Hereditary Myopathies

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75 Hereditary Myopathies

Hereditary muscle disorders are usually generalized muscle disorders that are progressive and are variously categorized as channelopathies, metabolic and mitochondrial myopathies, muscular dystrophies, and congenital myopathies (Table 75-1).


There are a few inherited skeletal muscle disorders that typically have an acute onset mimicking an acquired myopathy; this is especially so when there is no known family history. These disorders are primarily the various channelopathies or inborn errors of metabolism affecting either glycogen or lipid metabolism.

Periodic Paralysis and Congenital Myotonic Disorders

Clinical Vignette

A 52-year-old physician presented with increasing nonfluctuating weakness characterized by problems climbing stairs and more recently arising from low seats. In early adolescence, he had first experienced recurrent episodes of postexercise relatively severe proximal extremity weakness that interfered with his walking, especially stepping up and getting out of chairs as well as problems lifting his arms overhead and using his hands. At his worst, as an adolescent, he could not stand or raise his hands and arms over his head. He never had symptoms that implicated any cranial nerve or respiratory muscle dysfunction. Between these intermittent episodes of weakness he was totally asymptomatic, his clinical neuromuscular examination was normal, and he could play singles tennis.

These periods of exercise-induced weakness typically were precipitated by brief periods of rest. Most events resolved within 30–120 minutes; however, on rare occasions his weakness might last a few days. Acetazolamide, a carbonic anhydrase inhibitor, 250 mg three times daily, significantly diminished the frequency of these attacks and allowed him to play tennis regularly. As he reached middle age, this physician began to note more chronic symptomatology on a daily basis. This did not respond to various pharmacologic interventions. By this time, one of his two sons and a daughter were beginning to experience similar periodic spells of weakness.

Occasionally he also noted some hand stiffness as well as inability to open his eyelids immediately after squinting. This suggested a myotonic component, something that was later confirmed by electromyography (EMG). Myotonia is a nonspecific finding occurring with hyperkalemic periodic paralysis (HyperKPP), as well as various other channelopathies presenting with myotonic syndromes. DNA testing confirmed the diagnosis of a sodium channelopathy that typified the HyperKPP in this patient as well as his children.

Comment: This patient is a classic example of individuals having periodic paralysis; symptoms typically begin in mid-childhood. Although the use of a carbonic anhydrase inhibitor initially protected him from frequent attacks of weakness, as he reached his fifth and sixth decades he developed a fixed proximal weakness that limits his activities of daily living (ADL).

The various genetically determined hyperkalemic or hypokalemic channelopathies are phenotypically similar disorders related to abnormal ion passage within the muscle membrane ion channels. Their clinical picture is stereotypical as illustrated by the above vignette. It is often difficult to document the occurrence of the transient hyperkalemia or hypokalemia as it is unusual to evaluate the patient during an episode per se where the abnormal values typically occur. On the rare occasion when a persistent hyperkalemia is demonstrated, and there is no genetic component, adrenal insufficiency (Addison disease) must be considered in the differential diagnosis.

Variable mutations within genes encoding muscle membrane ion channels are responsible for the different forms of periodic paralyses as well as other myotonic disorders (Table 75-2). Most of these patients have an autosomal dominant inheritance. During the episodic paralyses, the skeletal muscle membrane excitability transiently disappears. The degree of weakness may vary from one family member to another; boys and men are more often significantly affected.

Hyperkalemic periodic paralysis (HyperKPP) and paramyotonia are sodium channel disorders, whereas hypokalemic periodic paralysis (HypoKPP) is due to voltage-gated calcium channel dysfunction. The congenital myotonias are chloride channel disorders inherited in either a dominant (Thomsen disease) or recessive (Becker disease) fashion.

Clinical Presentation

Although most instances of weakness related to periodic paralysis have a symmetric distribution, occasionally a patient may have a focal or asymmetric distribution of weakness. The latter occurs when a few specific muscles are overutilized; for example, we had a jeweler who developed symptoms confined to his dominant hand, obviously the side that he primarily used most of his working day. The hypokalemic patient may also have paralytic events precipitated by rest after exercise, as well as occurring subsequent to either a significant carbohydrate intake, or ethanol ingestion and sometimes cold weather. Bulbar and respiratory muscles are not affected. However, by midlife the periodic events usually cease and some individuals may develop a fixed weakness as illustrated in the above vignette.

Paramyotonia congenita is an even more uncommon hyperkalemic disorder often associated with periodic paralysis. Similar to myotonia congenita, cold weather exacerbates muscle stiffness in paramyotonia. In contrast to myotonia congenita, where rest promotes weakness, exercise exacerbates the stiffness in paramyotonia congenita patients.

Myotonia congenita, a chloride channelopathy, is especially aggravated by immobility and ameliorated by exercise and warming; here the myotonia per se is easily elicited on examination. Fixed weakness is not usually present in dominant myotonia congenita. A rather unique characteristic of Thomsen disease variant is the pseudo-hypertrophy of the skeletal muscles providing the patient with a rather pseudo-herculean habitus (Fig. 75-2). It may be so profound that athletic coaches enthusiastically encourage these individuals to participate in sports activities. Unfortunately, some of these individuals may develop a mild progressive weakness. Transient episodes of true weakness precipitated by sudden movements after rest that are relieved by exercise are characteristic of myotonia congenita. Interesting examples include a baseball player who cannot run after hitting the ball or a subway rider who wishes to get off when the train stops but is frozen in place or falls when he arises to leave the train.

Diagnostic Approach

The clinical history is the best means to diagnose a channelopathy. This may be relatively simple in patients with a positive family history examined while symptomatic and documented to have an abnormal serum potassium level or found to have demonstrable myotonia on EMG. In sporadic cases, diagnosis may prove elusive, especially when clinical examination results are normal and provocative testing does not demonstrate any biochemical or neurophysiologic abnormalities.

