Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features.

Diana Lehmann,Stephan Zierz,Leila Motlagh,Dina Robaa

doi:10.3390/ijms18010082

Abstract

CPT (carnitine palmitoyltransferase) II muscle deficiency is the most common form of muscle fatty acid metabolism disorders. In contrast to carnitine deficiency, it is clinically characterized by attacks of myalgia and rhabdomyolysis without persistent muscle weakness and lipid accumulation in muscle fibers. The biochemical consequences of the disease-causing mutations are still discussed controversially. CPT activity in muscles of patients with CPT II deficiency ranged from not detectable to reduced to normal. Based on the observation that in patients, total CPT is completely inhibited by malony-CoA, a deficiency of malonyl-CoA-insensitive CPT II has been suggested. In contrast, it has also been shown that in muscle CPT II deficiency, CPT II protein is present in normal concentrations with normal enzymatic activity. However, CPT II in patients is abnormally sensitive to inhibition by malonyl-CoA, Triton X-100 and fatty acid metabolites. A recent study on human recombinant CPT II enzymes (His6-N-hCPT2 and His6-N-hCPT2/S113L) revealed that the wild-type and the S113L variants showed the same enzymatic activity. However, the mutated enzyme showed an abnormal thermal destabilization at 40 and 45 °C and an abnormal sensitivity to inhibition by malony-CoA. The thermolability of the mutant enzyme might explain why symptoms in muscle CPT II deficiency mainly occur during prolonged exercise, infections and exposure to cold. In addition, the abnormally regulated enzyme might be mostly inhibited when the fatty acid metabolism is stressed.

Highlights

In contrast to carnitine deficiency, it is clinically characterized by attacks of myalgia and rhabdomyolysis without persistent muscle weakness and lipid accumulation in muscle fibers
The carnitine palmitoyltransferase (CPT) system consists of two enzymes, CPT I and CPT II, and is involved in the transport of long-chain fatty acids into the mitochondrial compartment
Muscle carnitine palmitoyl transferase II deficiency was mostly considered to be associated with adult or late onset [22,35,36,37] rather than early childhood manifestation [38,39,40,41,42,43]

Summary

Introduction

The carnitine palmitoyltransferase (CPT) system consists of two enzymes, CPT I and CPT II, and is involved in the transport of long-chain fatty acids into the mitochondrial compartment. In one Western blot study on one patient, there was no detectable CPT II protein at all [21] In another immunoreactivity study, prior to the identification of the disease-causing mutations, five groups of patients were differentiated according to enzyme activity and protein content, but none of the patients had complete loss of the CPT protein [16]. Prior to the identification of the disease-causing mutations, five groups of patients were differentiated according to enzyme activity and protein content, but none of the patients had complete loss of the CPT protein [16] In these studies, antibodies against bovine liver CPT II [21] and rat liver CPT II [16] have been used. The mutant enzyme showed a marked thermolability and was abnormally inhibited by malonyl-CoA [24,25]

Clinical Presentation of Patients with Muscle CPT II

Biochemical Studies in Patients with CPT II Muscle Deficiency

Protective Effect of Natural Substrates

Findings

Summary and Conclusions