Carnitine palmitoyltransferase 2 deficiency (CPT2)
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A 22-year-old develops severe muscle pain and tea-colored urine after a long hike in cold weather. CK is >50,000. This is his third episode of rhabdomyolysis triggered by prolonged exertion or fasting.
AR; CPT2 (matrix-side enzyme that regenerates acyl-CoA from acylcarnitine after translocation).
- Common adult variant: c.338C>T, p.Ser113Leu
- Severe variants cluster in the lethal neonatal form
Three phenotypes by severity:
- Lethal neonatal: cardiomyopathy, arrhythmia, hyperammonemia, hypoglycemia, often with congenital malformations (renal cysts, brain anomalies). Resembles CACT.
- Infantile hepato-cardio-muscular: hypoketotic hypoglycemia, cardiomyopathy, liver failure precipitated by illness.
- Adult myopathic (most common): recurrent exercise-induced rhabdomyolysis. Triggers include prolonged exercise, cold exposure, fasting, intercurrent illness, and certain medications. Strength is normal between episodes.
The adult myopathic form is the most common inherited cause of recurrent rhabdomyolysis in adults.
Acylcarnitine profile: elevated C16, C18, C18:1 (same as CACT).
- Newborn screening (RUSP) acylcarnitine profile: elevated long-chain species (C16, C18, C18:1); does not reliably detect the adult myopathic form, which may be missed
- In the adult myopathic form, the acylcarnitine profile is often normal between episodes; suspect after recurrent exercise- or fasting-induced rhabdomyolysis with markedly elevated CK
- Profile is indistinguishable from CACT; reduced CPT2 enzyme activity in fibroblasts/muscle and CPT2 molecular testing confirm
- Avoid known triggers (prolonged fasting, prolonged exercise, cold)
- MCT supplementation; low long-chain-fat diet for severe forms
- Bezafibrate has been studied in adults; evidence mixed
"2 is for the matrix." CPT2 sits on the matrix side of the inner mitochondrial membrane; it is the last step of the carnitine cycle before beta-oxidation begins.
Cold + exercise + fasting = CPT2 attack. The triad of triggers for the adult myopathic form. Think of a marathoner in cold weather who skipped breakfast.