Mutations that can be associated with the muscle form of carnitine palmitoyltransferase II deficiency. The most common S113L mutation and the second most frequent mutations, P50H and Q413fs-F448L, are shown in boldface type. References are shown in brackets.
Biochemical data of patients with muscle carnitine palmitoyltransferase (CPT) II deficiency. NCP indicates noncollagen protein; error bars, standard deviation.
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Deschauer M, Wieser T, Zierz S. Muscle Carnitine Palmitoyltransferase II Deficiency: Clinical and Molecular Genetic Features and Diagnostic Aspects. Arch Neurol. 2005;62(1):37–41. doi:10.1001/archneur.62.1.37
Muscle carnitine palmitoyltransferase (CPT) II deficiency is an autosomal recessive disorder of fatty acid oxidation characterized by attacks of myalgia and myoglobinuria. This review summarizes the clinical features of this disease, analyzing data of 28 patients with biochemically and genetically confirmed CPT II deficiency. The review shows that exercise-induced myalgia is the most frequent symptom, whereas myoglobinuria, known as the clinical hallmark, is missing in 21% of the patients. Typically, myalgia starts in childhood, whereas attacks with myoglobinuria mostly emerge in adolescence or early adulthood. However, there are also patients with only myalgia, patients with attacks triggered by factors other than exercise, and patients with late-onset disease. Molecular or biochemical analysis is necessary for diagnosis, since no myopathologic hallmark exists. For screening patients, analysis of not only the common S113L mutation but also the P50H and Q413fs-F448L mutations is recommended. The phenotype of muscle CPT II deficiency might be influenced by the underlying mutation, and patients with a truncating mutation on 1 allele might be affected more severely.
Muscle carnitine palmitoyltransferase (CPT) II deficiency is a common cause of inherited recurrent myoglobinuria. Since the first description of the disease in 1973,1 more than 150 patients have been described, but most of the reports include only single cases.2 So far, to our knowledge, there is no study that analyzes clinical signs and symptoms in a large series of patients with genetically proved muscle CPT II deficiency. In this review, we summarize the clinical findings in a large group of 28 patients. In all patients, muscle CPT II deficiency has been confirmed biochemically and genetically. These data have been published previously.3-6 Frequencies of symptoms and signs and allele frequencies are compared with other studies.
The CPT system mediates the transport of long-chain fatty acids into the mitochondrial matrix. This system includes CPT I located in the outer mitochondrial membrane and CPT II located in the inner membrane, which catalyzes the formation of acyl–coenzyme A (CoA) from acylcarnitine and CoA. Although CPT II in contrast to CPT I exists in only one isoform across various tissues, there are different phenotypes of CPT II deficiency that are inherited in an autosomal recessive trait. There is a lethal neonatal form, a severe multisystemic infantile form, and a milder muscle form that starts in childhood or adulthood. The milder muscle form is characterized by attacks of exercise-induced muscle pain with rhabdomyolysis and myoglobinuria. Molecular analysis of the CPT2 gene in patients with the muscle form revealed that there is a common mutation (S113L) in approximately 60% of mutant alleles7 and several rare mutations. A genotype-phenotype correlation has not been established so far in patients with the muscle form of CPT II deficiency.
Between the attacks, persistent weakness is uncommon in patients with muscle CPT II deficiency and was communicated only in single cases8,9 in contrast to patients with McArdle disease. McArdle glycogenosis, another metabolic myopathy that can be associated with exercise-induced myoglobinuria, is associated with fixed weakness in 26% of patients.10 Clinical examination results were normal between the attacks in all our patients except one (patient 24), who showed a moderate proximal weakness of the lower limbs 1 month after an attack of rhabdomyolysis.4 The creatine kinase levels were within the reference range between the attacks in 16 of our patients and slightly elevated only in 3 patients (88, 311, and 313 U/L; reference range, <80 U/L), whereas in patients with McArdle disease creatine kinase levels are almost consistently elevated.11 An early meta-analysis8 showed elevated creatine kinase levels in 15% of 26 cases with muscle CPT II deficiency.
Myalgia, either single attacks of severe myalgia (often with myoglobinuria) or frequent exercise-induced myalgia, was the most frequent symptom in 27 (96%) of our CPT II–deficient patients. Only 2 patients complained of muscle cramps, which occur frequently (93%) in patients with McArdle disease.10 Frequent exercise-induced myalgia that is characteristic for McArdle disease is less common in muscle CPT II deficiency.
