Lipid is an important muscle energy source during rest and during prolonged, submaximal exercise.
Fatty acids are derived from circulating very low density lipoprotein (VLDL) in the blood or from triglycerides stored in muscle fibers and fatty acids can be divided into groups based on the number of carbon atoms: short-chain, medium-chain, long-chain, and very long–chain fatty acids.
Oxidation of fatty acids occurs in the mitochondria .
The major fraction of fatty acids, long-chain fatty acids (LCFA) cannot enter the mitochondria by simple diffusion, contrary to medium- or short-chain fatty acids.
After their activation by a long-chain fatty acyl-CoA synthetase on the outer mitochondrial membrane, long-chain fatty acyl-CoAs are imported into the mitochondrial matrix by the carnitine palmitoyltransferase system.
This enzymatic complex is made up of two distinct proteins named carnitine palmitoyltransferase (CPT 1) and (CPT 2).
While CPT2 is the same protein bodywide , two tissue-specific isoforms of CPT1—the so-called “liver” and “muscle” CPT1s—have been identified. Two additional proteins are required for the mitochondrial transport of LCFA: a plasma membrane carnitine transporter dedicated to the maintenance of the intracellular level of carnitine and a carnitine acylcarnitine translocase that shuttles long-chain acylcarnitines across the inner-mitochondrial membrane in exchange for free carnitine.
In recent years an increasing number of patients with inherited disorders of mitochondrial fatty acid oxidation have been described.
The fatty acid oxidation disorders include transport of long-chain fat across the mitochondrial membrane (ie, CPT deficiency) and transport of carnitine into the cell (ie,carnitine transporter deficiency), and the majority of defects being attributed to mutations in b-oxidation directly [ie, long-chain acyl-CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, trifunctional protein (TFP), deficiency].
These disorders are inherited with an autosomal recessive inheritance pattern.
In many of these disorders the underlying defect becomes clinically apparent only during periods of fasting, or other metabolic stresses.
When the utilization of lipid becomes more important such as during long-term endurance activity, patient refers often cramps, muscle pain, and inability to continue the activity. In some cases, severe myalgias with rhabdomyolysis and renal failure can be the presenting symptom of fatty acid oxidation disease. The lipidoses arise due to defects of intra-mitochondrial b-oxidation enzymes or failure to transport fatty acids into mitochondria secondary to carnitine or CPT deficiencies. Muscle pain and fatigue are frequent complaints .
CPT II is located on the inner mitochondrial membrane and is essential for the transport of long-chain fatty acids into mitochondria . CPT II catalyzes the formation of palmitoyl-CoA from palmitoylcarnitine imported into the matrix via the acylcarnitine translocase. The catalytic core of the CPT II enzyme contains three important binding sites that recognize structural aspects of CoA, palmitoyl and carnitine.
The carnitine binding site is made accessible by the conformational change induced in the enzyme by the binding of CoA.
The majority of the genetic abnormalities in CPT II deficient patients effect amino acid residues and these mutations are thus thought to compromise the stability of the protein rather than the catalytic activity of the enzyme.
Inheritance is autosomal recessive, although disease manifests more commonly in men .
Around 60 different disease-causing mutations within the CPT II gene (locus 1p32) have been reported.
Theories regarding the biochemical significance of the two most common mutations are noted below:
Mutation between Ser113 and Arg 498 may disturb the hydrogen-bonding and the ion-pair network between Arg498 and Asp376, and thereby indirectly affect the catalytic efficiency of the His372 residue
The mutation indirectly compromises the association between CPT II and the inner mitochondrial membrane and disturbs the shuttling of the palmitoylcarnitine substrate into the active site of the enzyme
Three different clinical manifestations of CPT II deficiency are recognized
These vary in severity and are defined according to the age of onset. Many patients with myopathic fatty acids oxidation diseases are asymptomatic without a metabolic stress.
Neonatal disease is fatal within the first few months of life.
The infantile form presents as cardiomyopathy, acute liver failure, hypoketotic hypoglycaemia and seizures and has a high mortality.
In children have been reported the two main metabolic stressors : viral illness or prolonged fasting, nausea, and vomiting with decreased fluid and caloric intake.
Late-onset disease has a more benign phenotype and is characteristically restricted to muscle, though a case of severe sustained hypoglycaemia attributed to adult-onset CPT II deficiency has recently been reported. Patient with the adult form can often perform high-intensity activity for short periods without difficulty.The majority of affected patients develop symptoms before the age of 30, although presentation as late as the seventh decade has been described . The characteristic clinical picture is one of acute episodes of muscle pain, stiffness and weakness induced by sustained low intensity exercise or fasting. Myoglobinuria occurs in approximately 80% of cases. Most patients are asymptomatic with normal muscle function between crises; however, potentially fatal complications include respiratory failure and acute tubular necrosis.