MyopathyDz

Synonyms: Metabolic diseases of muscle, metabolic myopathies, statin-induced myopathy, drug-induced myopathy.

ICD-9 Codes: Myopathy, 359.9; alcoholic, 359.4; amyloid, 359.6; toxic, 359.4; Tarui disease, 271.2; deficiency of carnitine, 277.81; carnitine palmityl transferase, 791.3

ICD-10 Codes: G71 – G72; M60 – M63

Definition: Myopathy is a generalized term applied to a heterogeneous group of disorders that affect muscle. Inflammatory muscle disease is considered elsewhere. The differential diagnosis of weakness and myopathy is expansive and includes inflammatory, infiltrative, metabolic and disorders born of inborn errors (Table). The metabolic myopathies include disorders of skeletal muscle caused by alterations in biochemical pathways and divided into disorders of glycogenolysis, lipid metabolism, and mitochondrial myopathies.

Etiology: Most of these disorders have a genetic basis and show an autosomal recessive pattern of inheritance. Hypokalemic periodic paralysis is an autosomal dominant disorder. Mitochondrial myopathies show a maternal pattern of transmission because all mitochondrial DNA is derived from the mother. A small number of cases are acquired and are attributable to other underlying disorders such as cirrhosis, renal failure, metabolic disorders, or drugs.

Pathology: Light microscopic examination of the muscle biopsy specimen may demonstrate lipid deposition (shown on oil red O stain) in lipid storage myopathies. Mitochondrial abnormalities may also be seen on routine microscopic examination, and the presence of irregular, ragged red fibers suggests a mitochondrial disorder. On electron microscopic examination, increased collagen deposition may be observed in patients with glycogen storage diseases. However, biopsy specimens from some patients may appear normal.

Demographics: Most primary inherited cases become apparent in children and adolescents but may occur later in life.

Cardinal Findings: These disorders impair muscle function on demand and often manifest as fatigue, aches, cramps, and myalgia and may result in myoglobinuria, rhabdomyolysis, or fixed weakness in some. In most, symptoms only develop when muscular activity or nutritional defect unmasks the underlying defect. Most patients show muscle weakness. Some are able to perform normal daily activities without problems but become symptomatic at higher levels of exercise.  Clinical assessment should exclude central nervous system disorders or peripheral (denervation) neuropathy as the cause of muscle weakness or complaint.

Myopathy Subsets

DISORDERS OF GLYCOGENOLYSIS

—McArdle’s disease: Caused by a myophosphorylase deficiency (see Mcardle’s disease)
—Tarui’s disease: Caused by a phosphofructokinase deficiency, Tarui’s disease has features similar to those of McArdle’s disease, but there may also be nausea, vomiting, and a hemolytic anemia. Most patients are diagnosed as adults and may or may not recall exercise intolerance when younger. Patients with phosphofructokinase deficiency cannot utilize glucose, and thus high carbohydrate meals may exacerbate exercise intolerance.
—Acid maltase deficiency: An autosomal recessive disease with three phenotypes. It may manifest before 2 years of age as Pompe’s disease with infantile weakness, hypotonia, heart failure, and early death. A second variety begins in early childhood with truncal, proximal, and respiratory muscle weakness. Last, a milder adult subset may begin in the third or fourth decade, with muscle weakness and a pattern indistinguishable from polymyositis or limb- girdle muscular dystrophy. Acid maltase deficiency causes a vacuolar myopathy, and biochemical studies are necessary to prove the diagnosis.
—Others: Episodic myopathy may occur as a result of deficiency of lactate dehydrogenase, aldolase, B-enolase, phosphorylase b kinase, or phosphoglycerate mutase. Brancher enzyme deficiency causes chronic proximal myopathy in children or older adults. Debrancher enzyme deficiency causes distal, rather than proximal, myopathy in the third to fourth decade of life.
—Myoadenylate deaminase deficiency: Myoadenylate deaminase is a muscle- specific isoenzyme and is involved in the purine nucleotide cycle production of fumarate. It is characterized by exercise-related cramps in children and rarely leads to myoglobinuria. May be associated with delayed motor and speech development, hypotonia, or cardiomyopathy. Muscle enzymes are normal or high, but there is a lack of myoadenylate deaminase activity on histochemical staining of muscle. On ischemic forearm exercise testing, these patients are unable to generated an increase in serum ammonia levels.

DISORDERS OF LIPID METABOLISM

—Carnitine deficiency: Deficient transfer of long-chain free fatty acids to the mitochondria results from carnitine deficiency. Muscle weakness begins in childhood and may be associated with myalgias, proximal weakness, respiratory muscle weakness, cardiomyopathy, myoglobinuria, increased creatine phosphokinase, hypoketotic hypoglycemia, and increased lipid in muscle.
—Carnitine palmityltransferase deficiency: An autosomal recessive disorder, carnitine palmityltransferase deficiency typically affects males, with exercise intolerance, myalgias, cramps, stiffness, and myoglobinuria. Attacks are triggered by exercise or fasting. Creatine phosphokinase and ischemic exercise tests are usually normal. Diagnosis is based on biochemical analysis of enzyme activity in muscle. Some of these patients develop rhabdomyolysis and renal failure, which is reversible if appropriately treated.

