Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of carnitine palmitoyltransferase 1A deficiency, hepatic carnitine palmitoyltransferase deficiency, hepatic CPT deficiency, CPT I(A) deficiency, CPT1A. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Carnitine palmitoyltransferase 1A deficiency is a rare genetic disorder of energy metabolism that presents clinically with profound hypoglycemia, leaving survivors with neurologic damage. The author describes the mechanisms of pathogenesis and diagnostic pathways for the disorder including diagnosis through newborn screening. A unique genetic variant that is very common in individuals of Inuit background and of unknown clinical or lifestyle-adaptive significance is also featured in this description.
• Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of the carnitine cycle that results in impaired mitochondrial long-chain fatty acid oxidation.
• CPT1A deficiency is primarily hepatic, and presentation results from failure of ketogenesis, although renal tubular acidosis may also be present.
• CPT1A deficiency does not present with skeletal muscle or cardiac disease.
• CPT1A deficiency can be diagnosed in the newborn period by acylcarnitine analysis using ratios of nonesterified (free carnitine, C0) to long-chain esterified carnitine (C16 + C18 species). The sensitivity of this approach has not yet been established. Dried, blood-soaked, filter paper spots are the preferred samples for these determinations.
CPT1 deficiency is an autosomal recessive disorder of the mitochondrial beta-oxidation of long-chain fatty acids. It is a defect in the initial step of the so-called “carnitine shuttle” or carnitine cycle. During periods of fasting or increased energy demands, long-chain fatty acids are directed to the mitochondria for production of energy in the form of adenosine triphosphate or, specifically in liver, production of ketone bodies. Ketone bodies, acetoacetate and 3-hydroxybutyrate, can be transported as an alternate energy source to tissues, such as brain, which cannot directly oxidize fatty acids. CPT1 is found at the outer mitochondrial membrane and catalyzes the conversion of long-chain (C16 and C18) acyl-CoA species, which cannot cross into the mitochondrial matrix, to acylcarnitines, which can be directed into the mitochondrial matrix.
CPT1 enzyme activity is regulated by the intracellular concentration of malonyl-CoA, a product of carbohydrate metabolism. When fasting, the level of cellular malonyl-CoA is low, and this activates CPT1 to direct fatty acids into the mitochondria for oxidation. In the postprandial state, cellular levels of malonyl-CoA are high. This high level inhibits CPT1 activity and directs metabolism towards the synthesis of fatty acids and lipid storage and away from fatty acid oxidation in the mitochondria.
The second component of the carnitine shuttle is carnitine:acylcarnitine translocase (CACT), an integral membrane transporter protein that transports the acylcarnitines into the mitochondrial matrix. Once inside the matrix, the acylcarnitines are enzymatically converted back to acyl-CoAs by carnitine palmitoyltransferase 2 (CPT 2), the third component of the carnitine cycle (26; 34). These long-chain acyl-CoA species are then fully oxidized by the enzymes of beta-oxidation.
CPT1 is unique amongst all of the enzymes of the fatty acid oxidation pathway in that there are genetically determined tissue-specific isoforms. CPT1A is present in liver, kidney, and fibroblasts. The expression in cultured fibroblasts is particularly valuable for diagnostic purposes. CPT1B is present in cardiac and skeletal muscle, and CPT1C is present in the brain. To date, only deficiency of CPT1A has been described in humans.
Of particular historical interest, the description of a liver-specific defect of CPT enzymatic activity was demonstrated prior to McGarry’s seminal description of the carnitine shuttle in 1989 and prior to the knowledge that there were unique CPT1 and CPT2 enzymes. The defect in CPT1A was originally described as liver-specific CPT deficiency, which distinguished it from a distinct clinical phenotype of muscle-specific CPT deficiency (08; 12; 06). Muscle-specific CPT deficiency was later shown to result from a myopathic presentation of inner-mitochondrial CPT2 deficiency and is now known to be distinct from CPT1A deficiency (35).
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