Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Carnitine palmitoyltransferase II deficiency is the most frequent hereditary disorder of fatty acid metabolism affecting muscle. Exercise-induced attacks of rhabdomyolysis are the clinical hallmark. The author summarizes the clinical features of the disease and reviews pilot studies on bezafibrate and triheptanoin treatment that revealed uncertain therapeutic effects.
• Carnitine palmitoyltransferase II deficiency frequently manifests with episodes of rhabdomyolysis after prolonged exercise and fasting leading to myoglobinuria and myalgia.
• This muscle form of the disease is the most frequent cause of hereditary myoglobinuria.
• A severe infantile form with liver failure and hypoketotic hypoglycemia and a lethal neonatal form represent other rarer manifestations.
• Analysis of acylcarnitine profile in blood by tandem mass spectrometry that is used in newborn screening is helpful to identify patients in later life.
• High intake of carbohydrate is recommended before exercise to prevent episodes of rhabdomyolysis.
Carnitine palmitoyltransferase II deficiency is an inherited disorder of lipid metabolism affecting the entry of long-chain fatty acids into mitochondria. Abnormalities of lipid catabolism as possible causes of human disease were first suggested in the late 1960s by morphological observations of excessive accumulation of lipid droplets within muscle fibers (10). In 1973, carnitine palmitoyltransferase type II deficiency was the first enzyme defect of fatty-acid oxidation to be discovered. DiMauro and Melis-DiMauro described this enzyme defect in 2 brothers suffering from recurrent episodes of muscle pain and pigmenturia with occasional renal failure. The recurrent attacks were triggered by prolonged exercise, especially when the patient fasted (16). Several hundred patients have since been reported worldwide, and it has been clearly established that the defective enzyme is carnitine palmitoyltransferase II, the inner mitochondrial membrane component of the carnitine palmitoyltransferase system. Deficiency of the outer mitochondrial membrane component of the system, carnitine palmitoyltransferase I, was discovered in 1981 in a young girl with a pure "hepatic" presentation characterized by morning seizures due to fasting hypoglycemia (09).
Although exercise-induced recurrent myoglobinuria remains the most common manifestation of carnitine palmitoyltransferase II deficiency, other multisystemic phenotypes have been ascribed to a defect of this enzyme. Severe or lethal early-onset forms have been reported in neonates (31; 74) and children (11) who present with hypoketotic hypoglycemia, liver failure, cardiomyopathy, generalized steatosis, developmental abnormalities, and early death.
In 1991 the human carnitine palmitoyltransferase II cDNA was cloned (26), and 1 year later, the first mutation in a patient with carnitine palmitoyltransferase II deficiency was identified (63).
Despite the apparent coordinated function of carnitine palmitoyltransferase I and carnitine palmitoyltransferase II in all tissues, the clinical manifestations of deficiencies of the 2 enzymes generally differ. Carnitine palmitoyltransferase I deficiency is commonly referred to as the hepatic form of carnitine palmitoyltransferase deficiency. This disease is discussed in a separate article. Although carnitine palmitoyltransferase II exists only in 1 isoform across various tissues, there are 3 different phenotypes of carnitine palmitoyltransferase II deficiency that are inherited as an autosomal recessive trait. There is a muscle form that presents in childhood or adulthood, a multisystemic infantile form, and a lethal neonatal form with congenital malformations.
Muscle form (OMIM 255110). This form is the most common disorder of lipid muscle metabolism and the most frequent cause of hereditary myoglobinuria (68). Typically, it presents with attacks of exercise induced muscle pain with rhabdomyolysis and myoglobinuria (78). But myoglobinuria with brown-colored urine, the clinical hallmark of muscle carnitine palmitoyltransferase II deficiency (17), is absent in 10% to 20% of the patients (43; 14; 34). Myalgia is the most frequent symptom reported by nearly all carnitine palmitoyltransferase II deficient patients (14; 34; 36), but only a few patients complain of muscle cramps. Instead, patients describe a feeling of "tightness" and pain in the exercising limb or trunk muscles before the appearance of myoglobinuria. This can impair daily activities. Many patients complain of subjective muscle weakness during the attacks (14; 36).
