The International Journal of Molecular Sciences has published a review article on the myopathic form of CPTII that examines the disorder in terms of both its clinical features and the controversies regarding its enzymatic functions.
CPTII has two forms, a myopathic form that affects skeletal muscles and a heptomyocardio form that may be considered lethal in infants with major organ damage or may be survivable, though serious, as it potentially affects the heart, liver, and brain. These are not strict tissue-specific isoforms, but instead are due to simple differences in the mutations. The review article considered only the myopathic form.
The authors cite a recent study that found that both the wild-type (not mutated) CPTII gene and the common S113L variant showed the same enzymatic activity except under thermal stress. It additionally found that the mutated CPTII gene showed a greater sensitivity to another CoA enzyme, malony-CoA. The former likely explains why muscle pain and break-down occurs during prolonged exercise, infections, or exposure to extreme temperatures. The latter seems to occur when fatty acid oxidation is stressed, effectively creating a one-two punch.
Other studies cited showed various levels of enzyme production and inhibition. One study showed that myopathic CPTII patients have fully functional enzymatic production but are abnormally sensitive to inhibition. Another study showed that treatment with trypsin, a serine protease (found in the digestive system) that hydrolyses proteins, rendered the enzymatic inhibition insensitive, correcting for this issue.
The studies encompassed both human patient and lab studies. Whether it is the amount of enzyme produced or inhibited has been the focus of study for some time.
The thermolability of CPTII was demonstrated in studies where the wild-type gene and the mutated gene were each subjected to incubation at 40-45 degrees Celsius. Both decreased production but the mutated gene showed a significantly faster decrease. Another study showed not only a decrease in enzyme production, but also fatty acid beta oxidation and ATP production.
All studies confirmed the thermolability of the mutated CPTII.
The review also looked at studies with potentially protective substrates. Prior to incubation, treatment with L-carnitine seemed to grant greater kinetic stability. Also, C10, C12, and C14, as well as C16 acyl-L-carnitines stabilized the mutated enzyme to the level of the wild-type at 45 degrees Celsius with a decrease observed at 45 degrees
Inhibition by malonyl-CoA appears to be a significant factor in myopathic CPTII. When pre-incubated with malonyl-CoA, the wild-type gene responded with 70 percent of normal protein production but the S113L gene ‘s production shrunk to just 5 percent. Also observed in the reviewed studies were the docking points of the various substances that affect CPTII. Changes in how and where the S113L mutation catalyzes substrates could either lead to an enhancement of the binding of malonyl-CoA or malonate, or result in a weaker binding of the native substrate, either of which would create greater symptoms due to a reduction in protein production.
Most of this will come as no surprise to those who live with myopathic CPTII. However, it should come as some encouragement that science is beginning to understand all the systems that are affected and are learning how to control this.
You may read the paper in its entirety, for free, by using the doi below.
Int. J. Mol. Sci. 2017, 18(1), 82; doi:10.3390/ijms18010082
Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features
Diana Lehmann 1,*,†, Leila Motlagh 1,†, Dina Robaa 2 and Stephan Zierz 1