Dataset Information

Detection of Early Onset Carnitine Palmitoyltransferase II Deficiency by Newborn Screening: Should CPT II Deficiency Be a Primary Disease Target?

ABSTRACT: Early-onset carnitine palmitoyltransferase II deficiency (CPT II deficiency) (OMIM 600650) can result in severe outcomes, which are often fatal in the neonatal to infantile period. CPT II deficiency is a primary target in the Maritime Newborn Screening Program. We report a case of neonatal-onset CPT II deficiency identified through expanded newborn screening with tandem mass spectrometry. Identification through newborn screening led to early treatment interventions, avoidance of metabolic decompensation, and a better clinical outcome. Newborn screening for CPT II deficiency is highly sensitive and specific with no false positives identified. The only screen positive case detected identified a true positive case. This experience illustrates the importance of newborn screening for CPT II deficiency and demonstrates why reconsideration should be taken to add this disease as a primary newborn screening target.

SUBMITTER: Mador-House R

PROVIDER: S-EPMC8395870 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Detection of Early Onset Carnitine Palmitoyltransferase II Deficiency by Newborn Screening: Should CPT II Deficiency Be a Primary Disease Target?

Mador-House Rachel R Liu Zaiping Z Dyack Sarah S

International journal of neonatal screening 20210813 3

Early-onset carnitine palmitoyltransferase II deficiency (CPT II deficiency) (OMIM 600650) can result in severe outcomes, which are often fatal in the neonatal to infantile period. CPT II deficiency is a primary target in the Maritime Newborn Screening Program. We report a case of neonatal-onset CPT II deficiency identified through expanded newborn screening with tandem mass spectrometry. Identification through newborn screening led to early treatment interventions, avoidance of metabolic decomp ...[more]

PMID: 34449523

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Project description:Carnitine palmitoyltransferase (CPT) catalyzes the transfer of long- and medium-chain fatty acids from cytoplasm into mitochondria, where oxidation of fatty acids takes place. Deficiency of CPT enzyme is associated with rare diseases of fatty acid metabolism. CPT is present in two subforms: CPT I at the outer mitochondrial membrane and carnitine palmitoyltransferase II (CPT II) inside the mitochondria. Deficiency of CPT II results in the most common inherited disorder of long-chain fatty acid oxidation affecting skeletal muscle. There is a lethal neonatal form, a severe infantile hepato-cardio-muscular form, and a rather mild myopathic form characterized by exercise-induced myalgia, weakness, and myoglobinuria. Total CPT activity (CPT I + CPT II) in muscles of CPT II-deficient patients is generally normal. Nevertheless, in some patients, not detectable to reduced total activities are also reported. CPT II protein is also shown in normal concentration in patients with normal CPT enzymatic activity. However, residual CPT II shows abnormal inhibition sensitivity towards malonyl-CoA, Triton X-100 and fatty acid metabolites in patients. Genetic studies have identified a common p.Ser113Leu mutation in the muscle form along with around 100 different rare mutations. The biochemical consequences of these mutations have been controversial. Hypotheses include lack of enzymatically active protein, partial enzyme deficiency and abnormally regulated enzyme. The recombinant enzyme experiments that we recently conducted have shown that CPT II enzyme is extremely thermoliable and is abnormally inhibited by different emulsifiers and detergents such as malonyl-CoA, palmitoyl-CoA, palmitoylcarnitine, Tween 20 and Triton X-100. Here, we present a conceptual overview on CPT II deficiency based on our own findings and on results from other studies addressing clinical, biochemical, histological, immunohistological and genetic aspects, as well as recent advancements in diagnosis and therapeutic strategies in this disorder.

Project description:BackgroundNewborn screening for primary carnitine deficiency (NBS) is commonly implemented worldwide; however, it has poor sensitivity. This study aimed to evaluate the feasibility of improving screening by including a second-tier genetic assay.ResultsAn Agena iPLEX assay was developed to identify 17 common SLC22A5 mutations in Chinese populations and was applied in NBS as a second-tier screening. From January 2017 to December 2018, 204,777 newborns were screened for PCD using tandem mass spectrometry. A total of 316 (0.15%) residual NBS-positive specimens with low free carnitine (C0) levels were subjected to this second-tier screening. The screening identified 20 screen-positive newborns who harboured biallelic mutations in theSLC22A5 gene, 99 carriers with one mutation, and 197 screen-negative newborns with no mutations. Among the 99 carriers, four newborns were found to have a second disease-causing SLC22A5mutation by further genetic analysis. Among the 197 screen-negatives were four newborns with persistently low C0 levels, and further genetic analysis revealed that one newborn had two novel SLC22A5 pathogenic variants. In total, 25 newborns were diagnosed with PCD, for a positive predictive value of 7.91% (25/316). Based on these data, we estimate the incidence of PCD in Quanzhou is estimated to be 1:8191.Thirteen distinct SLC22A5 variants were identified, and the most common was c.760C > T, with an allelic frequency of 32% (16/50), followed by c.1400C > G (7/50, 14%), and c.51C > G (7/50, 14%).ConclusionData from this study revealed that 24% (6/25) of PCD cases would have been missed by conventional NBS. This high-throughput iPLEX assay is a powerful tool for PCD genotyping. The addition of this second-tier genetic screening to the current NBS program could identify missed PCD cases, thereby increasing PCD detection. However, further studies are needed to optimise the workflow of the new screening algorithm and to evaluate the cost-effectiveness of this screening approach.

Dataset Information

Detection of Early Onset Carnitine Palmitoyltransferase II Deficiency by Newborn Screening: Should CPT II Deficiency Be a Primary Disease Target?

Publications

Detection of Early Onset Carnitine Palmitoyltransferase II Deficiency by Newborn Screening: Should CPT II Deficiency Be a Primary Disease Target?

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