Acylcarnitine ratio indices in diagnosing carnitine-acylcarnitine translocase deficiency in newborns
We read with great interest the recent article by Shi et al. (1). The authors demonstrated promising sensitivity and false-positivity of acylcarnitine ratio indices in diagnosing carnitine-acylcarnitine translocase (CACT) deficiency. As a rare mutation-induced disorder of mitochondrial fatty acid oxidation, CACT deficiency is characterized by reduced free carnitine (C0) accompanied by elevated long-chain acylcarnitines and causes death within neonatal period in most cases. Through comprehensive calculation, the authors indicated the superior diagnostic performance of several acylcarnitine ratio indices compared with conventional acylcarnitine markers (C12, C14, C16, C18, C16:1, C18:1, and C18:2) alone.
We appreciate the authors’ contribution to effective diagnosis of this life-threatening disease in newborn. However, more details are needed to make their conclusions more convincing and certain modifications should be made. The authors stated that (C16 + C18)/C0, (C16 + C18:1)/C2, C14/C3 and some other ratio indices perfectly identify CACT deficiency according to calculated reference values. While most patients presented with decreased C0 (80%), concentrations of C2 and C3 were not shown. Most cases from two other studies (2,3) had low or borderline low levels of C2, inferring the significance of this short-chain acylcarnitine in diagnosing CACT deficiency. Similarly, positive number and corresponding false positive rates of C0 and C2 were supposed to be listed in Tab. 3.
Merely 1.2% and 3.6% increase in C16 and C18:1, respectively, were found in heterozygous carriers in comparison to normal controls, while (C16 + C18:1)/C2 and C16/C2 were remarkably elevated. This again revealed the importance of C2 in identifying disease status of CACT deficiency. Since changes in C0 and C2 were likely more significant among different disease status, ratios of long-chain acylcarnitines over the sum of C0 and C2 were anticipated to be more effective, for instance, C16/(C0 + C2) and (C16 + C18:1)/(C0 + C2). Lastly, specific statistical method was not described in the article, and Student’s t-test seemed to be applied which might not be the optimal choice. We are wondering if analysis based on receiver operating characteristic (ROC) curves could better determine the sensitivity and specificity of these ratio indices.
Minor issues were to point out. C12 was missed from primary acylcarnitine markers in the inclusion criteria of false-positive samples (page 873). Details were not presented in the comparison between patients and false-positive ones (Fig. 1), including mean value, standard deviation and significance of differences. To sum up, the authors carried out a great study based on the largest number of newborn cases ever reported in China which significantly improved early diagnosis of CACT deficiency. We believe more details about short-chain acylcarnitines and further exploration of ratio indices will strengthen the reliability of this work.
Acknowledgments
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References
- Shi C, Ao Z, Liu B, et al. Increased acylcarnitine ratio indices in newborn screening for carnitine-acylcarnitine translocase deficiency shows increased sensitivity and reduced false-positivity. Transl Pediatr 2023;12:871-81. [Crossref] [PubMed]
- Tang C, Liu S, Wu M, et al. Clinical and molecular characteristics of carnitine-acylcarnitine translocase deficiency: Experience with six patients in Guangdong China. Clin Chim Acta 2019;495:476-80. [Crossref] [PubMed]
- Habib A, Azize NAA, Rahman SA, et al. Novel mutations associated with carnitine-acylcarnitine translocase and carnitine palmitoyl transferase 2 deficiencies in Malaysia. Clin Biochem 2021;98:48-53. [Crossref] [PubMed]
