Carnitine Palmitoyltransferase II Deficiency: A Clinical, Biochemical, and Molecular Review

ArticleinLaboratory Investigation 83(11):1543-54 · November 2003with33 Reads
DOI: 10.1097/01.LAB.0000098428.51765.83 · Source: PubMed
Congenital deficiency of carnitine palmitoyltransferase (CPT) II has been known for at least 30 years now, and its phenotypic variability remains fascinating. Three distinct clinical entities have been described, the adult, the infantile, and the perinatal, all with an autosomal recessive inheritance pattern. The adult CPT II clinical phenotype is somewhat benign and requires additional external triggers such as high-intensity exercise before the predominantly myopathic symptoms are elicited. The perinatal and infantile forms involve multiple organ systems. The perinatal disease is the most severe form and is invariably fatal. The introduction of mass spectrometry to analyze blood acylcarnitine profiles has revolutionized the diagnosis of fatty acid oxidation disorders including CPT II deficiency. Its use in expanded neonatal screening programs has made presymptomatic diagnosis a reality. An increasing number of mutations are being identified in the CPT II gene with a distinct genotype-phenotype correlation in most cases. However, clinical variability in some patients suggests additional genetic or environmental modifiers. Herein, we present a new case of lethal perinatal CPT II deficiency with a rare missense mutation, R296Q (907G>A) associated with a previously described 25-bp deletion on the second allele. We review the clinical features, the diagnostic protocol including expanded neonatal screening, the treatment, and the biochemical and molecular basis of CPT II deficiency.
    • "CPT II de-ficiency, which is an autosomal recessive disorder, was first reported in 1973 by DiMauro et al. [122] in adults with exercise-induced rhabdomyolysis. In patients with CPT-2 deficiency, heavy exercise, cold exposure, infection, emotional stress or fasting is associated with the appearance of recurrent myalgia, rhabdomyolysis and myoglobinuria [121]. CPT-2 allows acyl Co-As into the mitochondrial matrix for β-oxidation of fatty acids, which are the major energy source for sustained skeletal muscle exercise [123] . "
    [Show abstract] [Hide abstract] ABSTRACT: Statins reduce cardiovascular morbidity and mortality in primary and secondary prevention. Despite their efficacy, many persons are unable to tolerate statins due to adverse events such as hepatotoxicity and myalgia/myopathy. In case of most patients, it seems that mild-to-moderate abnormalities in liver and muscle enzymes are not serious adverse effects which do not outweigh benefits of coronary heart disease risk reduction. The risk for mortality or permanent organ damage ascribed to statin use is very small and limited to cases of myopathy and rhabdomyolysis. Statin-induced muscle related adverse events is highly heterogeneous clinical disorder with numerous, complex etiologies and a variety of genetic backgrounds. Every patient who presents with statin related side effects cannot undergo the type of exhaustive molecular characterization that would include all of these mechanisms. Frequently the only solution is to either discontinue of statin therapy/reduce the dose or attempt intermittent dosing strategies at low dose.
    Full-text · Article · Mar 2016
    • "Although a large proportion of CPT II deficiency patients exhibit phenotype of compound hetero/homozygous variations2627282930, the molecular mechanism of how the CPT II deficiency induces energy crisis has yet to be clarified. The genotype-phenotype correlation analysis of CPT2 missense mutations has enabled the myopathic form of CPT II deficiency to be associated with " mild " mutations, while the null mutations resulting to truncation of mRNA or protein degradation are associated with the lethal neonatal forms [18, 30,35363738. Many disease causing mutations from inherited disorders effect on impair protein folding or reduce protein stability despite almost normal protein folding. "
    [Show abstract] [Hide abstract] ABSTRACT: Carnitine palmitoyltransferase II (CPT II) deficiency is one of the most common causes of fatty acid oxidation metabolism disorders. However, the molecular mechanism between CPT2 gene polymorphisms and metabolic stress has not been fully clarified. We previously reported that a number of patients show a thermal instable phenotype of compound hetero/homozygous variants of CPT II. To understand the mechanism of the metabolic disorder resulting from CPT II deficiency, the present study investigated CPT II variants in patient fibroblasts, [c.1102 G>A (p.V368I)] (heterozygous), [c.1102 G>A (p.V368I)] (homozygous), and [c.1055 T>G (p.F352C)] (heterozygous) + [c.1102 G>A (p.V368I)] (homozygous) compared with fibroblasts from healthy controls. CPT II variants exerted an effect of dominant negative on the homotetrameric proteins that showed thermal instability, reduced residual enzyme activities and a short half-life. Moreover, CPT II variant fibroblasts showed a significant decrease in fatty acid β-oxidation and adenosine triphosphate generation, combined with a reduced mitochondrial membrane potential, resulting in cellular apoptosis. Collectively, our data indicate that the CPT II deficiency induces an energy crisis of the fatty acid metabolic pathway. These findings may contribute to the elucidation of the genetic factors involved in metabolic disorder encephalopathy caused by the CPT II deficiency.
    Full-text · Article · Mar 2015
    • "The CPT II gene has been assigned to chromosome 1p32. It contains five exons and more than 25 mutations have been described [3]. The S113L is the most common mutation in the myopathic form. "
    [Show abstract] [Hide abstract] ABSTRACT: Aim. To raise the awareness of adult-onset carnitite palmitoyltransferase II deficiency (CPT II) by describing clinical, biochemical, and genetic features of the disease occurring in early adulthood. Method. Review of the case characteristics and literature review. Results. We report on a 20-year-old man presenting with dyspnea, fatigue, fever, and myoglobinuria. This was the second episode with such symptoms (the previous one being three years earlier). The symptoms occurred after intense physical work, followed by a viral infection resulting in fever treated with NSAIDs. Massive rhabdomyolysis was diagnosed, resulting in acute renal failure necessitating plasmapheresis and hemodialysis, acute hepatic lesion, and respiratory insufficiency. Additionally, our patient had cardiomyopathy with volume overload. After a detailed workup, CPT II deficiency was suspected. We did a sequencing analysis for exons 1, 3, and 4 of the CPT II gene and found that the patient was homozygote for Ser 113 Leu mutation in exon 3 of the CPT II gene. The patient recovery was complete except for the cardiomiopathy with mildly impaired systolic function. Conclusion. Whenever a patient suffers recurrent episodes of myalgia, followed by myoglobinuria due to rhabdomyolysis, we should always consider the possibility of this rare condition. The definitive diagnose of this condition is achieved by genetic testing.
    Full-text · Article · Jan 2014
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