Carnitine Palmitoyltransferase II Deficiency

Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder of mitochondrial long chain fatty acid oxidation due to biallelic variants in CPT2. It has three forms: a mild adult myopathic form with exercise induced rhabdomyolysis, a severe infantile hepatocardiomuscular form, and a lethal neonatal form.

Pathophysiology. CPT II converts long chain acylcarnitines back into acyl-CoA inside the mitochondrial matrix, after CPT I and the carnitine acylcarnitine translocase. Loss of function blocks beta oxidation of long chain fatty acids, which are the main muscle fuel in prolonged exercise and fasting.

The common adult variant p.Ser113Leu retains partial activity.

Attacks are triggered by exercise, fasting, cold, fever and certain drugs.

• Adult myopathic form: recurrent muscle pain, weakness and rhabdomyolysis with myoglobinuria after prolonged exercise, fasting, infection or cold, with normal strength and creatine kinase between attacks.
• Acute kidney injury after severe rhabdomyolysis.
• Infantile hepatocardiomuscular form: hypoketotic hypoglycaemia, liver failure, cardiomyopathy, arrhythmia, and myopathy.
• Neonatal form: respiratory failure, liver failure, cardiomyopathy, renal dysplasia and brain malformations; usually fatal.
• Men are affected more often than women in the adult form.

• Acylcarnitine profile: raised C16 and C18:1 with a raised (C16 + C18:1)/C2 ratio, which can be normal between attacks.
• Creatine kinase: markedly raised during attacks, with myoglobinuria.
• CPT2 sequencing with deletion and duplication analysis; p.Ser113Leu accounts for most adult cases.
• CPT II enzyme activity in muscle or fibroblasts.
• Glucose, ketones, ammonia, liver tests and lactate during infantile illness.
• Echocardiography and ECG in infants.
• Newborn screening by acylcarnitines detects the severe forms.

Differential diagnosis.

• Very long chain acyl-CoA dehydrogenase deficiency
• McArdle disease and other glycogen storage diseases
• Carnitine palmitoyltransferase I deficiency
• Mitochondrial myopathy
• Statin associated myopathy and exertional heat illness

• Prevention of attacks: avoid prolonged exercise and fasting, eat frequent carbohydrate rich meals, and take a carbohydrate snack before and during exercise.
• Diet: low long chain fat intake (under 20% of energy in the adult myopathic form, under 30% in infants), supplemented with medium chain triglycerides 10 to 20% of energy, or triheptanoin up to 35% of daily calories in 4 divided doses with meals.
• Acute rhabdomyolysis: intravenous 10% glucose and 0.9% sodium chloride at 1.5 to 2 times maintenance, aiming for urine output of at least 2 mL/kg/hour, with monitoring of creatine kinase, potassium, creatinine and urinary pH. Treat hyperkalaemia and acute kidney injury, and use haemodialysis for refractory hyperkalaemia or renal failure.
• Infantile form: avoid fasting (feeds every 3 to 4 hours, overnight continuous feeds), manage hypoglycaemia with 10% dextrose at 8 to 10 mg/kg/min, and treat cardiomyopathy and arrhythmia.
• Drug avoidance: valproate, ibuprofen and other NSAIDs, general anaesthetics such as propofol (long infusions), and diazepam at high doses may precipitate attacks.
• Carnitine: supplementation is controversial because long chain acylcarnitines accumulate; use only under specialist supervision.
• Exercise advice: moderate, regular exercise with adequate carbohydrate, and avoidance of cold exposure.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Surgery and anaesthesia: continue intravenous glucose through fasting periods, and avoid propofol infusions and tourniquets where possible.

Monitoring. Creatine kinase between attacks, and renal function after any episode. Echocardiography and ECG yearly in infantile forms, and dietary review yearly.

Referral and escalation. Refer to clinical genetics, metabolic medicine and nephrology when needed. Emergency for dark urine with muscle pain, oliguria, hypoglycaemia or arrhythmia.