Patients with the childhood- or adult-onset form of CPT II deficiency experience recurrent episodes of severe muscle pain associated with rhabdomyolysis accompanied with extreme elevation of serum CPK and myoglobinuria. These episodes are often triggered by fasting, infection, or excessive exercise. As reported in this and other studies,1
the diagnosis can be difficult to establish, often involving decades. Enzyme assay for CPT II activity from muscle biopsies, fibroblast cultures, and lymphocytes are uniformly definitive. Analysis for the “common” DNA mutation, S113L, was not always reliable, nor was acylcarnitine analysis or serum CPK, as seen in the results with our patients, except during episodes of rhabdomyolysis. Residual CPT II activity may be responsible for the difficulty in early recognition of this disorder.
Therapy has focused on reducing dietary fat intake while increasing carbohydrate mainly to reduce the abnormal accumulation of both long-chain acyl–coenzyme A (CoA) and acylcarnitine intermediates. During a rhabdomyolytic crisis, excessive lipolysis associated with myoglobinuria is the primary concern. Acute therapy includes glucose infusion (often with an insulin drip) to reduce lipid mobilization and large volumes of fluid and alkalinization to enhance renal excretion of myoglobin. The dietary restriction of fat, even with substitution of medium-chain even-carbon triglycerides (MCT oil), although a sound rationale, has not been successful, because exercise restriction is required, muscle pain on exertion persists, and recurrent hospitalizations continue to occur.
Skeletal muscle relies on oxidation of fat, glucose, and amino acids for energy. Our treatment hypothesis is based on the likelihood that energy metabolism is seriously compromised by the inability to fuel the citric acid cycle (CAC) by β-oxidation in this and other long-chain fat oxidation defects that feature recurrent rhabdomyolysis. For effective function of the CAC linked to the respiratory chain for adenosine triphosphate (ATP) production, adequate oxaloacetate along with acetyl-CoA is required for the citrate synthase reaction. Because glucose and medium-chain fatty acids (C8
) can only provide acetyl-CoA, we evaluated the effect of triheptanoin as an intramitochondrial source of acetyl-CoA and also oxaloacetate derived from the propionyl-CoA moiety. When given enterally, 1 mole of triheptanoin provides 1 mole of glycerol and 3 moles of heptanoate. Heptanoate is almost totally taken up by the liver12
and does not require CPT I, carnitine–acylcarnitine translocase, or CPT II for entry into the mitochondrion. Once activated to heptanoyl-CoA and after one cycle of β-oxidation, acetyl-CoA and pentanoyl-CoA are produced. The latter is then oxidized to β-ketopentanoyl–CoA (BKP-CoA) that undergoes thiolytic cleavage, producing both acetyl-CoA and propionyl-CoA. Propionyl-CoA enters the CAC via succinyl-CoA and becomes the source of oxaloacetate as seen in the . Acetyl-CoA can also be converted to acetoacetyl-CoA in liver. Acetoacetyl-CoA and BKP-CoA can both proceed via the β-hydroxy-β-methylglutaryl–CoA pathway, forming “ketone bodies” containing either 4 or 5 carbons. When exported from liver, both sets of ketone bodies can be taken up by all peripheral organs, including brain.13
As occurs with acetoacetate and β-hydroxybutyrate, the ketone-using enzymes in other organs, e.g., muscle, activate both BKP and BHP to the corresponding CoA thioesters. BHP-CoA is converted to BKP-CoA and then cleaved to acetyl-CoA and propionyl-CoA as occurred in liver. Both acetyl-CoA and oxaloacetate are then available for the citrate synthase reaction in muscle. The result is increased ATP formation via the respiratory chain, potentially correcting the energy deficit.
Figure Metabolic fate of heptanoate derived from triheptanoin
Children and adults with CPT II deficiency are acutely aware of their physical limitations on a day-to-day basis, as evidenced by periods of muscle weakness, pain, and aching, related to mild to moderate exercise or illnesses.
Except for the two relatively asymptomatic children (patients 4 and 5), each patient in this study became aware of increased physical endurance without muscle fatigue or aching as early as the fourth day of therapy. Since beginning and adhering to the diet therapy, none of them required hospitalization for rhabdomyolytic episodes. All patients returned to unrestricted physical exercise. These activities included basketball, volleyball, skiing, aerobics, and near Olympic-type daily swimming protocols. Compared with their baseline evaluations, the PCS from the SF-36 questionnaire for these five symptomatic patients had improved to normal levels as early as 2 months and remained normal out to 33 months on the diet ().
The family with three affected children (patients 3, 4, and 5) is of particular interest. The eldest (patient 3) had three major episodes of rhabdomyolysis and a history of multiple hospitalizations for “hypoglycemia” before diagnosis, at age 11 years. At age 13 years, patient 3 was noncompliant for a short interval. This was associated with return of muscle aches, moderate elevations of serum CPK levels (300–500 IU/L), and noticeable decreased endurance, all of which were reversed within 24 hours with resumption of the anaplerotic diet. At 44 months into the protocol, when also noncompliant, she was hospitalized after excessive sport competition. She has had no further hospitalizations out to 52 months when compliant. Her younger siblings (patients 4 and 5), at ages 7 and 10 years, had minimal symptoms at the time of entry into the diet protocol after diagnosis. After 45 months on the diet, at ages 10 and 13 years, they remain asymptomatic. Comparison of the PCS scores from the SF-36 questionnaire for these three patients shows the improvement for patient 3 compared with the normal scores both before and after the diet therapy for the two younger siblings (). Longer-term evaluation might indicate some preventive value to this anaplerotic therapy that might be explored further with patients with CPT II deficiency detected by tandem mass spectrometry newborn screening.
This study reports successful management of CPT II deficiency using anaplerotic diet therapy with triheptanoin, in contrast to the patients’ previous experiences with the low-fat/high-carbohydrate diet. Further, there was no evidence of toxicity, undue weight gain, or abnormal body fat composition extending out to 61 months in any of the patients. None of these patients experienced recurrent episodes of rhabdomyolysis or required hospitalization while on the diet. Exercise restriction was eliminated, and the SF-36 scores indicated a return to a normal lifestyle without body pain.