MITOCHONDRIAL MYOPATHIES

Mitochondrial myopathies include a variety of disorders that result in alterations of mitochondria structure, number, or size. These may arise in children as limb myopathy, with or without ophthalmoplegia. Patients exhibit exercise intolerance, proximal or extraocular muscle weakness, myoclonus, salt craving, ataxia, sensorineural hearing loss, or peripheral neuropathy. Mitochondrial myopathies may arise in the adult as exercise intolerance, generalized or proximal weakness, and with normal or elevated creatine phosphokinase levels. Some may be acquired after exposure to mitochondrial toxins such as zidovudine or clofibrate.

STATIN MYOPATHY

Myopathy has been reported to occur with cerivastatin, lovastatin, and simvastatin much more commonly than with pravastatin or atorvastatin. Dose- dependent myotoxic effects (including myalgia, myositis, or rhabdomyolysis) of statins occurs in 1% to 7% of patients. A 2002 FDA review of statin safety suggested that the fatal rhabdomyolysis rate was 0.15 cases per every 106 prescriptions. Cerivastatin was removed from the market after 31 cases of fatal rhabdomyolysis and 52 deaths worldwide. Those at risk were on higher doses and took concomitant gemfibrozil. Other factors that may contribute to statin myopathy include age, renal insufficiency, biliary obstruction, preexisting myopathic disorders (e.g., hypothyroidism), and use of other myotoxic drugs or drugs that induce the cytochrome P-450 enzyme CYP3A4. Mechanisms are not fully delineated, but statins inhibit the formation of mevalonate and ultimately ubiquinone (coenzyme Q10). Ubiquinone deficiency may further inhibit mitochondrial adenosine 5′-triphosphate production and myocyte function. There is no evidence that ubiquinone supplementation will have any clinical benefit in these patients. Treatment hinges on early recognition and drug cessation when appropriate.

Diagnostic Tests: Serum potassium, magnesium, and creatine kinase should be measured. Some, but not all, metabolic myopathies are associated with elevated creatine phosphokinase levels; normal values do not exclude these disorders. Defects in the glycogenolytic pathway such as myophosphorylase deficiency may be detected with the forearm ischemic exercise test (absence of the normal increase in postexercise serum lactate levels is diagnostic). Myoglobin should be measured in urine if rhabdomyolysis is suspected.

Biopsy: A muscle biopsy may be required to establish the diagnosis. Some metabolic syndromes are associated with elevated levels of muscle enzymes, but many do not show any abnormality or have findings only during episodes of rhabdomyolysis; in these cases, measurement of enzymatic activities in the biopsy specimen is usually required. Special handling of tissues is necessary to achieve accurate enzymatic determinations, and consultation with the pathology laboratory that will perform the analysis is essential to ensure that the specimen is collected correctly. The amount of tissue required for enzymatic analysis necessitates an open, rather than a needle, biopsy.

Keys to Diagnosis: Muscle biopsy and measurement of muscle enzyme levels are usually required to establish the diagnosis in a patient with episodic or exercise-induced weakness or rhabdomyolysis. Secondary cases might be detected by routine blood and urine testing for metabolic imbalances.

Therapy: Specific treatments are not always required. However, because the patient may be advised to modify diet and exercise to minimize problems, establishing the diagnosis is very important. For example, patients with carnitine palmityltransferase deficiency should be advised to avoid fasting and strenuous exercise; carbohydrate loading before moderate exercise may be useful.

Carnitine deficiency may be treated by dietary supplements (as much as 4 g/day of carnitine), and anecdotal reports suggest the utility of L-carnitine, coenzyme Q10, or menadione in patients with mitochondrial myopathies.

Acute rhabdomyolysis, which may occur in some of these syndromes, constitutes a medical emergency, requiring aggressive hydration, mannitol (for urine dilution) and alkalinization of urine to avoid permanent renal damage.

Prognosis: Most patients can pursue normal daily activities and do not develop progressive problems. Precautions regarding diet and exercise are an important component of a successful outcome.

BIBLIOGRAPHY

Martin A, Haller RG, Barohn R. Metabolic myopathies. Curr Opin Rheumatol 1994;6:552–558.PMID:7865373

Rosenson RS. Current overview of statin-induced myopathy. Am J Med 2004;116:408–416.PMID:15006590

Wortmann RL, DiMauro S. Differentiating idiopathic inflammatory myopathies from metabolic myopathies. Rheum Dis Clin North Am2002;28:759–778.PMID:12506771