The Newborn Screening Paradox: Sensitivity vs. Overdiagnosis in VLCAD Deficiency

Abstract

Objective: To improve the efficacy of newborn screening (NBS) for very long chain acyl-CoA dehydrogenase deficiency (VLCADD).Patients and Methods: Data on all dried blood spots collected by the Dutch NBS from October 2007 to 2010 (742.728) were included. Based solely on the C14:1 levels (cutoff !0.8 mmol/L), six newborns with VLCADD had been identified through NBS during this period. The ratio of C14:1 over C2 was calculated. DNA of all blood spots with a C14:1/C2 ratio of !0.020 was isolated and sequenced. Children homozygous or compound heterozygous for mutations in the ACADVL gene were traced back and invited for detailed clinical, biochemical, and genetic evaluation.Results: Retrospective analysis based on the C14:1/C2 ratio with a cutoff of !0.020 identified an additional five children with known ACADVL mutations and low enzymatic activity. All were still asymptomatic at the time of diagnosis (age 2-5 years). Increasing the cutoff to !0.023 resulted in a sensitivity of 93% and a positive predictive value of 37%. The sensitivity of the previously used screening approach (C14:1 !0.8) was 50%.Conclusion: This study shows that the ratio C14:1/C2 is a more sensitive marker than C14:1 for identifying VLCADD patients in NBS. However, as these patients were all asymptomatic at the time of diagnosis, this suggests that a more sensitive screening approach may also identify individuals who may never develop clinical disease. Long-term follow-up studies are needed to establish the risk of these VLCADD-deficient individuals for developing clinical signs and symptoms.

Impact of newborn screening for very‐long‐chain acyl‐CoA dehydrogenase deficiency on genetic, enzymatic, and clinical outcomes

“…Of the NBS patients (n = 37), one died before screening could be performed and nine were not detected by initial NBS. Six out of these nine patients were later identified by retrospective analysis of bloodspot cards demonstrating an increased C14:1/C2 ratio, which led to the adaptation of the Dutch screening for VLCADD . This retrospective analysis was initiated because of identification of a patient missed by NBS.…”

“…Since 2013, the cutoff value (COV) of the C14:1/C2 ratio for referral of newborns has been set at ≥0.023. Between 2007 and 2013, screening was solely based on C14:1 levels (COV ≥ 0.8 μmol/L), which failed to identify five patients who were only diagnosed retrospectively upon reevaluation of the blood spot results in 2010 …”

Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle

“…Although DBS is good matrix for detecting most lcFAODs, acylcarnitine levels in CPT2-deficient patients can be in the normal range [ 56 ]. The use of ratios of acylcarnitines improves sensitivity [ 46 , 57 ]. For example for VLCAD deficiency, the ratio of tetradecenoylcarnitine (C14:1) over acetylcarnitine (C2) resulted in less false-negative results when compared to C14:1 as the only marker [ 46 , 57 ].…”

Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Can Be Improved by Lowering Accumulation of Fatty Acid Oxidation Intermediates

“…Mechanisms underlying cardiac arrhythmias in VLCADD, which can occur even in the absence of structural cardiac malformation [4,9] are not well understood. Two putative pathophysiological mechanisms have been proposed for the cardiac phenotype-(1) energy shortage due to deficient adenosine triphosphate (ATP) synthesis from lcFAO, and (2) accumulation of lcFAO intermediates including long-chain acylcarnitines (LCACs) [9,10]. Of note, in acute myocardial ischemia, rapid LCAC accumulation also occurs [11] and for this reason the modulating effects of LCACs on cardiac action potentials (APs) and ion currents have been widely studied [12][13][14][15][16][17].…”