The severity of the attacks can be highly variable and 20% of the patients suffer from life-threatening rhabdomyolysis requiring dialysis (14; 37). Respiratory failure due to muscle weakness and paroxysmal dysrhythmias are also life-threatening complications that rarely occur (67; 58). Frequency of attacks ranges from 1 attack to dozens of attacks per year (36). Between the attacks, persistent weakness is uncommon and was communicated only in single cases (17; 29).
Although carnitine palmitoyltransferase II deficiency is evident in other tissues (eg, liver, leukocytes, fibroblasts), extramuscular manifestations are typically not present. There are usually no clinical signs of liver dysfunction. Fasting hypoglycemia is never observed, and cardiac involvement is unusual.
Typically, the attacks occur after prolonged exercise. In some patients, symptoms were induced only by heavy or long-term exercise such as mountain hiking; in others, symptoms resulted after mild exercise such as strolling. Unlike patients with glycolytic defects, patients with carnitine palmitoyltransferase II deficiency do not show reduced tolerance to brief strenuous exercise, do not experience a "second-wind" phenomenon (switch to utilization of fatty acids), and may not feel premonitory symptoms. Exercise is a relevant trigger in 90% of patients (14; 34). Another frequent trigger is fasting or low nutritional intake. Sometimes infections, cold temperatures, and even emotional stress can trigger attacks (14; 34). Often, attacks were induced by a combination of triggers (eg, extensive skiing in the cold without appropriate food intake). Moreover, there are reports that attacks can be triggered by drugs like ibuprofen (54), high doses of diazepam (02), valproate (40), or by general anesthesia (38). Sometimes, however, there is no apparent cause for the rhabdomyolysis.
The first episode usually occurs in childhood or adolescence but not in infancy. In approximately 50% of the patients, the first attack occurred in childhood (34); thus, the term “adult” carnitine palmitoyltransferase II deficiency for the muscle form in contrast to “infantile” carnitine palmitoyltransferase II deficiency for the multisystemic form can be misleading.
A male predominance (68% to 86%) was reported in several studies (78; 07; 43; 14; 34). But it remains unknown if this is due to gender-related differences in exercise activities, a modifier gene on the X chromosome, or hormonal factors, such as estrogen, that seem to be a regulator of carnitine palmitoyltransferase (72).
Multisystemic infantile form (OMIM 600649). This less common form of carnitine palmitoyltransferase II deficiency is sometimes referred to as the "hepato-cardio-muscular" form. It is characterized by recurrent attacks of acute liver failure with hypoketotic hypoglycemia and cardiac arrhythmias. Age of onset ranges from 3 months to 2 years. Parental consanguinity is often observed. Frequently, there is a family history of unexpected death in infants following a Reye-like episode. Carnitine palmitoyltransferase II deficiency was also diagnosed postmortem in patients with sudden infant death (76). The disease always manifests with lethargy and encephalopathy as consequences of hypoketotic hypoglycemia. As is usually observed in this group of disorders, fasting and febrile infection are trigger factors. Hepatomegaly is always present. Signs of cardiac involvement are found in most cases. Although cardiomyopathy is the usual expression of heart injury in other disorders of fatty-acid oxidation, patients with the infantile form of carnitine palmitoyltransferase II deficiency characteristically exhibit dysrhythmias with or without cardiomegaly. Skeletal-muscle involvement is usually restricted to a mild increase in serum creatine kinase levels and can be demonstrated by histological examination. Muscle tone may be reduced, and patients may suffer of muscle weakness. However, rhabdomyolysis and myoglobinuria are rarely observed (11; 46; 07; 08).
Lethal neonatal form (OMIM 608836). This is the most severe form of carnitine palmitoyltransferase II deficiency. It is commonly associated with congenital anomalies. Affected neonates present at birth with profound metabolic decompensation characterized by hypoketotic hypoglycemia, hyperammonemia, metabolic acidosis, respiratory distress, hepatomegaly, and cardiomegaly. Cardiac resuscitation is often required. Hypotonia and hyperreflexia, as well as generalized seizures, may develop. There appears to be no variability within families, as affected siblings exhibit the same clinical phenotype and pathologic changes. Most patients die during the first month of life because of the occurrence of hepatic and renal failure, cardiac arrhythmias, and infection. Hepatic steatosis is a constant feature (08). Brain abnormalities (polymicrogyria and hemorrhages) and dysmorphic features are common, and enlarged kidneys with bilateral multiple congenital cysts, which have been described in all but 1 case (31; 04), are a distinctive finding in this disorder.
