Carnitine Palmitoyltransferase Deficiency

At a glance

Carnitine Palmitoyltransferase (CPT) Deficiency comprises a group of disorders caused by decreased activity of the enzymes CPT I or II. Type II is the most common human lipid myopathy. The metabolic myopathy can be triggered by exercise, anesthesia/surgery, or stress and results in episodes of rhabdomyolysis and myoglobinuria.

Synonym

Metabolic Myopathy and Carnitine Palmitoyltransferase Deficiency.

Incidence

Unknown, but approximately 50 cases of CPT I deficiency in about 30 families and approximately 350 families of CPT II deficiency have been reported (lethal neonatal [perinatal] type in about 20 families, severe infantile [hepatocardiomuscular] type in about 30 families, and myopathic type in over 300 families), making this the most common metabolic cause of recurrent myoglobinuria.

Genetic inheritance

CPT I can theoretically be caused by mutations in one of three isoenzymes with CPT IA (expressed in liver, kidney, fibroblasts, and cardiac ventricular myocytes) encoded by chromosome 11q13.3, CPT IB (expressed in skeletal muscle and cardiac ventricular myocytes) encoded by chromosome 22q13.33, and CPT IC (in the brain, eg, in hypothalamus, amygdala, and hippocampus, regions that are associated with the control of food intake) encoded by chromosome 9q13.33. However, to date only CPT IA (the hepatic type) has been found to be pathogenetic and inheritance is autosomal recessive (while it is autosomal dominant for CPT IC). A higher prevalence has been detected among the Inuit population in Canada, Greenland, and Alaska and Hutterite in Canada. Three polymorphisms and more than 100 mutations have been identified in the CPT2 gene among patients with CPT II deficiency, with the responsible genetic defect mapped to chromosome 1p32.3. Based on the clinical course, three types of CPT II can be distinguished: a lethal neonatal, an infantile, and a myopathic type (or stress-induced, adult, or late-onset type). All three types have an autosomal recessive inheritance pattern, but the myopathic type can be autosomal dominant transmitted.

Pathophysiology

CPT I and II exist as two functionally distinct mitochondrial enzymes, embedded in the outer (CPT I) and inner (CPT II) mitochondrial membranes. Fatty acids entering the cells are rapidly esterified to form coenzyme A compounds. Beta-oxidation of long-chain fatty acids mandates their transport from the cytosol across the mitochondrial membrane into the mitochondrial matrix. The required transesterification of fatty acids with free carnitine to generate fatty acylcarnitine is catalyzed by CPT I. Carnitine-acylcarnitine translocase is responsible for the transport of fatty acylcarnitine through the inner mitochondrial membrane, where its transesterification to regenerate long-chain fatty acyl-CoAs is catalyzed by CPT II.

Diagnosis

Skin/muscle biopsy can be used to detect reduced CPT enzyme activity. Molecular genetic testing may be required to confirm the diagnosis. Prompt diagnosis can help to avoid risk factors and to prevent rhabdomyolysis and renal failure secondary to myoglobinuria.