Response to Chen et al.: Carnitine Uptake Defect (Primary Carnitine Deficiency): Risk in Genotype–Phenotype Correlation

Authors

  • Marzia Pasquali,

    1. Division of Medical Genetics, /Pediatrics, University of Utah, Salt Lake City, Utah
    2. ARUP Institute for Clinical and Experimental Pathology®, ARUP Laboratories, Salt Lake City, Utah
    3. Department of Pathology, University of Utah, Salt Lake City, Utah
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  • Nicola Longo

    Corresponding author
    1. ARUP Institute for Clinical and Experimental Pathology®, ARUP Laboratories, Salt Lake City, Utah
    2. Department of Pathology, University of Utah, Salt Lake City, Utah
    • Division of Medical Genetics, /Pediatrics, University of Utah, Salt Lake City, Utah
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  • Communicated by Johannes Zschocke

  • Contract grant sponsor: National Institutes of Health (R01 DK 53824).

Correspondence to: Nicola Longo, Division of Medical Genetics, Department of Pediatrics, University of Utah, 2C412 SOM, 50 North Mario Capecchi Drive, Salt Lake City, Utah 84132. E-mail: Nicola.Longo@hsc.utah.edu

Chen et al. (2013) provide their experience and very useful comments about our manuscript “Genotype–Phenotype Correlation in Primary Carnitine Deficiency” [Rose et al., 2012]. Our manuscript indicated that, on average, cells obtained from mothers diagnosed with primary carnitine deficiency because of an abnormal newborn screening in their infants had higher residual carnitine transport activity. In addition, none of our mothers was homozygous or compound heterozygous for two mutations, causing the premature insertion of stop codons. This is obviously not the case in their series in which at least one mother is homozygous for the p.R254X mutation. Their data, however, also support in part our findings showing that 11/18 or 61.1% of mutations identified in symptomatic patients caused the premature insertion of a stop codon compared with eight of 26 or 30.7% of mutations in mothers with carnitine uptake defect, as shown in their Table.

We fully agree with Chen et al. (2013) that the presence of residual carnitine transport activity does not prevent clinical manifestations. Cardiomyopathy, cardiac arrest, and cardiac electrical abnormalities have been reported in women with primary carnitine deficiency [Schimmenti et al., 2007]. More importantly, in at least one case, syncope and long QT syndrome have resolved with carnitine supplementation [De Biase et al., 2011]. Recent data from the Faroe Islands where primary carnitine deficiency has a very high incidence indicate that several young adults have died of the disease despite carrying missense mutations (p.N32S is prevalent in this population) [Rasmussen et al., 2013]. Additional factors, such as exposure to pivalic-acid-containing antibiotics, infections, or severe catabolic state might be necessary to precipitate clinical manifestations in these patients [Rasmussen et al., 2013]. Because it is not possible to know when precipitating factors will occur, it is our clinical practice to treat every person with primary carnitine deficiency with carnitine supplements (including asymptomatic women) and to monitor carnitine levels over time.

We also agree with Chen et al. (2013) that patients with primary carnitine deficiency might be missed by newborn screening. We do not know whether this is due to specific mutations as they suggest and/or due to problems related to the timing of collection of the newborn screening sample. Carnitine is transferred from the mother to the child via the placenta, and immediately after birth, levels of free carnitine (C0) are usually lower in infants of mothers with primary carnitine deficiency as compared with infants with the disease themselves (Table 1). In our experience, three out of four infants with primary carnitine deficiency had levels of free carnitine (C0) above the laboratory cutoff at the time of the first screening (2 days of age or less). With time, levels decreased in infants with primary carnitine deficiency, but remained stable or slightly increased in infants of mothers with primary carnitine deficiency (Table 1). The diagnosis can obviously be missed if the testing is performed too close to birth, and no second screening is obtained. Algorithms including carnitine species other than free carnitine are being tested for their efficacy to better identify infants with primary carnitine deficiency even shortly after birth.

Table 1. Free Carnitine (C0) Levels in Dried Blood Spots of Infants with Primary Carnitine Deficiency as Compared with Infants of Mothers with Primary Carnitine Deficiency
 Age at first screening (days)C0 (μmol/L)Age at second screening (days)C0 (μmol/L)
  1. Note the lower levels of carnitine in the first screening in infants of mothers with primary carnitine deficiency. Three out of four infants with primary carnitine deficiency had levels of C0 above the laboratory cutoff at the time of the first screening.

  2. a

    aP < 0.05 versus infants with carnitine uptake defect (first or second screen) using t-test.

  3. CUD, carnitine uptake defect.

Infant with CUD (4)1.5 ± 0.613.7 ± 7.114.0 ± 1.87.2 ± 1.7
Maternal CUD (6)1.8 ± 0.44.3 ± 2.0*13.2 ± 1.25.0 ± 1.3*

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