Muscle form. The muscle form of carnitine palmitoyltransferase II deficiency is usually a benign disease with a favorable evolution. Except for during episodes of myoglobinuria, muscle strength and serum creatine kinase level are normal. Patients usually have an excellent long-term prognosis. In many cases, after the diagnosis is made, attacks can be effectively prevented by dietary regimen and extra carbohydrate intake during prolonged exercise or other situations that can provoke rhabdomyolysis. Acute tubular necrosis, as a result of massive myoglobinuria, is the only life-threatening complication. Although renal failure has been documented in approximately 20% of patients, if it is promptly recognized and appropriately treated, a complete recovery should be expected in virtually all cases. Cardiac arrest can occur during an attack, and a single case has been reported with a fatal outcome (39).
Multisystemic form. The clinical course is not benign because of the occurrence of life-threatening cardiac dysrhythmias and the neurologic sequelae of hypoglycemic episodes, such as severe static encephalopathy with spastic paraplegia or psychomotor developmental delay (64; 23). There are several reports of sudden death (11; 03). However, patients with survival up to 20 years were also reported (44; 08).
Lethal neonatal form. The prognosis is severe due to infections and cardiac and renal complications. There is no patient known who survived longer than 1 month.
A 25-year-old man reported that he developed muscle pain and weakness after exercise beginning at age 19. At age 23 he was hospitalized for the first time because of severe muscle weakness and muscle pain after playing football. There was severe rhabdomyolysis that required dialysis. Four months later, he developed identical symptoms during an upper respiratory illness and, at age 24, after practicing sports excessively. Neither his parents nor other family members exhibited similar symptoms. Neurologic examination between the attacks was normal. During all episodes, creatine kinase was elevated (up to 42,000 IU/l) but returned to normal after the attack. Histological analysis of a muscle biopsy was normal, but biochemical analysis of the biopsy and molecular genetic investigation revealed carnitine palmitoyltransferase II deficiency (13).
Carnitine palmitoyltransferase II deficiency is an autosomal recessive inherited disorder of lipid metabolism. Mutations in the carnitine palmitoyltransferase II gene result in a defective carnitine palmitoyltransferase II enzyme (EC 188.8.131.52). This enzyme is part of the carnitine shuttle system that is responsible for the transport of long-chain fatty-acids into mitochondria. Thus, beta-oxidation of long-chain fatty-acids is altered in carnitine palmitoyltransferase II deficiency.
Biochemical basis. In contrast to short-chain and medium-chain fatty-acid esters (acyl-CoAs), long-chain acyl-CoAs (C14 to C20) cannot enter mitochondria directly. As the inner mitochondrial membrane is impermeable to long-chain acyl-CoAs, but not to their carnitine esters, a long-chain acyl-CoA must be transesterified by carnitine palmitoyltransferase I to form a long-chain fatty acylcarnitine. Carnitine and acylcarnitine translocase then carry the acylcarnitine across the barrier of the inner mitochondrial membrane in exchange for free carnitine. Finally, on the matrix side of the inner mitochondrial membrane, a second transesterification reaction catalyzed by carnitine palmitoyltransferase II generates matrix long-chain acyl-CoAs that enter the mitochondrial beta-oxidation. Carnitine palmitoyltransferase I is located on the inner side of the outer mitochondrial membrane, is specifically inhibited by malonyl-CoA, and loses activity on exposure of mitochondria to strong detergents. By contrast, carnitine palmitoyltransferase II is located on the inner mitochondrial membrane, is insensitive to malonyl-CoA inhibition, and is released in active form on exposure of mitochondria to a variety of detergents (45; 75). The crystal structure of rat carnitine palmitoyltransferase II was investigated, and the substrate binding site and membrane association domain have been described (55).
