Carnitine Uptake Defect (Primary Carnitine Deficiency): Risk in Genotype-Phenotype Correlation

Abstract

Rose et al. (2012) reported on genotype–phenotype correlation in carnitine uptake defect (CUD; also known as primary carnitine deficiency). They demonstrated that cells from asymptomatic women have, on average, higher levels of residual carnitine transport activity as compared with that of symptomatic patients because of the presence of at least one missense mutation of the SLC22A5 (MIM# 603377) gene that encodes the organic cation transporter OCTN2. Those asymptomatic women are mothers with CUD, identified by low carnitine levels in their infants by newborn screening. However, this article would give a dangerous impression that all mothers identified by newborn screening are asymptomatic. We have reported one CUD mother who had cardiomyopathy and the genotype of p.S467C/p.[S467C, R282Q] [Lee et al., 2010]. Recently, another mother who had the p.F17L/p.R254X genotype died suddenly. She experienced a few episodes of syncope since 13 years of age without knowing the etiology. She died at home 1 year after delivering a baby. The diagnosis was made retrospectively from the family's blood spot samples obtained for the screening of Fabry disease. However, we have also followed one CUD mother who had homozygous p.R254X mutation for a few years, but she still had no symptom. We have documented CUD in 16 newborns and 13 mothers identified by our screening program, and in nine patients who presented with symptoms (Table 1). p.R254X [Tang et al., 2002], p.S467C, and p.F17L are all common mutations in the Chinese population (Table 1). p.R254X is a severe mutation that is most prevalent in symptomatic children (55.6%), whereas p.S467C appears to be a mild mutation [Rose et al., 2012], which we found most prevalent in mothers (six of 13, 46%; Table 1)[Rose et al., 2012]. However, now we understand that patients with one p.S467C mutation can still be symptomatic [Koizumi et al., 1999]. The CUD newborns have a lower percentage of p.S467C (12.5%) than the CUD mothers, suggesting that CUD newborns carrying one p.S467C mutation that may be missed during newborn screening. The high percentage of the unknown mutations in the CUD newborns (21.9%) also raises a concern that some CUD patients carrying deleterious mutations may not survive to reproduction age. Newborn screening offers a chance for early treatment for CUD, but the dilemma is which patients to treat when they are asymptomatic. Because the treatment, oral supplementation of carnitine, is simple and safe [El-Hattab et al., 2010], it is prudent to maintain a reasonable level of free carnitine in the blood for patients with CUD before we can accurately predict their phenotypes.