Muscle Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Conceptual Approach

Abstract

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.

Nutrition and Exercise in a Case of Carnitine Palmitoyl-Transferase II Deficiency

“…Following exercise training combined with diet adjustment, RMR increased and RQ decreased toward normalization, suggesting an improvement of metabolic active muscles combined with the optimization of macronutrient utilization. In light of the genetic nature of the impaired fatty acids metabolisms, the observed change in RQ probably reflects an increased efficiency in the energy disposal and utilization of carbohydrates at rest and/or an amelioration of the residual fat utilization through alternative pathways ( Joshi and Zierz, 2020 ).…”

“…Nevertheless, as a single case report, the results must be interpreted with caution and cannot be generalized to other patients, and future studies with proper statistical analysis are needed to confirm the findings. Moreover, we considered a young female patient, and we cannot exclude the possibility that different outcomes may be obtained from training male CPTII deficient subjects, who experience more severe and frequent clinical presentation of the disease ( Joshi and Zierz, 2020 ).…”

“…CPTII deficiency is considered to be an autosomal recessive disorder, so incidence is equal in males and females. Of importance, more than 75% of patients reported so far are males, and it is currently unknown whether the gender predominance is due to sex-related differences in exercise activities, hormonal factors, or both ( Joshi and Zierz, 2020 ).…”

Severe rhabdomyolysis in homozygote carnitine palmitoyltransferase II deficiency

“…This form of CPT II deficiency may be found at any age, but approximately 70 % appear early during childhood. Several other genetic variants are associated with mild and/or severe forms of myopathy (Joshi and Zierz, 2020[ 9 ]). Additional pathogenetic, some not yet known, mechanisms are discussed.…”

“…In the inner mitochondrial membrane, carnitine palmitoyltransferase-2 (CPT-II) is involved in long-chain fatty acid (LCFA) oxidation for energy production (Houten and Wanders, 2010[ 5 ]). Inherited carnitine palmitoyltransferase II (CPT II) deficiency (c.338C>T, p.Ser113Leu) represents a defect LCFA oxidation (Joshi and Zierz, 2020[ 9 ]). Commonly, patients with CPT II deficiency are clinically not recognized (Balasubramanian et al, 2018[ 2 ]) and are therefore rarely reported (Zach et al, 2019[ 17 ]).…”