Mitochondrial beta-oxidation of long-chain fatty acid is a major source for energy production particularly at times of stress or fasting. Long-chain fatty acid oxidation contributes to energy homeostasis especially in the heart, the liver, and the skeletal muscle. In the liver, oxidation of long-chain fatty acids produces ketone bodies (which provide auxiliary fuel for nonhepatic tissues) and enhances gluconeogenesis. Therefore, hepatic fatty acid oxidation contributes to energy homeostasis during fasting. Skeletal muscle can use carbohydrates or lipids as fuel, depending on the degree of activity. During the early phase of exercise (up to approximately 45 minutes), energy is derived mainly from blood glucose and muscle glycogen metabolism. During prolonged exercise, there is a gradual shift from glucose to fatty-acid utilization. After a few hours of exercise, about 70% of the skeletal-muscle energy requirement is met by the oxidation of long-chain fatty acids.
Carnitine palmitoyltransferase II deficiency makes long-chain fatty acids unavailable for use by the mitochondria. The vulnerability of muscle to the metabolic block depends on the activity level of the muscle. When patients with carnitine palmitoyltransferase II deficiency exercise for prolonged periods, glycogen stores may be exhausted, and rhabdomyolysis may occur. In patients with the muscle form of carnitine palmitoyltransferase II deficiency, oxidation of long-chain fatty acids was normal at rest but impaired during prolonged exercise (48). Fasting worsens the situation because it reduces the availability of both muscle glycogen and blood glucose, further increasing the dependence of muscle on fatty-acid metabolism. In some cases, reduced hepatic production of ketone bodies deprives muscle of another alternative fuel. Reduced availability of alternative energy sources and/or increased dependence on lipid oxidation may predispose to metabolic crises. Thus, cold exposure may be deleterious because of impaired ketogenesis (which, in unaffected individuals, is stimulated by exposures to low temperatures) and shivering, which is an involuntary form of muscle activity particularly dependent on long-chain fatty acid oxidation. Infection probably acts by inducing an abnormally increased dependence on lipid metabolism. The biochemical pathogenesis of myoglobinuria might be explained by the inability to utilize fatty acids as an alternative energy source for the production of the ATP needed to maintain sarcolemmal integrity.
Other symptoms observed in the more severe early-onset forms may be explained by defective energy production. Hypoglycemia, characteristically accompanied by hypoketosis that occurs in affected individuals during fasting, can be caused by (1) an increase in peripheral glucose utilization because of the deficient production of ketone bodies and (2) impaired acetyl-CoA synthesis that typically stimulates gluconeogenesis via allosteric activation of pyruvate carboxylase. Possible pathogenetic mechanisms for the development of cardiomyopathy and sudden death in patients with early-onset carnitine palmitoyltransferase II deficiency include both inadequate energy supply in the heart and myocardial damage and arrhythmogenesis due to the toxic effects of elevated intracellular concentration of acylcarnitines. Long-chain acylcarnitines, which are known to cause myocardial injury and rhythm disturbances during myocardial ischemia and infarction, are thought to promote arrhythmogenesis via direct activation of Ca2+ channels (47). Association of congenital anomalies with prenatal energy deprivation is observed in a number of inborn errors of metabolism (eg, multiple acyl-CoA dehydrogenase deficiency, fumarase deficiency).
The distinct metabolic and clinical consequences of carnitine palmitoyltransferase II deficiency observed in the early-onset multisystemic and late-onset muscle forms of the disease might depend in part on the magnitude of carnitine palmitoyltransferase II residual activity (11). As a matter of fact, a nonlinear relationship between carnitine palmitoyltransferase II activity and long-chain fatty acid oxidation has been observed in fibroblasts. As compared with controls, a residual activity lower than 10% found in the early-onset cases resulted in a greater than 90% decrease of palmitate oxidation, whereas a residual activity higher than 15% found in the adult-onset cases maintained palmitate oxidation above 50%. Nothing is known concerning the level of carnitine palmitoyltransferase II activity necessary to maintain normal long-chain fatty acid oxidation in tissues other than fibroblasts, namely the liver, heart, and skeletal muscle. This threshold activity could vary among tissues. Thus, the residual carnitine palmitoyltransferase II activity found in the adult-onset form of the disease would be rate-limiting for long-chain fatty acid oxidation only in skeletal muscle. Carnitine palmitoyltransferase II activity that is reduced more, as in the early-onset forms of the disease, impairs long-chain fatty acid oxidation not only in skeletal muscle but also in heart, liver, and kidney. This may account for the multiorgan involvement in the neonatal form of the disease.
