In skeletal muscle, long-chain fatty acids required for fuel are only able to traverse the mitochondrial membrane after esterification with carnitine in a reaction catalyzed by carnitine palmitoyltransferase I (CPT I). After translocation across the membrane, the fatty acid is reactivated to acyl-CoA by carnitine palmitoyltransferase II (CPT II) in a rate-limiting step for entry into the β-oxidation cycle, and carnitine is recycled. Palmitoylcarnitine accumulates when CPT II activity is reduced and is able to passively diffuse across mitochondrial membranes thereby gaining access to myoplasmic subcellular components.1 Long-chain acylcarnitines activate the skeletal muscle Ca2+ release channel ryanodine receptor isoform 1 (RYR1), the locus of most recognized malignant hyperthermia (MH)-associated mutations, in a fashion that is both concentration and fatty acid chain length dependent.2–4 Here we describe the occurrence of a MH-like event in a patient who was heterozygous for a pathogenic CPT2 mutation.
A 4-yr, 4-mo-old girl presented for resection of a recurrent cerebellar astrocytoma. She weighed 15.0 kg, had no known drug allergies, was not taking chronic medications, and was in otherwise good health with no evidence of neuromuscular disease. She was anesthetized for an angiogram 6 mo earlier with thiopental, succinylcholine, ethrane, nitrous oxide, curare, and meperidine without incident. Anesthesia for a primary resection 6 mo earlier consisted of thiopental, halothane, nitrous oxide, pancuronium, and fentanyl and was uncomplicated. There was no abnormality on the preoperative physical examination other than a mildly wide-based gait. The complete blood and platelet count, prothrombin time and partial thromboplastin time, and urinalysis before surgery were normal. There was no family history of anesthesia-related complications or other inherited disorders.
The patient was premedicated with atropine (0.2 mg) and meperidine (25 mg) IM. In the operating room, general anesthesia was induced with thiopental (25 mg), and tracheal intubation was facilitated with succinylcholine (40 mg) and pancuronium (1.5 mg) IV. Anesthesia was maintained with halothane 0.4%–1.0%, nitrous oxide 60%, and oxygen. End-tidal CO2 and noninvasive oxygen saturation monitors were not available at the time of the procedure. At 2 h and 15 min after induction of anesthesia, the patient's heart rate was 120 bpm and systolic blood pressure was 90 mm Hg, with mechanical ventilation at 300 cc tidal volume at 15 bpm. An arterial blood gas at this interval revealed a compensated metabolic acidosis with a base excess of −5.9 meq/L (Table 1). The respiratory rate was increased to 17 bpm and the procedure was completed without complication 2 h and 30 min later. The total anesthesia time was 4 h and 45 min, with an estimated blood loss of 75 mL.
Her vital signs on arrival in the postanesthesia recovery room showed a heart rate of 128 bpm, a respiratory rate after extubation of 24 bpm, an arterial blood pressure of 108/66 mm Hg, and a rectal temperature of 37.4°C. One hour later, as the patient was being readied for discharge from the recovery room, she was noted to have an irregular heart rate with the electrocardiogram monitor revealing occasional sinus pauses at a heart rate of 130 bpm. An arterial blood gas showed metabolic acidosis with a base deficit of −11.3 meq/L and −11.2 meq/L on a repeat sample (Table 1). Her serum electrolyte levels were normal with a potassium of 3.4 meq/L. During the next 45 min, the patient developed tachycardia to 160 bpm, tachypnea to 32 bpm, and fever with a rectal temperature of 38.7°C. Two hours after completion of the procedure, the patient was given 10 meq of sodium bicarbonate twice over 30 min, and an additional 10 meq of sodium bicarbonate was added to the IV solution. Two subsequent base excess levels revealed −8.3 and −6.3 meq/L, with a creatine kinase (CK) level of 5250 mU/mL (Table 1). The rectal temperature remained elevated at 39°C despite active cooling with a cooling blanket and ice bags, and acetaminophen (240 mg) PR. Five hours after the conclusion of the procedure, the patient was given dantrolene (20 mg) IV, with a second administration of dantrolene (10 mg) IV 30 min later. Within the following hour, her heart rate decreased to 110 bpm, the respiratory rate decreased to 20 bpm, and the temperature fell to 38.6°C. An arterial blood gas showed a resolved metabolic acidosis with a base excess of 0.4 meq/L. Fibrin degradation products in the blood were <10 μg/mL (normal). At 8 h after completion of the procedure, the patient was transferred to the pediatric intensive care unit for observation. Throughout the period of acidosis and fever, the patient's postanesthesia recovery scores were maintained at 9–10. At no point was the patient noted to have hypertension or hypotension, axial or extremity muscle rigidity, dark urine or oliguria, hypercarbia, hyperkalemia, or a bleeding diathesis. Dexamethasone (2 mg) IV was given twice during the recovery room stay for brain swelling prophylaxis. The patient was afebrile over the first postoperative evening and thereafter with stable vital signs and serial arterial blood gases showing a base excess that varied between 1.2 and −1.6 meq/L (Table 1). The next morning her CK level was 10,000 mU/mL, with a serum myoglobin of 975 ng/mL, but the urine was negative for myoglobin. Urine output over the first 16 h after surgery was 1100 mL.
