The decision to discontinue screening for carnitine uptake disorder in New Zealand

Abstract

When screening for carnitine uptake disorder (CUD), the New Zealand (NZ) newborn screening (NBS) service identified infants as screen-positive if they had initial and repeat free carnitine (C0) levels of less than 5.0 μmol/L. Since 2006, the NBS service has identified two infants with biochemical and genetic features consistent with neonatal CUD and nine mothers with features consistent with maternal CUD. A review of the literature suggests that these nine women reflect less than half the true prevalence and that CUD is relatively common. However, the NZ results (two infants) suggest a very low sensitivity and positive predictive value of NBS. While patients presenting with significant disease due to CUD are well described, the majority of adults with CUD are asymptomatic. Nonetheless, treatment with high-dose oral L-carnitine is recommended. Compliance with oral L-carnitine is likely to be poor long term. This may represent a specific risk as treatment could repress the usual compensatory mechanisms seen in CUD, such that a sudden discontinuation of treatment may be dangerous. L-carnitine is metabolized to trimethylamine-N-oxide (TMAO) and treated patients have extremely high plasma TMAO levels. TMAO is an independent risk factor for atherosclerosis and, thus, caution should be exercised regarding long-term treatment with high-dose carnitine of asymptomatic patients who may have a biochemical profile without disease. Due to these concerns, the NZ Newborn Metabolic Screening Programme (NMSP) initiated a review via a series of advisory and governance committees and decided to discontinue screening for CUD.

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

“…With the rapidly expanding NBS programs worldwide, it is important to realize that the benefit of NBS is not always easy to prove and that there is no generally accepted guideline on how to monitor outcome and hence fully benefit from NBS programs . It is even more complicated to substantiate the decision to discontinue screening, as was recently done in New Zealand for carnitine uptake disorders . Although most NBS programs use the criteria from Wilson and Jungner and the adaptations from the World Health Organization for inclusion of disorders in the NBS panel, no clear standardized long‐term clinical follow‐up system exists, despite the fact that the adapted criteria clearly state “the objectives of screening should be defined at the outset” and “program evaluation should be planned from the outset” .…”

Primary carnitine deficiency – diagnosis after heart transplantation: better late than never!

“…A study conducted in the Faroe Islands revealed that post-neonatal screening beyond 2 months of age successfully identified additional affected patients whose newborn screening results had been unremarkable [23]. The low sensitivity and specificity of newborn screening for PCD and the numerous asymptomatic mothers identified makes including PCD generally within newborn screening programmes controversial [8]. In our family, patient 2's having undergone newborn screening for PCD ultimately enabled its diagnosis in two children.…”

“…Pilot studies are now evaluating an extension of the newborn screening panel to include PCD also in individual screening laboratories in Germany [6,7]. However, the New Zealand newborn screening programme just recently decided to discontinue screening for PCD; their reasons included poor sensitivity, a high false-positive rate, and numerous asymptomatic adults with PCD [8].…”

“…The long-term prognosis is favourable as long as children and adults remain on carnitine treatment [1,3]. However, compliance with long-term carnitine supplementation may be inadequate, and potential side-effects entailing elevated levels of trimethylamine-N-oxide (TMAO) resulting from high-dose carnitine supplementation have recently been reported [8].…”

Primary carnitine deficiency – diagnosis after heart transplantation: Better late than never!

“…The long-term prognosis is favourable as long as children and adults remain on carnitine treatment [1,3]. However, compliance with longterm carnitine supplementation may be inadequate, and potential side-effects entailing elevated levels of trimethylamine-N-oxide (TMAO) resulting from high-dose carnitine supplementation have recently been reported [8].…”