Myopathic carnitine deficiency (MCD) is a type of primary carnitine deficiency. It is a hereditary disorder that differs from systemic carnitine deficiency (SCD) in that low levels of carnitine occur in the muscles only, while plasma concentrations of carnitine are within physiological ranges. Symptoms are non-specific and comprise progressive muscle weakness, increased muscle fatigue, and myalgia. Cardiomyopathy is a rare but life-threatening complication of MCD, which usually follows a benign course. The diagnosis of MCD is based on clinical and histological findings, namely lipid storage in muscle cells. The underlying gene defect could not yet be identified and, in view of the phenotypic heterogeneity, may indeed vary between individual patients.
MCD is characterized by progressive muscle weakness due to lipid storage myopathy, primarily in type I muscle fibers . Symptom onset may occur during infancy but is often delayed until the second or third decade of life   . Isolated cases have been described of patients seeking medical attention in old age only  , but regardless of their age at first presentation, the majority of individuals with MCD has a longstanding history of minor, non-disabling muscle weakness  . They may describe predominantly proximal myalgia and muscular fatigability most pronounced during prolonged physical exercise . As the disease progresses, symptoms may become present at rest and increasingly interfere with everyday activities.
Hypertrophic cardiomyopathy is not a common feature but has been described repeatedly   . It may lead to congestive heart failure and premature death. These patients may present with generalized fatigue and weakness, decreased tolerance to exercise, dyspnea, and cough. They may or may not present any of the classical symptoms of MCD .
The following diagnostic criteria have been established for any type of primary carnitine deficiency :
Blood samples as well as liver and skeletal muscle biopsy specimens must be obtained to confirm the selective deficiency of carnitine in muscle tissues. In MCD, circulating carnitine levels are within physiological ranges, as is the carnitine content of hepatic tissue. Skeletal muscle carnitine contents are reduced to about 20% of the normal values  . Creatine kinase serum concentrations are generally increased. Beyond that, urine samples may be analyzed to determine the fractional renal excretion of carnitine. Renal wasting of carnitine is not a typical feature of MCD, but Vielhaber and colleagues described impaired renal reabsorption of carnitine in one of their patients .
Carnitine deficiency interferes with fatty acid catabolism by β-oxidation and results in an increased formation of triglycerides. Hence, the histological equivalent of MCD is that of a lipid storage myopathy with excess numbers of lipid droplets in muscle fibers predominately of type 1 at the light and electron microscopy level . Carnitine-dependency can be shown by the addition of carnitine to muscle homogenates : In the presence of carnitine, MCD muscle cells oxidize fatty acids at essentially the same rate as do those of healthy controls.
An exhaustive list of "other primary defects in fatty acid oxidation" that must be considered in the differential diagnosis of MCD cannot be provided. Such defects may affect the carnitine cycle or the β-oxidation cycle, which both rely on a number of enzymes: carnitine palmitoyl transferases I and II, carnitine-acylcarnitine translocase, acyl-CoA dehydrogenases that target fatty acids of varying chain length, 3-hydroxyacyl-CoA dehydrogenases, 3-ketoacyl-CoA thiolases, and 2,4-dienoyl-CoA reductase, to name but a few . While disorders of carnitine transport and the carnitine cycle have been reviewed by Longo et al. , the interested reader is referred to the comprehensive overview published by Moczulski and colleagues to learn more about genetic disorders of β-oxidation .
The dietary supplementation of carnitine has been shown to be beneficial  , although muscle carnitine stores cannot be replenished by the mere increase of oral carnitine intake. Here, carnitine deficiency is the consequence rather than the cause of the disease, and a greater supply of carnitine can have but little effect on the muscle carnitine content if the myocytes themselves are unable to take it up or to keep it.
The patient described by Engel and colleagues experienced clinical improvement under prednisone therapy . Histological abnormalities became less pronounced but could not be rectified. What's more, the mechanism by which lipid storage diminished under prednisone remains unknown. The authors speculated the drug to have exerted its effect via a compensatory mechanism that can reduce muscle lipid levels independent of carnitine transport. While similar observations have been made in other patients , treatment with prednisone could not prevent the fatal outcome in a later case of MCD with cardiomyopathy .
Some patients have been prescribed special diets based on medium-chain triglycerides, which may contribute to the recovery of strength in the affected muscles  .
MCD generally follows a benign course. The resolution of clinical symptoms seams feasible despite the fact that muscle carnitine levels cannot be restored to physiological values . Yet, the patients' response to carnitine supplementation varies largely and ranges from moderate improvement to the normalization of muscle strength . In the rare case of cardiac involvement, the prognosis seems to be less favorable, and a fatal outcome is possible .
