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Newborn Screening with (C16 + C18:1)/C2 and C14/C3 for Carnitine Palmitoyltransferase II Deficiency throughout Japan
Go Tajima1,2, Keiichi Hara2,3, Miyuki Tsumura2
1Division of Neonatal Screening, Research Institute, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
Insights
Carnitine palmitoyltransferase II deficiency screening is improving. A new index, C12/C0, shows promise in reducing false positives for this fatty acid oxidation disorder, particularly the dangerous hypoglycemic form.
Area of Science:
- Biochemistry
- Genetics
- Newborn Screening
Background:
- Carnitine palmitoyltransferase (CPT) II deficiency is a serious long-chain fatty acid oxidation disorder.
- It presents in lethal neonatal, hypoglycemic, and myopathic forms, with the hypoglycemic form posing a risk of sudden infant death, especially in Japanese populations.
- Previous newborn screening (NBS) pilot studies used (C16 + C18:1)/C2 and C14/C3, with C14/C3 showing lower false positivity, leading to its nationwide adoption in 2018.
Purpose of the Study:
- To evaluate the diagnostic utility of existing and novel acylcarnitine ratios in infants identified as positive by newborn screening for CPT II deficiency.
- To identify improved screening markers that reduce false positives while ensuring detection of true positive cases, particularly for the hypoglycemic form.
Main Methods:
- Analysis of acylcarnitine profiles, including various chain lengths (C18 to C2) and free carnitine (C0), in 71 NBS-positive infants.
- Comparison of the diagnostic performance of established ratios (C14/C3, (C16 + C18:1)/C2) with novel ratios, specifically C12/C0.
Main Results:
- Existing screening indices, C14/C3 and (C16 + C18:1)/C2, showed significant overlap between patients with CPT II deficiency and healthy infants.
- The novel index C12/C0 demonstrated potential to decrease false-positive results without compromising the detection of true positive cases.
- While C12/C0 may not detect all myopathic form cases, it is effective in preventing life-threatening hypoglycemic CPT II deficiency onset.
Conclusions:
- The C12/C0 ratio is a promising biomarker for improving the specificity of newborn screening for Carnitine palmitoyltransferase II deficiency.
- This new index can help reduce unnecessary follow-up testing and anxiety associated with false positives.
- Implementing C12/C0 could enhance the early detection and management of the critical hypoglycemic form of CPT II deficiency.
Abstract:
Carnitine palmitoyltransferase (CPT) II deficiency is a long-chain fatty acid oxidation disorder. It manifests as (1) a lethal neonatal form, (2) a hypoglycemic form, or (3) a myopathic form. The second form can cause sudden infant death and is more common among Japanese people than in other ethnic groups. Our study group had earlier used (C16 + C18:1)/C2 to conduct a pilot newborn screening (NBS) study, and found that the use of C14/C3 for screening yielded lower rates of false positivity; in 2018, as a result, nationwide NBS for CPT II deficiency started. In this study, we evaluated the utility of these ratios in 71 NBS-positive infants and found that the levels of both C14/C3 and (C16 + C18:1)/C2 in patients overlapped greatly with those of infants without the disease. Among the levels of acylcarnitines with various chain lengths (C18 to C2) and levels of free carnitine (C0) as well as their ratios of various patterns, C12/C0 appeared to be a promising index that could reduce false-positive results without missing true-positive cases detected by current indices. Although some cases of the myopathic form may go undetected even with C12/C0, its use will help prevent life-threatening onset of the hypoglycemic form of CPT II deficiency.
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