Molecular genetic basis. The human carnitine palmitoyltransferase II gene contains 5 exons that span approximately 20 kilobases of DNA in chromosome 1p32 (27). More than 75 disease-causing mutations have been identified to date (24; 37). Some mutations are recurrent, but most are identified only in single patients. Missense mutations and truncating mutations in all exons and some splice-site mutations have been identified (13; 57). Important clues for genotype-phenotype correlations in carnitine palmitoyltransferase II deficiency exist. For example, less severe missense mutations are associated with the muscle form of the disease, and some “severe” mutations are associated with the multisystemic infantile or lethal neonatal form if they are present in homozygous state. However, the correlation is not perfect because 1 mutation (p.R631C) has been identified in the multisystemic infantile form and in the muscle form in homozygous state (07).The lethal neonatal form is frequently associated with truncating mutations on both alleles (22; 71; 57). Compound heterozygosity for a “mild” and a “severe” mutation can be associated either with the relatively mild muscle form or with the severe multisystemic infantile form (Bonnenfont et al 1999; 71). Finally, symptomatic individuals with only a single mutation in the gene have been reported, and these mutations likely have a dominant negative effect on the enzyme (60; 48; 51; 33; 24; 35). Biochemical investigations in these individuals revealed intermediate activities (35), and in-vivo oxidation of long-chain fatty acids was impaired (48).
In Caucasian patients with the muscle form, a common mutation (p.S113L) is identified in 60% to 70% of mutant alleles (62; 14). This mutation was never observed in patients with the multisystemic or lethal form. The p.P50H and c.1238delAG mutations are less frequent mutations associated with muscle carnitine palmitoyltransferase II deficiency but are not private mutations. The p.P50H mutation, which is also associated mainly with the muscle form, was found in 5% of the alleles (60; 66; 14; 34). The c.1238delAG mutation that was found in a frequency of 20% of mutant alleles in an American study on 10 patients (60) was found only in 4% of the alleles in German patients (14; 34). This mutation is known to be of Ashkenazi Jewish origin (60), and this might explain why it was found more frequently in that American study. The c.1238delAG mutation was found in a homozygous state in 2 siblings with a lethal neonatal form (22). In contrast to the muscle form, there is no common mutation in the lethal neonatal or multisystemic infantile form. In Japan there is distinct frequent mutation p.F383Y in patients with carnitine palmitoyltransferase II deficiency (77). Three polymorphisms are known in the carnitine palmitoyltransferase gene that do not cause the disease but might influence enzyme activity (08).
Several hundred patients with the muscle form of carnitine palmitoyltransferase II deficiency have been reported worldwide (08; 14; 33; 24; 34). This makes carnitine palmitoyltransferase II deficiency the most common inherited disorder of lipid metabolism affecting skeletal muscle as well as the most frequent cause of hereditary myoglobinuria worldwide (65; 68). The severe multisystemic infantile and lethal neonatal forms are much rarer, and both forms were reported in about 15 patients each in 2004 (08). Accurate figures about the incidence are not available but can be estimated from data on newborn screening of carnitine palmitoyltransferase II deficiency. However, frequency will be underestimated because patients can be missed, eg, with the muscle form (32; 21; 61). In patients with the muscle form abnormal acyl-carnitine profiles are seen in plasma/serum reliably but not in dried blood spots that are used in newborn screening (12). In Germany the frequency of the disease in neonatal screening was calculated at 1 in 231,714 (42) and in Japan a similar frequency was observed (1:248,627) (61).
This disease cannot be prevented. However, appropriate prophylactic management (see Management section of this article) and acute care treatments can prevent significant morbidity and mortality.