Myoglobinuria, which is known to be the clinical hallmark of muscle CPT II deficiency, was missing in 6 (21%) of our patients. In a series of 14 Spanish patients with muscle CPT II deficiency, 14% also had no history of myoglobinuria.12 The early meta-analysis8 revealed that myoglobinuria was present in nearly all patients (97%). This difference might be because we screened more patients without myoglobinuria for CPT II deficiency.
Severity of the attacks can be highly variable, and life-threatening rhabdomyolysis that required dialysis was not frequent in our series (5 [18%] of 28 patients) or in previous reports8,12 (Table 1). Seventeen (61%) of our patients complained of subjective muscle weakness during the attacks.
The most important trigger factor for attacks was exercise, which was present in 27 (96%) of our 28 patients, similar to the series of DiMauro and Papadimitriou.8 Attacks were not triggered by exercise in only 1 patient. Other trigger factors were infections in 13 patients (46%), fasting or low nutritional intake in 5 (18%), and cold in 4 (14%). In 1 patient, an attack was triggered by emotional stress. Often attacks were induced by a combination of trigger factors (eg, extensive skiing in the cold without appropriate food intake). Moreover, there are reports that attacks can be triggered by drugs (eg, ibuprofen,13 very high doses of diazepam,14 and valproate sodium15) or by general anesthesia.16 Frequencies of signs and trigger factors are given in Table 1, and detailed clinical features of our patients are given in Table 2. Remarkably, infections were a more frequent trigger factor than fasting in our patients compared with the series of DiMauro and Papadimitriou.8 Severity of exercise that triggered symptoms and frequency of symptoms were highly variable. In some patients symptoms were induced only by heavy or very long-term exercise, such as mountain hiking, whereas in others symptoms were triggered by mild exercise, such as strolling. Frequency of the attacks ranged from a single attack to attacks every month. In addition to the attacks, some patients complained of moderate but frequent exercise-induced myalgia; thus, daily activities were impaired. Three patients never had severe attacks but did have frequent exercise-induced myalgia.
Onset of the disease was in childhood or early adulthood in all our patients except 1. This is similar to the Spanish study, which included patients with disease onset between 6 and 27 years of age.12 However, the occurrence of first symptoms at the age of 61 years in 1 patient shows that late manifestation can occur rarely. In 19 of our patients (68%), myalgia started in childhood (0-12 years of age), whereas first attacks of myoglobinuria frequently occurred in adolescence or early adulthood (Table 2). Thus, the terms adult CPT II deficiency for the muscle form in contrast to infantile CPT II deficiency for the multisystemic form with involvement of heart, liver, and muscle2 can be misleading.
A male predominance of 86% and 76%, respectively, was reported in the studies by Martin et al10 and Blanc et al.14 This male predominance was present in our series, too, but it was milder (19 patients [68%]). The question remains of whether the male predominance is due to sex-related differences in exercise activities, an X-chromosomal modifier gene, or hormonal factors such as estrogen that seem to be a regulator of CPT.17,18
Diagnostic workup of exercise-induced myalgia or myoglobinuria typically includes a muscle biopsy, but histologic investigation cannot establish CPT II deficiency, since there is no myopathologic hallmark. In contrast to carnitine deficiency, which typically shows lipid accumulation,19 normal muscle was found in half (11) of 23 patients and only unspecific myopathic changes in the other half (atrophic fibers and increased variability in fiber size in 12 patients) with sometimes slight lipid accumulation (7 patients). Similarly, the Spanish study12 observed lipid accumulation in only 1 of 14 CPT II–deficient patients.
Molecular analysis of our 23 index cases4-6 showed a frequency of 76% (35/46) for the common S113L mutation, which is slightly higher than that previously reported.7 The P50H and Q413fs-F448L mutations are less frequent mutations associated with muscle CPT II deficiency, but no private mutations were revealed. The P50H mutation was observed in our series4-6 in 3 (7%) of the 46 alleles, which is similar to previous studies.20-22 The Q413fs-F448L mutation that was found in a frequency of 20% of mutant alleles in a US study21 of 10 patients was found in only 2 (4%) of the alleles in our series.4-6 This mutation is known to be of Ashkenazi Jewish origin,21 which might explain why it was found more frequently in the US study (Table 3). In addition, our group4-6 and others12,20-28 have communicated at least 19 private mutations in patients with muscle CPT II deficiency (Figure 1). Exact genotypes of our patients are given in Table 2.
