Newborn screening for carnitine palmitoyltransferase II deficiency using (C16+C18:1)/C2: Evaluation of additional indices for adequate sensitivity and lower false-positivity.

Abstract

BACKGROUND:

Carnitine palmitoyltransferase (CPT) II deficiency is one of the most common forms of mitochondrial fatty acid oxidation disorder (FAOD). However, newborn screening (NBS) for this potentially fatal disease has not been established partly because reliable indices are not available.

METHODS:

We diagnosed CPT II deficiency in a 7-month-old boy presenting with hypoglycemic encephalopathy, which apparently had been missed in the NBS using C16 and C18:1 concentrations as indices. By referring to his acylcarnitine profile from the NBS, we adopted the (C16+C18:1)/C2 ratio (cutoff 0.62) and C16 concentration (cutoff 3.0nmol/mL) as alternative indices for CPT II deficiency such that an analysis of a dried blood specimen collected at postnatal day five retroactively yielded the correct diagnosis. Thereafter, positive cases were assessed by measuring (1) the fatty acid oxidation ability of intact lymphocytes and/or (2) CPT II activity in the lysates of lymphocytes. The diagnoses were then further confirmed by genetic analysis.

RESULTS:

The disease was diagnosed in seven of 21 newborns suspected of having CPT II deficiency based on NBS. We also analyzed the false-negative patient and five symptomatic patients for comparison. Values for the NBS indices of the false-negative, symptomatic patient were lower than those of the seven affected newborns. Although it was difficult to differentiate the false-negative patient from heterozygous carriers and false-positive subjects, the fatty acid oxidation ability of the lymphocytes and CPT II activity clearly confirmed the diagnosis. Among several other indices proposed previously, C14/C3 completely differentiated the seven NBS-positive patients and the false-negative patient from the heterozygous carriers and the false-positive subjects. Genetic analysis revealed 16 kinds of variant alleles. The most prevalent, detected in ten alleles in nine patients from eight families, was c.1148T>A (p.F383Y), a finding in line with those of several previous reports on Japanese patients.

CONCLUSIONS:

These findings suggested that CPT II deficiency can be screened by using (C16+C18:1)/C2 and C16 as indices. An appropriate cutoff level is required to achieve adequate sensitivity albeit at the cost of a considerable increase in the false-positive rate, which might be reduced by using additional indices such as C14/C3.

• Authors: Go Tajima, Keiichi Hara, Miyuki Tsumura, Reiko Kagawa, Satoshi Okada, Nobuo Sakura, Shinsuke Maruyama, Atsuko Noguchi, Tomonari Awaya, Mika Ishige, Nobuyuki Ishige, Ikuma Musha, Sayaka Ajihara, Akira Ohtake, Etsuo Naito, Yusuke Hamada, Tomotaka Kono, Tomoko Asada, Hideo Sasai, Toshiyuki Fukao, Ryoji Fujiki, Osamu Ohara, Ryosuke Bo, Kenji Yamada, Hironori Kobayashi, Yuki Hasegawa, Seiji Yamaguchi, Masaki Takayanagi, Ikue Hata, Yosuke Shigematsu, Masao Kobayashi
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 122 Issue 3 Pg. 67-75 (11 2017) ISSN: 1096-7206 [Electronic] United States
• PMID: 28801073 (Publication Type: Case Reports, Evaluation Study, Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Palmitoylcarnitine
• Carnitine O-Palmitoyltransferase

Topics

• Alleles
• Carnitine O-Palmitoyltransferase (analysis, deficiency, genetics)
• Dried Blood Spot Testing (methods)
• False Negative Reactions
• False Positive Reactions
• Female
• Humans
• Hypoglycemia (complications)
• Infant
• Infant, Newborn
• Male
• Metabolism, Inborn Errors (diagnosis, genetics)
• Neonatal Screening
• Palmitoylcarnitine (analysis)
• Sensitivity and Specificity
• Tandem Mass Spectrometry