SAN FRANCISCO—An athletic 19-year-old male has an episode of rhabdomyolysis, a breakdown of muscle tissue that leads to contents of muscle fiber in the blood, after weight-lifting and basketball drills. But his labs come back normal.
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Explore This IssueMarch 2016
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He cuts down on his exercise, but has a second episode four months later, then finally sees a rheumatologist seven months after the first problems arose.
He has at-rest creatinine kinase levels ranging from the upper level of normal to more than triple that amount. In a forearm ischemic exercise test (FIET)—a test of the body’s metabolic processes when under relative anaerobic conditions—he shows a normal rise in lactate, but a suboptimal rise in ammonia.
“I know what you’re thinking, and maybe even feeling,” said Kenneth O’Rourke, MD, professor of medicine in the Section on Rheumatology and Immunology at Wake Forest School of Medicine, in a talk on metabolic myopathies during the 2015 ACR/ARHP Annual Meeting. “When this kind of patient presents to the adult rheumatologist in the office with all of these funny lab tests, I think it’s very common that all of us experience some degree of baseline fear.
“The fear, I think, is not unexpected—these are really uncommon diseases,” he added. “Many of them are congenital or seen in pediatrics.” Plus, he said, much of the research on them is not found in the typical rheumatology literature, but in neurology and genetics literature.
But with a little baseline knowledge and a little guidance on what to look for, Dr. O’Rourke said, clinicians can more easily identify metabolic myopathies—genetic disorders involving impaired production of adenosine triphosphate (ATP), the chemical energy currency within cells. Symptoms generally appear symmetrically in the limb-girdle areas, but there are variations, he said.
When a patient comes into the office complaining of muscle problems, the tendency is often to look for inflammatory myositis—including fixed proximal weakness, rash and inflammatory changes on electromyography.
But it’s important to look for clues that indicate that it might not be myositis, Dr. O’Rourke said: weakness tied to exercise, cramping, weakness of an episodic nature, muscle hypertrophy, myotonia and—the main hallmark—no improvement with immunosuppressants.
One mimic is muscle channelopathy. Muscle channelopathies are marked by, among other things, myotonia, or episodic paralysis and weakness. The most common of these is hypokalemic periodic paralysis 1—of the muscle channelopathies, the one most likely to be associated with fixed weakness, as well as attacks that last hours or days, and has an onset when people are in their 20s.
Other mimics are the muscular dystrophies, a diverse group of inherited disorders of muscle sarcolemmal proteins with dystrophic changes seen on muscle biopsy, usually marked by progressive muscle weakness. The gold standard for diagnosis is identifying the genetic defect.
Energy Source for Muscle Metabolism
Then, Dr. O’Rourke said, there are metabolic myopathies, and to properly identify and treat these, clinicians need to understand how muscles get their energy.
“You have to have some basic understanding of the biochemistry in order to ask the right clinical questions, as well as to order the right testing to get to the right answer,” he said.
He used the analogy of a hybrid car, with its starter motor for cold starts; gas engine for rapid, mass acceleration but its problems of inefficiency, limited energy capacity and pollution; electric motor for cruising and idling, which is efficient but has limited immediate power; and the transmission, which integrates the power from both of those engines to get the wheels to turn.
When you first contract a muscle, there is a creatinine kinase (CK) reaction, which produces a very limited amount of stored ATP. This is like the muscle’s starter motor.
“The CK reaction allows you a few extra seconds to create additional ATP to get things going before glycolysis takes over,” Dr. O’Rourke said.
And instead of gasoline, there’s glycogen, which is limited and pollutes, in the absence of sufficient oxygen, in the form of lactic acid. Through glycolysis, glucose is converted into pyruvate, which in the presence of adequate oxygenation is then further metabolized in the Krebs cycle.
The transmission is the electronic transport chain (ETC) that leads to the production of ATP. And the electric motor is essentially the oxidation of fats into pieces that can be used by the ETC to make ATP.
Dr. O’Rourke suggested two pattern-recognition stages that can be helpful in getting to a diagnosis.
In the first, clinicians should ask a series of questions about symptoms, how long symptoms last, family history, what brings about the muscle fatigue, whether there are associated systemic problems and how the weakness is distributed.
In metabolic myopathies, weakness typically stems from exertion or an infection or from eating or fasting, and is episodic. Because the majority of these diseases are mainly autosomal recessive, there may be no known family history.
The other recognition stage, he said, is assessing for changes on either side of the clog or metabolic block. In these disorders, because there is a breakdown in metabolic processing, levels of whatever is not being processed properly should be higher than normal on one side of the clog, and the product of that process should be lower than normal on the other.
In metabolic myopathies defects of glycogenolysis or glycolysis type, glycogen is accumulated upstream, and a lack of lactate rise (on forearm exercise testing) is seen downstream. In disorders of lipid metabolism, there is an increased free fatty acid to ketone ratio upstream, and recurrent hypoketotic hypoglycemia is seen downstream. And in mitochondrial myopathies, elevated serum lactate or lactate to pyruvate ratio is sometimes seen upstream, while mitochondrial proliferation and impaired extraction of oxygen from the blood, manifested by an exaggerated cardiopulmonary response to exercise, are seen downstream.
The most common form of glycogenolytic disorder, McArdle’s disease, has the hallmarks of chronic CK elevation even at rest, and the experience of a second wind about six to eight minutes into moderate aerobic exercise.
In lipid disorders, weakness is seen after long exercise or fasting without cramping or a second wind phenomenon.
Mitochondrial myopathies are marked by exercise intolerance, with extreme fatigue and shortness of breath even at relatively low levels of exertion.
Treatment generally involves changes in physical activity, adjusting diet and dietary supplements. It’s important to keep physical therapy in mind, Dr. O’Rourke said, adding that “the key, however, [is] always balancing the need to avoid disease exacerbation, while at the same time you want to keep them active enough to inhibit disuse atrophy.”
Thomas R. Collins is a medical writer based in Florida.
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