Alternative titles; symbols
ORPHA: 157, 228302; DO: 0060235;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p32.3 | CPT II deficiency, myopathic, stress-induced | 255110 | Autosomal dominant; Autosomal recessive | 3 | CPT2 | 600650 |
A number sign (#) is used with this entry because the stress-induced myopathic form of carnitine palmitoyltransferase II (CPT II) deficiency is caused by homozygous or compound heterozygous mutation in the carnitine palmitoyltransferase II gene (CPT2; 600650) on chromosome 1p32. Some patients with heterozygous mutations in CPT2 have been reported.
Carnitine palmitoyltransferase II deficiency is an inherited disorder of mitochondrial long-chain fatty acid oxidation. The myopathic form presents most frequently in children or young adults with muscle pain with or, in most cases, without myoglobinuria with elevation of serum creatine kinase precipitated by strenuous exercise, cold, fever, or prolonged fasting. Severity of attacks is highly variable. Myoglobinuria can cause kidney failure and death (summary by Deschauer et al., 2005 and Longo et al., 2006).
See also the lethal neonatal (608836) and infantile (600649) forms of the disorder, which are also caused by mutation in the CPT2 gene.
Engel et al. (1970) reported 18-year-old identical twin sisters who experienced muscle aching with myoglobinuria, sometimes induced by exercise, from early childhood. Fasting, or high-fat low-carbohydrate isocaloric diet, induced muscle aches and a marked rise in serum muscle enzymes without associated ketonemia or ketonuria, suggesting a defect in an energy source to muscle. As administration of medium-chain triglycerides produced the expected normal ketonemia and ketonuria, Engel et al. (1970) postulated a defect in long-chain fatty acid utilization. Bressler (1970) suggested involvement of the carnitine system.
DiMauro and DiMauro (1973) reported a patient who likely had the same disorder as the twins of Engel et al. (1970). Three different methods detected very low activity of muscle carnitine palmitoyltransferase; the authors noted that deficiency of muscle carnitine palmitoyltransferase had been reported in children and young adults. Clinical features included recurrent attacks of myoglobinuria precipitated by prolonged exercise, especially after fasting, by cold exposure, or by stress; all conditions normally associated with an increased dependency of muscle on lipid metabolism.
Cumming et al. (1976) described a patient who had muscle cramps and myoglobinuria triggered by violent exercise after fasting and suppressed by a high-carbohydrate diet. Hostetler et al. (1978) reported a patient with recurrent myoglobinuria. Muscle metabolism of carbohydrates was normal. Prolonged fasting increased serum creatine phosphokinase levels. Plasma levels of free fatty acids, acetoacetate, and beta-hydroxybutyrate rose normally with fasting. A partial deficiency of carnitine palmitoyltransferase was found in muscle. Electron microscopy showed lipid droplets in the patient's muscle, and lipid analysis showed a 3-fold increase in triglycerides. Bank et al. (1975) described similar clinical features in 2 brothers who had increased plasma triglycerides and reduced ketone production despite high plasma free fatty acids. A low-fat diet of the type used for type I hyperlipoproteinemia (238600) was recommended, as caloric restriction may aggravate myoglobinuria.
DiDonato et al. (1978) reported a young man with CPT II deficiency who had reduced enzyme activity in muscle biopsy and in cultured fibroblasts, suggesting that it is a systemic rather than exclusively muscular condition. Scholte et al. (1979) described an otherwise healthy young man who had muscle pain and myoglobinuria after strenuous exercise. During fasting, serum creatine kinase remained low and ketogenesis was normal. Deficiency of CPT II was present in skeletal muscle and leukocytes, whereas CPT I activity was normal and showed normal kinetics. Skeletal muscle biopsy showed no abnormal lipid storage.
Bertorini et al. (1980) reported the unusual case of a man who had symptomatic onset of CPT deficiency at age 51 when infection precipitated acute respiratory failure and myoglobinuria. His parents were first cousins. At birth, he had required resuscitation, and severely impaired vision and mild bilateral spasticity led to a relatively sedentary life, which may have been responsible for his escape from earlier symptoms. At age 46 years, he had increased serum creatine phosphokinase of 1200 units (normal, 0-200) without obvious cause. Deficiency of CPT in muscle, leukocytes, and liver was documented at the time of his acute episodes at age 51 years. The liver enzyme defect explained the decreased production of ketone bodies during fasting, thus depriving the muscle of crucial sources of energy. Plasma ketone bodies rose normally when medium-chain triglycerides were administered.