More than 95% of our patients carried the S113L mutation on at least 1 allele. Thus, CPT II deficiency is not likely in patients who do not carry the S113L mutation and even less likely if the P50H and Q413fs-F448L mutations are also excluded. Molecular testing of these 3 mutations can establish the diagnosis of muscle CPT II deficiency in three quarters of the patients by identifying mutations on both alleles. However, in one quarter of the patients, 1 of these 3 mutations is found on only 1 allele; thus, biochemical investigation is necessary to confirm CPT II deficiency.
In all our index patients, we detected CPT II deficiency in muscle homogenate3-6 by using the isotope forward assay under optimal conditions as previously described.3 Diagnosis of CPT II deficiency was based on biochemical evidence of abnormal inhibition of CPT II by malonyl-CoA (0.2mM) and 0.4% Triton X-100 but normal total CPT activity (Figure 2). Indirect biochemical evidence of CPT II deficiency can be achieved by analyzing fatty acids of patient serum with tandem mass spectrometry. This noninvasive test shows a characteristic elevation of acylcarnitines, especially an increase in the C16:0/C18:1/C2 ratio,29 but was performed in only 1 of our patients (patient 23), the results of which showed the typical pathologic profile. Moreover, accumulation of long-chain acylcarnitines can be measured by fatty acid oxidation studies in cultured fibroblasts as shown in patient 25.5
Important clues for genotype-phenotype correlations in CPT II deficiency already exist, because some “mild” missense mutations are associated with the muscle form (including the common S113L mutation) and some “severe” mutations are associated with the multisystemic infantile or lethal neonatal form (including the truncating Q413fs-F448L mutation) if they are present in the homozygous state.2 The lethal neonatal form was frequently associated with truncating mutations on both alleles.30-32 Compound heterozygosity for a mild and a severe mutation can be associated with either the mild muscle form or the severe multisystemic infantile form.2,31 The reason for this remains enigmatic. Comparing our patients with missense mutations on both alleles (patients 1-19 and 26) with patients with a severe truncating mutation (patients 20-25) on 1 allele showed that in 5 of the 6 patients with a truncating mutation attacks were triggered by fasting, in contrast to patients with missense mutations who did not report this. Thus, fasting seems to be less likely a trigger of symptoms in patients homozygous for the S113L mutation. All our patients with a truncating mutation complained of weakness during the attacks compared with half of the patients with missense mutations. Both observations might indicate that the phenotype of muscle CPT II deficiency is influenced by the underlying mutation and that patients with a truncating mutation on 1 allele might by affected more severely. Although CPT II deficiency is an autosomal recessive disease, reports exist of symptomatic patients heterozygous for only a single mutation (even after extensive molecular analysis) with biochemical evidence of moderate enzyme deficiency.21,33 The simplest explanation would be that a second mutation was missed. However, it has been speculated that additional enzyme defects, such as myoadenylate deaminase deficiency, might be the cause of heterozygous patients becoming symptomatic.33
There is no treatment of CPT II deficiency other than dietary therapy to prevent attacks and symptomatic treatment of myoglobinuria and possible renal complications. Frequent meals with carbohydrate intake before exercise and restriction of long-chain fatty acid intake along with medium-chain fatty acid supplementation are recommended. Recently, it was shown that a carbohydrate-rich diet that contained polysaccharides (but not glucose) can improve exercise intolerance in patients with muscle CPT II deficiency.34
Correspondence: Marcus Deschauer, MD, Klinik und Poliklinik für Neurologie, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Str 40, 06097 Halle/Saale, Germany (firstname.lastname@example.org).
Accepted for Publication:: February 5, 2004.
Author Contributions:Study concept and design: Deschauer. Acquisition of data: Deschauer, Wieser. Analysis and interpretation of data: Deschauer, Wieser, Zierz. Drafting of the manuscript: Deschauer. Critical revision of the manuscript for important intellectual content: Wieser, Zierz. Obtained funding: Zierz. Study supervision: Zierz.
Funding/Support: Dr Deschauer was supported by the Roux-Programm of the University of Halle-Wittenberg.
Acknowledgment: We thank Rolf Schröder, MD, Bonn, Germany, for referring several patients and Klaus Gempel, MD, Munich, Germany, for analyzing fatty acids with tandem mass spectrometry in 1 patient’s serum sample.
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