Several well-known disorders affecting skeletal muscle either are not congenital or do not yet have any conspicuously useful laboratory test. Among these are disorders whose primary defect is located in the central nervous system or peripheral nervous system rather than in skeletal muscle itself. In this group are various neurologic diseases that secondarily result in symptoms of muscle weakness. The following discussion involves inherited muscle disorders. Some can be diagnosed in the first trimester of pregnancy by means of amniotic villus biopsy.

Muscular dystrophies. The muscular dystrophies can be divided into several subgroups. The most common is Duchenne’s (pseudohypertrophic) dystrophy. Duchenne’s muscular dystrophy and the closely related Becker’s muscular dystrophy is transmitted as a familial sex-linked recessive disorder in 60%-65% of cases and is said to be the most common lethal sex-linked genetic disease. As in all sex-linked genetic diseases, the X chromosome carriers the abnormal gene. In Duchenne’s dystrophy this gene controls production of dystrophin, a protein found in skeletal, cardiac, and smooth muscle at the muscle fiber outer membrane, where it apparently helps provide strength and elasticity to the muscle fiber. Although both males and females may have the defective gene, females rarely develop clinical symptoms. About one third of cases are sporadic gene mutations. The male patient is clinically normal for the first few months of life; symptoms develop most often between ages 1 and 6 years. The most frequent symptoms are lower extremity and pelvic muscle weakness. There is spotty but progressive muscle fiber dissolution, with excessive replacement by fat and fibrous tissue. The latter process leads to the most characteristic physical finding of the disease, pseudohypertrophy of the calf muscles.

Laboratory tests. Screening tests are based on the fact that certain enzymes are found in relatively high amounts in normal skeletal muscle. These include creatine phosphokinase, aldolase, aspartate aminotransferase (AST), and lactic dehydrogenase (LDH). Despite external pseudohypertrophy, the dystrophic muscles actually undergo individual fiber dissolution and loss of skeletal muscle substance, accompanied by release of muscle enzymes into the bloodstream. In many tissues AST, LDH, and aldolase are found together. Pulmonary infarction, myocardial infarction, and acute liver cell damage among other conditions cause elevated serum levels of these enzymes. Aldolase follows a pattern similar to AST in liver disease and to LDH otherwise. Creatine Kinase (previously creatine phosphokinase) or CK is found in significant concentration only in brain, heart muscle, and skeletal muscle.

The two most helpful tests in Duchenne’s muscular dystrophy are CK and aldolase assays. Aldolase and CK values are elevated very early in the disease, well before clinical symptoms become manifest, and the elevations usually are more than 10 times normal, at least for CK. This marked elevation persists as symptoms develop. Eventually, after replacement of muscle substance has become chronic and extensive, the aldolase level often becomes normal and the CK level may be either normal or only mildly elevated (less than 5 times normal). In the hereditary type of Duchenne’s dystrophy, most males with the abnormal gene have elevated CK values. In females with the abnormal gene, about 50%-60% have elevated CK. Aldolase values are much less frequently abnormal; AST and LDH values tend to parallel CK and aldolase values but at a much lower level. Therefore, other than CK, these enzymes are not of much use in detecting carriers. Even with CK, a normal result does not exclude carrier status.

The CK isoenzyme pattern in Duchenne’s dystrophy may show an increased MB isoenzyme as well as MM fraction, especially in the earlier phases of the illness.

In fascioscapulohumeral dystrophy and limbgirdle dystrophy, conditions that resemble Duchenne’s dystrophy in many respects, CK and aldolase levels are variable but frequently are normal.

Other muscular disorders in which the serum enzyme levels may be elevated are trauma, dermatomyositis, and polymyositis. The levels of elevation are said to be considerably below those seen in early cases of Duchenne’s dystrophy. Neurologic disease is usually not associated with elevated levels, even when there is marked secondary muscular atrophy.