The remainder of the patient's perioperative course was uncomplicated. Physical examination on discharge showed moderate gait ataxia, mild ataxia in the left upper extremity, and moderate increased tone in the right lower extremity. The patient had no atrophy, pain, cramping, fatigue, or other skeletal muscle signs or symptoms. The cerebellar signs resolved over the following months, with no evidence of a primary neuromuscular disease and no exposure to anesthesia or surgery in the ensuing 12 yr. CK levels in the mother and father were 120 and 150 mU/mL, respectively. The father has had moderate elevations of CK after orthopedic injuries, including cervical and lumbar disk injuries (408 mU/mL), and a meniscal tear of the knee (550 mU/mL).
With approval of the IRB of the University of Wisconsin School of Medicine and Public Health, Madison, WI, written informed consent was obtained from the patient and both parents. DNA was isolated from blood using the PureGene DNA Isolation kit (Gentra Systems, Minneapolis, MN) and amplified as previously described.5 Samples were screened by allele-specific oligonucleotide analysis for both mutant and wild-type alleles at residue 503 and for five other common CPT2 mutations using previously described methods.5
Screening of the patient and her parents for the CPT2 C1507T mutation resulting in the R503C substitution in CPT II revealed that both the patient and her mother were heterozygous carriers of the mutation. The father was found to be homozygous for the wild-type allele at this locus.
We report the occurrence of a MH-like syndrome in a patient who was heterozygous for a R503C mutation in the CPT2 gene encoding the enzyme CPT II. Features of the episode that are shared with a typical MH “trigger” include tachydysrhythmia, tachypnea, and fever after exposure to succinylcholine and halothane, in association with severe metabolic acidosis, hyperCKemia, myglobinemia, and rapid recovery without residual effects upon administration of dantrolene, sodium bicarbonate, and active cooling. The time course of the event, with its full expression delayed until after completion of the procedure, has been recognized as a possible, if uncommon, component of conventional MH.6,7 Muscle rigidity, hypercarbia, and hyperkalemia were not observed. Signs and symptoms compatible with a diagnosis other than that of MH-like syndrome, including, for example, infection, transfusion reaction, thyrotoxicosis, or pheochromocytoma, were also absent.
CPT II (EC220.127.116.11) deficiency is an autosomal recessive disorder with three clinical phenotypes: an adult myopathic form (MIM 25510); a severe infantile form (MIM 60649); and a lethal neonatal form (MIM 608836).8 Presently, more than 60 disease-causing mutations in CPT2 have been identified. In homozygotes, the R503C missense mutation causes a severe infantile phenotype comprising liver failure, cardiomyopathy, and skeletal muscle pathology.9 R503C heterozygotes may either be asymptomatic or they may exhibit myopathic symptoms.5 We have previously reported that CPT activity (i.e., predominantly CPT II activity) in lymphoblasts from the patient and her mother was reduced to 50% below normal.10 The father's CPT activity was normal. Wieser et al.11 measured CPT activity in frozen muscle bundles from 18 individuals known to be susceptible to MH by virtue of positive results on in vitro contracture tests of biopsied skeletal muscle, and observed no difference in mean CPT activity in comparison with controls. Despite the small sample size, the presence of two sibling pairs within the sample, and the absence of CPT2 genotyping, the authors conclude that a clinically significant contribution of altered CPT enzyme activity to the MH phenotype can be excluded. We concur that rare, homozygous CPT2 mutations are unlikely to play a major role in many patients with MH arising from other causes, i.e., mutations in the gene (RYR1) encoding RYR1, but do not agree that the candidacy of CPT2 as a locus for MH-like syndromes in patients lacking RYR1 mutations can be excluded on the basis of so limited a study. For example, the carrier frequency of the most common pathogenic CPT2 allele is estimated at 1 in 270 individuals.12 Accordingly, if heterozygote status confers increased risk for MH-like events during anesthesia in manifesting carriers, episodes arising from CPT2 mutations may not be as rare as Wieser et al. conclude.11,13 We suggest that the presence of a pathogenic mutation in an apparently normal CPT2 heterozygote may be a significant risk factor upon exposure to drugs capable of triggering an MH-like syndrome.
The authors acknowledge the technical assistance of David Smail and R. Thomas Taggart.
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