Kerner and Hoppel explained that the distribution of carnitine in different tissues depends on a series of systems that transport carnitine into cells against a concentration gradient, that mediate its efflux, or facilitate an exchange mechanism . They hypothesized MDC to be caused by an increased loss of muscle carnitine via defective efflux carriers. Others proposed a tissue-specific defect of short-chain acyl-CoA dehydrogenase as the cause of lipid storage myopathy and limb weakness . To date, it remains unknown whether all patients who have been diagnosed with MCD suffered from the same disease or were carriers of distinct gene defects leading to phenotypically similar myopathies.
Although the underlying gene defect has yet to be determined, MCD is assumed to be inherited in an autosomal recessive pattern  . This hypothesis is based on the fact that intermediate levels of muscle carnitine were measured in the parents of some MCD patients, suggesting an allele-dose effect for the causal mutation.
MCD is a very rare disease. Since the initial description of MCD , about 100 cases with different forms of carnitine deficiency have been reported .
Carnitine is an essential cofactor for the transport of activated long-chain fatty acids from the cytosol to the mitochondrial matrix, where β-oxidation takes place. Dietary intake and endogenous synthesis are the main sources of carnitine, which is efficiently reabsorbed in the renal tubules so as to maintain adequate levels of circulating carnitine .
Regardless of the source, carnitine must actively be transported into muscle cells. Thus, low concentrations of carnitine in the muscles may be due to deficiencies in carnitine intake, biosynthesis, reabsorption in the kidneys, or systemic distribution, or may be caused by specific disorders of plasma-to-muscle carnitine transport . The former would be associated with low levels of circulating carnitine, while the latter is characterized by low muscle carnitine but physiological concentrations in the plasma and other tissues.
Gene defects interfering with carnitine biosynthesis have not yet been described. Generalized disorders of carnitine distribution and transmembrane transport, however, may occur and are associated with renal wasting of carnitine in patients with SCD. The selective deficiency of carnitine in muscle tissue is the hallmark of MCD.
Due to considerable knowledge gaps regarding the etiology and pathogenesis of MCD, no recommendations can be given to prevent the disease.
MCD is a rare type of myopathy. It is also referred to as muscle carnitine deficiency and has first been described by Engel and Angelini in 1973 . They wrote about a female patient in her early twenties who suffered from progressive muscle weakness. Histological studies revealed her muscle fibers to contain numerous lipid-filled vacuoles and led to the suspicion of a defect in the oxidative catabolism of fatty acids. This hypothesis could eventually be confirmed and related to low carnitine levels in the musculature. The molecular biological and genetic background of the disease has not been clarified, however.
This situation has not changed much until today. Some more cases have been reported during the 1970s  , but there are only anecdotal reports in the more recent literature. What's more, patients described so far cover a broad spectrum of phenotypes that ranges from the classical variant of sole skeletal muscle involvement to life-threatening cardiomyopathy, renal wasting of carnitine, and even peripheral neuropathy [Zhang], which blurs the distinction between MCD and SCD. The diagnosis of MCD has always been based on biochemical and histological abnormalities, but could never be associated with a precise cause. Thus, the correct classification of MCD remains unclear, and it may be doubted whether the same entity accounted for all cases reported to date.
Carnitine is derived from amino acids and required for the oxidation of fatty acids in mitochondria, the cell's supplier of energy. Humans cover their carnitine needs by diet and biosynthesis, and the compound is distributed throughout the body via systemic circulation. The uptake of carnitine by the cells is mediated by specific transporters, which account for it to finally reach the mitochondria. Accordingly, there are several circumstances that may result in cellular carnitine deficiency: a lack of carnitine intake, errors of carnitine biosynthesis or systemic distribution, or the unability of carnitine to cross cellular membranes, to name but a few.
If deficiencies in the cellular uptake of carnitine are limited to muscle cells, patients may experience progressive muscle weakness, increased muscular fatigability, and muscle pain, and they may be diagnosed with myopathic carnitine deficiency (MCD). There is no lack of carnitine supply or distribution, but a mere inability of muscle cells to capture carnitine from the plasma. This has diagnostic implications: In clinical practice, plasma levels of carnitine are commonly used to test for carnitine deficiency. These values, however, may not reflect tissue carnitine concentrations and are to be expected within the physiological range in patients with MCD. Muscle carnitine contents must be determined to confirm the suspicion of MCD. In affected individuals, they are decreased despite normal levels of plasma carnitine. Furthermore, skeletal muscle biopsies must be histologically examined for the presence of abnormal lipid storage. In the absence of carnitine, the oxidation of fatty acids is largely reduced, and lipids accumulate within muscle cells.
MCD is assumed to be a hereditary disorder, but the underlying gene defect could not yet be identified. Thus, the diagnosis of the disease is based on clinical, laboratory, and histological findings as described above. Carnitine supplementation is the mainstay of therapy, but patients respond differently to this type of treatment. Predisone and dietary adjustments may further contribute to the alleviation of symptoms, but the disease is currently not curable. In general, though, MCD follows a benign course.