Meola et al. (1987) demonstrated CPT deficiency in fibroblasts cultures from a patient with CPT deficiency. Similar studies of her parents and daughter showed intermediate enzyme levels, suggesting autosomal recessive inheritance. Kieval et al. (1989) reported a 17-year-boy with complete CPT deficiency (95% reduction in enzyme activity) who showed classic rhabdomyolysis precipitated by rigorous skiing. His mother, a presumed heterozygote, had partial CPT deficiency (enzyme activity 50% of normal) manifest as chronic myopathy with a 15-year history of lower limb muscle pain and stiffness, particularly following prolonged exercise. She had never experienced episodes of dark-colored urine, but leg weakness had been progressive. Examination showed proximal muscle weakness of the hip and shoulder girdles.
Kelly et al. (1989) reported a 13-year-old girl who developed severe rhabdomyolysis following an influenza B infection. Her course was complicated by episodes of hyperkalemia, hypocalcemia, hyperphosphatemia, myoglobinuria, renal failure, and lethal arrhythmia. Muscle biopsy showed CPT II deficiency. An asymptomatic sister was found to have the same disorder. Kelly et al. (1989) noted that phenotypic heterogeneity in CPT II deficiency may be due to differences in the extent of the enzymatic defect as well as to variable exposure to environmental factors such as prolonged exercise, cold, fasting, and infection.
Mongini et al. (1991) reported an 18-year-old man with classic late-onset CPT II deficiency characterized by recurrent myoglobinuria following exercise and fasting. His 53-year-old father had similar episodes, although his mother and elder brother were asymptomatic. The authors noted that the proband's parents originated from the same village in Italy with less than 1,000 inhabitants, and that the occurrence of the disorder in 2 generations showed 'quasidominant' inheritance.
In an 18-year-old female patient, Tein et al. (1994) described recurrent pancreatitis at the ages of 12 and 15 years, occurring after prolonged periods of exercise coupled with a high-fat diet. After the onset of recurrent myoglobinuria when she was 16 years old, deficiency of CPT II (32% residual activity) was established by study of cultured skin fibroblasts. Tein et al. (1994) concluded that CPT II deficiency can be a cause of pancreatitis and should be considered in the differential diagnosis, even in the absence of overt myoglobinuria.
Handig et al. (1996) reported a consanguineous CPT II deficient-family with 3 affected members who showed phenotypic variability. The proband, a male, suffered from a classic form of adult CPT II deficiency with recurrent rhabdomyolysis with myoglobinuria and serum creatine kinase levels up to more than 100,000 U/l. By contrast, a female cousin was almost asymptomatic and had never had episodes of acute muscular injury with rhabdomyolysis and myoglobinuria, although her affected sister had died at the age of 16 years during a severe attack of muscle injury.
Haap et al. (2002) performed a series of metabolic studies in a 43-year-old woman homozygous for the most common mutation in CPT II deficiency (S113L; 600650.0002). Compared with a female control group, the patient showed normal glucose tolerance but was severely insulin resistant; basal lipolysis was markedly reduced; and carbohydrate oxidation was maximally increased in the basal state and did not increase further during insulin stimulation. Conversely, lipid oxidation was virtually absent and did not decrease during insulin stimulation. Surprisingly, intramyocellular lipids were well within the range of the control group. The authors concluded that genetic CPT II deficiency is characterized by insulin resistance, which is not explained by increased intramyocellular lipids. Haap et al. (2002) concluded that the inability of skeletal muscle to oxidize long chain free fatty acids has far-reaching metabolic consequences, such as insulin resistance.
Olpin et al. (2003) noted that males comprise 88% of patients with myopathic CPT II deficiency.
Orngreen et al. (2005) used indirect calorimetry and stable isotope methodology to examine glucose and palmitate fuel utilization in patients with compound heterozygous and heterozygous mutations in the CPT2 gene. Patients with compound heterozygous mutations had normal long-chain fatty acid oxidation at rest, but severely impaired fatty acid oxidation during prolonged low-intensity exercise. Three individuals who were heterozygous for a single CPT2 mutation showed intermediate levels of impairment. The data indicated that the energy deficit in those with 2 CPT2 mutations was mitigated by enhanced muscle glycogenolysis. Residual CPT2 enzyme activity in fibroblasts ranged from 10 to 36% of normal controls in CPT II deficiency patients, and 46 to 65% in subjects with a single CPT2 mutation. The authors identified an E454X and a D213G CPT2 mutation (600650.0015 and 600650.0016) in 2 of the heterozygous patients who had reported myopathic symptoms with muscle cramping and rhabdomyolysis. Orngreen et al. (2005) concluded that some carriers of single CPT2 mutations may become symptomatic during exercise, which is consistent with a dominant-negative effect.
Deschauer et al. (2005) provided a review of the myopathic form of CPT II deficiency. In their series of 28 patients, exercise-induced myalgia was the most common symptom (96% of patients), whereas myoglobinuria was not found in 21% of patients.
