitine levels. While low acylcarnitine concentrations are often not reported due to a lack of lower reference cutoffs, ratios involving these metabolites relative to short-chain acylcarnitines could aid in identifying CRD cases via NBS. When comparing this pattern to CPT-Ia cases, we confirmed a nearly identical acylcarnitine pattern between these, and thus support the need to consider CRD in cases with NBS results suggestive of CPT-Ia. This study is the first case series to characterize NBS patterns in patients with CRD and highlights the unique opportunity for early detection, particularly in cases that are neonatally asymptomatic and have unremarkable confirmatory biochemical results.

Tandem mass spectrometry (MS/MS) is the most universal platform currently available for the analysis of enzymatic activities and biomarkers in dried blood spots (DBS) for applications in newborn screening (NBS). Among the MS/MS applications in NBS, the most common is flow-injection analysis (FIA-) MS/MS, where the sample is introduced as a bolus injection into the mass spectrometer without the prior fractionation of analytes. Liquid chromatography combined with MS/MS (LC-MS/MS) has been employed for second-tier tests to reduce the false-positive rate associated with several nonspecific screening markers, beginning two decades ago. More recently, LC-MS/MS has been applied to primary screening for new conditions for which FIA-MS/MS or other methods, including genomic screening, are not yet adequate. In addition to providing a list of the currently used LC-MS/MS-based assays for NBS, the authors share their experience regarding the maintenance requirements of LC-MS/MS vs. FIA-MS/MS systems. The consensus is that the maintenance of LC-MS/MS and FIA-MS/MS instrumentation is similar, and LC-MS/MS has the advantage of allowing for a larger number of diseases to be screened for in a multiplex, cost-effective fashion with a high throughput and an adequate turnaround time.