The differential diagnosis of the muscle form of carnitine palmitoyltransferase II deficiency is mainly that of myoglobinuria and exercise-induced myalgia. Although recurrent myoglobinuria is a characteristic of a number of inherited metabolic myopathies (65; 68), it is also a symptom common to several different disorders including strenuous exercise, chronic alcoholism, toxic agents (especially drugs such as statins or fibrates), infections, trauma, and other genetic diseases, such as muscular dystrophy or malignant hyperthermia.
Carnitine palmitoyltransferase II deficiency is the most common identifiable metabolic cause of myoglobinuria, followed by myophosphorylase deficiency (glycogenosis type V) (68). Some other rarer defects of glycogen metabolism can cause “pure” myoglobinuria also. Other fatty acid oxidation disorders are important to consider in the differential diagnosis. For example, symptoms of very-long-chain acyl-CoA dehydrogenase deficiency are similar to those of carnitine palmitoyltransferase II deficiency. Also, mutations in the ryanodine receptor 1 gene can result in exercise-induced rhabdomyolysis. Finally, there are several patients with mitochondrial disorders due to mutations in mitochondrial DNA and patients with treatable coenzyme Q deficiency who have presented with myoglobinuria.
The differential diagnosis of multisystemic carnitine palmitoyltransferase II deficiency primarily includes other genetic defects of fatty-acid oxidation. Many of these defects are similar, presenting with hypoketotic hypoglycemia and heart and skeletal-muscle involvement: Deficiency of carnitine, carnitine and acylcarnitine translocase, trifunctional protein, very long-chain and long-chain acyl-CoA dehydrogenases, short-chain 3-hydroxyacyl-CoA dehydrogenase, and multiple acyl-CoA dehydrogenase deficiency. Characteristically, cardiomyopathy and myopathy are never observed in carnitine palmitoyltransferase I deficiency and medium-chain acyl-CoA dehydrogenase deficiency. Other multisystemic mitochondrial disorders affecting oxidative phosphorylation or the Krebs cycle (eg, fumarase deficiency) have to be considered as well.
In many cases, a correct diagnosis will be made only if carnitine palmitoyltransferase II deficiency is specifically considered and appropriate tests are obtained.
Muscle form. Except during episodes of myoglobinuria, serum creatine kinase levels are usually normal. During acute episodes of rhabdomyolysis, laboratory findings are dominated by elevated urinary excretion of myoglobin and a significant increase in serum creatine kinase. There is no hypoglycemia, and ketonemia and ketonuria are appropriate.
Following attacks, serum creatine kinase levels usually return to normal by several weeks. Between attacks, routine laboratory tests are usually within normal limits and do not contribute to the diagnosis, except for elevated plasma triglyceride and cholesterol concentrations observed in some patients. Prolonged fasting at rest may result in delayed and reduced ketone body production or increased serum creatine kinase. EMG is sometimes described as generically "myopathic." MRI of muscles is normal or shows a mild increase of signal intensity in T1-weighted images (15). Biopsies taken shortly after an episode may show necrotic and regenerating fibers. Between exacerbations, muscle biopsies are normal in half of the patients and show nonspecific myopathic changes, such as slight lipid accumulation, in the other half (14).
During the symptom-free interval, tandem mass spectrometry of serum samples can frequently identify indirect evidence of carnitine palmitoyltransferase II deficiency by detecting an elevated ratio of C16 + C18:1/C2 (28; 14). Fatty acid oxidation studies in cultured fibroblast after incubation with palmitate can show elevation of C16/C2 ratio (13).
Despite the predominant muscular symptomatology, the enzyme deficiency can also be detected in fibroblasts and leukocytes. It was shown that residual activity in blood leukocytes was similar to muscle activity (08). Many laboratories prefer measurement in muscle; however, significantly different results have been obtained in normal and affected tissues, primarily related to the use of different assay conditions for measuring enzyme activity. When carnitine palmitoyltransferase is measured using the “forward assay” in muscle homogenate with optimal assay conditions, the measured activity includes both carnitine palmitoyltransferase I and II. Under these conditions, patients exhibit entirely normal total carnitine palmitoyltransferase activities. However, the enzyme activity of patients with muscle carnitine palmitoyltransferase II deficiency is abnormally inhibited in the presence of malonyl-coA, palmitoylcarnitine, and detergents such as Triton X-100 (73; 14). Thus, carnitine palmitoyltransferase II activity is not abolished in patients with muscle carnitine palmitoyltransferase II deficiency, but regulation of the enzyme is abnormal. This is consistent with a study showing that fatty acid oxidation in patients with the muscle form of carnitine palmitoyltransferase II deficiency is normal at rest, but impaired during exercise, and a study showing the normal protein content of carnitine palmitoyltransferase II in muscle (48; 41).