Gempel et al. (2002) compared the tandem mass spectra of serum acylcarnitines of 9 CPT II-deficient patients to those of a cohort of 99 patients with other neuromuscular disorders and metabolic conditions. The spectra in CPT II deficiency showed characteristic elevations of palmitoylcarnitine and oleoylcarnitine, while acylcarnitine was not elevated. In their study, the ratio of palmitoylcarnitine and oleoylcarnitine to acylcarnitine detected all CPT II deficiencies and discriminated them from unspecific alterations of serum acylcarnitines. Gempel et al. (2002) suggested mass spectrometry of serum acylcarnitines as a rapid screening test that should be included early in the diagnostic work-up of patients with recurrent myoglobinuria, recurrent muscular weakness, and myalgia.
Fontaine et al. (2018) reported a method to diagnose CPT II in affected individuals by using pentadeuterated palmitate in patient whole blood to measure fatty acid oxidation flux. In 8 individuals with a history of rhabdomyolysis, nondiagnostic acylcarnitine profiles, and biallelic mutations in the CPT2 gene, Fontaine et al. (2018) found that the flux assay showed normal deuterated palmitoylcarnitine (C16-cn) formation but abnormal downstream deuterated metabolites, resulting in increased C16-cn to downstream deuterated metabolites, resulting in increased C16-cn to deuterated C2-cn to C14-cn ratios. Fontaine et al. (2018) concluded that this assay is useful in diagnosing CPT II and in assessing the pathogenicity of novel CPT2 variants.
Elizondo et al. (2020) studied plasma acylcarnitine levels in 11 patients with CPT2 deficiency after an overnight fast, after a meal, and after exercise. After an overnight fast, the highest long chain acylcarnitine species level was 18:1. After a meal, the 18:1 level decreased by 61% and after exercise the 18:1 acylcarnitine increased by 223%, although the individual patient responses were variable. Elizondo et al. (2020) next correlated the sum of long chain acylcarnitines with free fatty acids to determine the contribution of lipolysis to long chain acylcarnitines after an overnight fast, after a meal, and after exercise in the 11 patients with CPT2 deficiency, 8 patients with VLCAD deficiency (201475), and 11 patients with LCHAD deficiency (609016). The free fatty acids correlated to total long chain acylcarnitines after overnight fasting but not after exercise, indicating that lipolysis is a significant contributor to acylcarnitine levels with fasting but not exercise.
Bonnefont et al. (2009) found that bezafibrate, a commonly used hypolipidemic drug, restored the capacity for normal fatty acid oxidation in muscle cells in patients with a mild form of CPT2 deficiency by stimulating the expression of the mutated gene. They administered bezafibrate to 6 adults with mild CPT2 deficiency for 6 months at a dose of 3 200-mg tablets per day. The primary end point was the level of fatty acid oxidation in skeletal muscle. Mitochondria were isolated from muscle biopsy specimens obtained before and after treatment, and mitochondrial respiration rates were measured in the presence of palmitoyl L-carnitine, the specific substrate of CPT2. Before treatment, the palmitoyl L-carnitine oxidation levels were markedly reduced (by 21 to 54% of the normal value), reductions that were consistent with CPT2 deficiency. After bezafibrate treatment, the values increased significantly in the 6 patients (by 60 to 284%, P = 0.03). In addition, CPT2 mRNA in skeletal muscle increased in all the patients (by 20 to 93%, P = 0.002), as did the CPT2 protein level. In vitro analysis of myoblasts from the patients showed that the initial defect in fatty acid oxidation (49 to 75% of control values) was fully corrected after the cells had been exposed to bezafibrate (P = 0.002). There were 3 to 24 episodes of rhabdomyolysis per patient over a 6-month period before treatment and 0 to 6 episodes per patient during treatment. Quality of life questionnaires indicated less bodily pain and less limitation of physical activity. Bonnefont et al. (2009) suggested that the positive results of this pilot study warranted a larger clinical trial.
In 8 unrelated patients with familial recurrent hemoglobinuria and CPT II deficiency, Taroni et al. (1993) identified a homozygous mutation in the CPT2 gene (S113L; 600650.0002). One of the patients had been reported by DiDonato et al. (1978). Among a total of 25 patients with the disorder, Taroni et al. (1993) found the S113L mutation in 56% of the mutant CPT II alleles. Handig et al. (1996) identified homozygosity for the S113L mutation in 3 affected patients from a consanguineous family.
Deschauer et al. (2005) found the S113L mutation in 35 of 46 mutant CPT II alleles (76%).
Orngreen et al. (2005) reported a patient with stress-induced myopathic carnitine palmitoytransferase II deficiency who was heterozygous for a truncating mutation in the CPT2 gene (600650.0015). The patient had an episode of rhabdomyolysis after ingestion of alcohol and no food the night before a swimming practice. Residual CPT enzyme activity was 46% of control values, and biochemical studies indicated impaired fatty acid oxidation with prolonged exercise.
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