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 highdose 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.

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

“…A study conducted in the Faroe Islands revealed that postneonatal 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 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].…”

Neonatal and carrier screening for rare diseases: how innovation challenges screening criteria worldwide

“…Another new criterion that emerged with the revision of screening criteria by Andermann et al ( 2008 ) is that screening programme evaluation needs to be planned from the outset (Table 2 ). As a consequence, a programme may be modified or even discontinued based on ongoing assessment (Andermann et al 2010 ; Wilson et al 2019 ). Guidelines for evaluation include feedback from a diagnostic unit to a screening laboratory, which enables evaluation of basic aspects like prevalence, sensitivity and specificity.…”

“…The discussions in these publications illustrate how emerging technologies impact the dynamics of screening principles and criteria, which in turn impact the governance and operation of current screening programmes. In this paper, after introducing NBS and carrier screening, we focus on four of the criteria which have received attention in recent discussions (Grosse et al 2006 ; Bombard et al 2010 ; Wilson et al 2019 ; Sinha et al 2020 ; Modell 2020 ): treatment, test, target population and programme evaluation.…”