In patients with the muscle form of carnitine palmitoyltransferase II deficiency, rapid molecular genetic testing is possible because a common mutation p.S113L is found on 60% to 70% of mutant alleles (62; 14). This mutation was detected in 22 of 23 index cases (96%) on at least on 1 allele in German patients (14). p.P50H and c.1238delAG are less common mutations that could be tested before sequencing of the gene is performed.
Multisystemic infantile and neonatal forms. In multisystemic carnitine palmitoyltransferase II deficiency, routine laboratory tests usually show evidence of hepatic insufficiency, hypoglycemia with low insulin levels and absent ketonemia or ketonuria, mild hyperammonemia, mild hyperlactacidemia, increased serum aspartate and alanine aminotransferases, elevated plasma free-fatty-acid concentrations, and prolonged prothrombin and partial thromboplastin times. Metabolic acidosis is often present, and serum creatine kinase may be elevated. Plasma and tissue levels of total carnitine are usually lowered (secondary carnitine deficiency) (08).
ECG and echocardiography can demonstrate the presence of dysrhythmias and dilated cardiomyopathy. Ultrasound analysis of the kidneys may reveal the presence of bilateral renal cysts, usually observed in neonatal-onset cases. Brain MRI studies may reveal malformations and other brain abnormalities, and MR spectroscopy may detect cerebral lipid accumulation (25).
Long-chain triglyceride loading fails to enhance ketogenesis and fasting shows a decline of blood glucose and low plasma ketone body values. A loading test with long-chain triglycerides (sunflower oil) given orally at the dose of 1.5 g/kg is safe, whereas a fasting test is potentially harmful and should be undertaken only in an intensive care unit under the close supervision of a trained specialist after the insertion of an intravenous line to permit immediate access for therapeutic quantities of glucose.
Tandem mass spectrometry is a rapid test to achieve indirect evidence of carnitine palmitoyltransferase II deficiency. It should be carried out in serum samples but can also be performed on dried blood spots (Guthrie cards) with lower sensitivity (01; 32; 12; 21; 61). Characteristically an elevated ratio of C16 + C18:1 is identified in patients with carnitine palmitoyltransferase II deficiency (01; 28). Palmitate oxidation in cultured fibroblasts is usually reduced to 10% to 20% of normal values but can be as low as 2% of control in the neonatal form.
Diagnosis is ultimately made by demonstrating the enzyme defect in the patients' tissue. In principle, all tissues can be examined. In fibroblasts, carnitine palmitoyltransferase II activity ranges from 5% to 15% of normal, the lowest values being observed in neonatal-onset patients. In contrast to the muscle form, molecular genetic testing requires sequencing of the CPT II gene because there is no common mutation.
Prenatal demonstration of carnitine palmitoyltransferase II deficiency is possible by measurement of impaired long-chain fatty acid oxidation and low carnitine palmitoyltransferase II activity in cultured amniocytes and sampled chorionic villi (69). In some families with the neonatal-onset form of the disease, fetal ultrasonography demonstrated renal abnormalities (eg, cyst) and brain abnormalities (eg, ventriculomegaly) (74; 22). If both mutant alleles are known in the family, DNA extracted from fetal cells obtained by amniocentesis or chorionic villus sampling can be used for molecular genetic prenatal testing.
Muscle form. To minimize the chances of developing acute tubular necrosis during acute episodes of myoglobinuria, patients should be promptly hydrated with forced diuresis.