Definitive diagnosis. Diagnosis of the muscular dystrophies may sometimes be made on the basis of the clinical picture and enzyme values. A more definitive diagnosis can be made with the addition of muscle biopsy. This becomes essential when the findings are not clear cut. The biceps or quadriceps muscles are the preferred biopsy location. The biopsy is best done at a pediatric or congenital disease research center where special studies (e.g., histochemical staining or electron microscopy) can be performed and the proper specimen secured for this purpose (these special studies provide additional information and are essential when biopsy results are atypical or yield unexpected findings). Biopsy specimens show greatly decreased dystrophin on assay or essentially absent dystrophin on tissue sections stained with antidystrophin antibody. In Becker’s dystrophy, dystrophin is present in tissue sections but considerably reduced. Another diagnostic method is DNA probe. About two thirds of Duchenne’s and Becker’s cases are due to partial deletion from the dystrophin gene. These cases can be diagnosed by standard DNA probe. The 35% without detectable deletion can be tested for with the restriction length polymorphism DNA probe method, which is less accurate than gene deletion DNA methods. Diagnosis in the first trimester of pregnancy can be done using DNA probe techniques on a chorionic villus biopsy specimen.

Malignant hyperpyrexia (MH) Malignant hyperpyrexia (MH) is a rare complication of anesthesia triggered by various conduction and inhalation agents (most commonly succinylcholine) that produces a marked increase in both aerobic and anaerobic skeletal muscle metabolism. This results in greatly increased production of carbon dioxide, lactic acid, and heat. Such overproduction, in turn, is clinically manifested by a marked increase in body temperature, tachycardia, muscle rigidity, tachypnea, and finally shock. The first clinical sign is said to be muscle rigidity, which occurs in about 70%-75% of patients. The next clinical evidence of developing MH is tachycardia or cardiac ventricular multifocal arrhythmias. A rise in temperature eventually occurs in nearly all patients (some cases have been reported without temperature elevation), first slowly and then rapidly. The characteristic temperature elevation may not be present in the early stages, or the initial elevation may be gradual. A defect in muscle cell membrane calcium release mechanism (“calcium channel”) has been postulated, leading to increased intracellular calcium. The majority of cases have been familial. There is frequent association with various hereditary muscle diseases, especially the muscular dystrophies.

Laboratory tests. Biochemical abnormalities include metabolic acidosis (markedly elevated lactic acid value) and respiratory acidosis (increased partial pressure of carbon dioxide [P CO2] due to muscle CO2 production). The anion gap is increased due to the lactic acid. In the early phases, venous P CO2 is markedly increased, whereas arterial P CO2 may be normal or only mildly increased (widening of the normal arteriovenous [AV] CO2 dissociation). The same accentuation of normal AV differences also occurs with the PO2 values. Later, arterial blood gas values also show increased PCO2, decreased pH, and decreased PO2. In addition to blood gas changes there typically is greatly increased CK levels (from muscle contraction), and myoglobin appears in the urine. In the later stages there may be hyperkalemia, hypernatremia, muscle edema, pulmonary edema, renal failure, disseminated intravascular coagulation, and shock. The serum calcium level may be normal or increased, but the ionized calcium level is increased.

Diagnosis. CK elevation without known cause has been proposed as a screening test; there is marked difference of opinion among investigators as to the usefulness of the procedure, either in screening for surgery or in family studies (literative reports vary from 0%-70% regarding the number of persons susceptible to develop MH that have elevated baseline total CK. About 30% may be a reasonable estimate. Also, elevated CK can be caused by a variety of conditions affecting muscle). Likewise, disagreement exists as to the CK isoenzyme associated with abnormality; BB has been reported by some, although the majority found MM to be responsible. However, CK assay is still the most widely used screening test. Muscle biopsy with special in vitro testing of muscle fiber sensitivity to such agents as caffeine and halothane (caffeine-halothane contractive test) is considered a definitive diagnostic procedure but is available only in a few research centers. Since the test should be performed less than 5 hours after the muscle biopsy, it is preferable (if possible) to have this biopsy performed at the institution that will do the test. Microscopic examination of muscle biopsy specimens shows only nonspecific abnormalities, most often described as compatible with myopathy.