Effective prevention of attacks may be accomplished by instituting a high-carbohydrate, low-fat diet with frequent and regularly scheduled meals, by avoiding the known precipitating factors (fasting, cold, prolonged exercise), and by increasing slow-release carbohydrate intake during intercurrent illness or sustained exercise. It was shown that ingestion of polysaccharides and glucose infusions can improve exercise intolerance but not oral glucose ingestion (49). Drugs that can trigger attacks such a valproate, diazepam, or ibuprofen should be avoided.
Studies with small sample sizes document some progress in finding effective treatment for carnitine palmitoyltransferase II deficiency. A small study with 7 patients suffering from muscle carnitine palmitoyltransferase II deficiency investigated an anaplerotic diet with triheptanoin (triglyceride containing the odd-chain fatty acid C7). Patients no longer suffered recurrent attacks with rhabdomyolysis requiring hospitalization and returned to a normal lifestyle during treatment (53). A study in 32 patients with long-chain fatty acid oxidation disorders (including 10 patients with carnitine palmitoyltransferase II deficiency, mainly muscle form) showed improvement of cardiomyopathy (30). However, cardiomyopathy is not a typical sign of muscle carnitine palmitoyltransferase II deficiency.
In-vitro studies have shown that bezafibrate (known as a lipid-lowering drug) treatment of fibroblasts and myoblasts from patients with muscle carnitine palmitoyltransferase II deficiency can improve the biochemical defect by stimulating the expression of the mutated gene (19; 18). A pilot trial with bezafibrate treatment for 6 months in 6 patients with the muscle form of the disease showed an increase in the oxidation of palmitoyl-carnitine in muscle, an improvement of general health, and a decrease of muscle pain (06). Clinical benefits persisted in a follow up study of 3 years (05). No side effects were observed. This is particularly important because bezafibrate itself can induce rhabdomyolysis. However, a 3-month, randomized, double-blind, crossover study of bezafibrate in patients with muscle carnitine palmitoyltransferase II deficiency did not improve fatty acid oxidation or heart rate during exercise, indicating that bezafibrate has no meaningful effects in vivo (50). Thus, a general recommendation for treatment cannot be given.
Multisystemic infantile and neonatal forms. Experience in treating these forms is limited. It seems, however, that restriction of dietary long-chain fat is of primary importance because of the toxic effects of long-chain acylcarnitines that accumulate as a consequence of the metabolic block. In general, fasting has to be avoided, and patients should be given a diet high in carbohydrate and low in long-chain fat. Supplementation with medium-chain triglycerides can be considered (59). Episodes of hypoglycemia, especially when associated with intercurrent illness, require admission to the hospital and immediate intervention with parenteral glucose. In 1 neonatal case, glucose and insulin infusions resulted in spectacular clinical improvement (08).
There is a paucity of information concerning pregnant women with the muscle form of carnitine palmitoyltransferase deficiency. Increased frequency of attacks of rhabdomyolysis during pregnancy has been reported, suggesting that hormonal factors may also have precipitating effects (78). In other reports, pregnancy did not appear to be particularly affected by the disease (20; 52). But exercise during delivery might be a potential trigger factor for attacks of rhabdomyolysis. Glucose infusions during delivery were recommended (52), and vaginal delivery without any complication is possible (56).
Muscle form. Neuromuscular diseases raise a lot of anesthesia-related problems, as many drugs used in anesthesia have an effect on muscle function. It was shown that inhibition of carnitine palmitoyltransferase by malonyl-CoA in human muscle is influenced by general anesthesia (79). Many patients with carnitine palmitoyltransferase II deficiency underwent anesthesia without any problems, but 3 cases with complications have been published. In 2 patients, malignant hyperthermia occurred (38; 70), and in another case, the individual developed postoperative myoglobinuria with acute renal failure (38). All patients recovered completely. Thus, hypoglycemia, cold, and depolarizing muscle relaxants should be avoided, and careful monitoring is necessary (including creatine kinase level).
Multisystemic infantile and neonatal forms. No information is available.
Marcus Deschauer MD
Dr. Deschauer of Technical University of Munich received honorariums from Genzyme for consulting work, honorariums from Destin and Genzyme for speaking engagements, and travel expenses from Biogen for congress participationSee Profile
Darryl De Vivo MD
Dr. De Vivo of Columbia University has no relevant financial relationships to disclose.See Profile
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