Whether the underlying channelopathy leads to hyperkalemia or hypokalemia, the serum potassium is normal between attacks. The clinician rarely has the opportunity to obtain a serum specimen during an event per se. However, during episodes of hyperkalemic periodic paralysis the serum potassium is elevated. It is between events that the cold-induced and EMG-defined myotonia occurs. Similarly, the hypokalemic periodic paralysis patient has low serum potassium findings, also confined to the precise time of paralysis.

Measurement of the serum potassium level is indicated in any patient observed during spontaneous episodes of weakness or, if recurrent, an attack of periodic paralysis.

Currently, the availability of a few DNA studies has greatly enhanced the specificity of the diagnostic evaluation of a patient with a question of periodic paralysis. These include DNA testing for the skeletal muscle sodium channel as seen in HyperKPP and the skeletal muscle calcium channel specific for HypoKPP. The previously used provocative studies, such as carbohydrate loading to make one hypokalemic, are no longer of much value today.

Nerve conduction studies sometimes demonstrate decreased compound motor action potential amplitudes in the rare instance one has the opportunity to examine a patient during an episode of periodic paralysis; otherwise, these are normal. In the EMG laboratory, having the potential periodic paralysis patient exercise for prolonged periods may lead to progressive diminution in compound motor action potential amplitudes. Much more rarely, when evaluating a patient during individual episodes of periodic paralysis, needle EMG will demonstrate that affected muscles are electrically inactive as they are fully depolarized. Myotonic discharges occur on EMG in the sodium channelopathy HyperKPP, as well as the chloride channelopathies. This electrophysiologic finding is particularly useful in the differential diagnosis of hyperkalemic and paramyotonic varieties from the nonmyotonic hypokalemic variety. Clinical myotonia is often not evident in HyperKPP although it may be so in paramyotonia when exposed to the cold.

Provocative testing, such as carbohydrate loading, is occasionally required in patients with clinical histories highly suggestive of periodic paralysis and in whom DNA testing is negative. This allows for documentation of abnormal serum potassium levels during episodes of weakness. A controlled clinical setting with appropriate monitoring equipment and facilities for emergent care must be available before initiating this testing. Serum creatine kinase levels are usually normal or minimally increased in the periodic paralyses and myotonic disorders.

Muscle biopsy is normal early in the course of periodic paralyses. However, after patients develop persistent weakness, biopsy may demonstrate vacuolar myopathy with tubular aggregates. Biopsy is rarely necessary for diagnosis.

Treatment and Prognosis

The treatment of choice for a patient having an acute attack of periodic paralysis is by correction of abnormal potassium levels. Severe hyperkalemia necessitates emergency treatment with intravenous (IV) glucose and insulin. Inhaled β-adrenergic agents or ingestion of carbohydrates is fine for less severe episodes. With any patient experiencing his or her first episode of hyperkalemia-associated paralysis, Addison disease is always a diagnostic possibility; therefore, the administration of IV corticosteroids is indicated after a serum cortisol level is obtained. IV potassium or in the milder case oral supplementation is the best means to care for the patient with a hypokalemic episode. These are prevented by avoiding dietary carbohydrate loads.

Maintenance therapy with the carbonic anhydrase inhibitor (CAI) acetazolamide is usually indicated to prevent attacks. Paradoxically, this is equally effective in patients with hyperkalemic or hypokalemic periodic paralysis. Dichlorphenamide, another CAI, is currently under study; previously it had become a mainstay therapy that seemed to be better than acetazolamide; however, the manufacturer withdrew it from production. It is hoped that this will soon return to the neurologist’s pharmacologic armamentarium. When treatment of myotonia per se is required, therapy with mexiletine or other membrane stabilizers is usually effective.

Generally, a diminution in frequency and severity of periodic paralysis attacks occurs in middle age. However, in some patients with periodic paralysis, as in the initial vignette of this chapter, permanent proximal weakness develops with increasing age. This is only minimally responsive to carbonic anhydrase inhibitors and awaits a better therapy.

Glycogen and Lipid Storage Disorders

Clinical Vignette

A 16-year-old boy presented with severe muscle pain and very dark urine subsequent to outrunning police officers who were concerned about his teenage prank. Because of his persistently dark urine he was taken to his family physician. An evaluation for liver disease was commenced after he was noted to have aspartate aminotransferase (AST) levels that were extraordinarily elevated. Paradoxically all other liver function tests (LFTs) were normal. His liver biopsy demonstrated “excess” glycogen but was otherwise unremarkable, and the serum creatine kinase (CK) level was found to be 50 times normal. Myoglobin was demonstrated in his urine. The patient was admitted to the hospital and treated with vigorous IV hydration. His symptoms resolved within several days.

The forearm exercise test (FET) failed to demonstrate the normally expected postexercise increase in lactate but did have significant and normal elevations of the venous ammonia levels. The latter demonstrated that the patient had successfully stressed his muscle metabolism. The combination of no change in lactate and appropriate rise in ammonia levels was classic for the presence of a glycogen storage disease. Subsarcolemmal blebs seen on a periodic acid-Schiff–stained muscle biopsy specimen were consistent with glycogen excess. Biochemical analysis demonstrated decreased levels of myophosphorylase, confirming the diagnosis of McArdle disease.

Comment: This is a classic example of muscle phosphorylase deficiency (Fig. 75-3) with onset in adolescence when individuals for the first time have the muscle power to allow them to stress their metabolic system to the point of actual muscle necrosis and subsequent myoglobinuria, the feature that most commonly brings them to medical attention.

Glycogen storage disorders (GSDs) are very uncommon clinical entities. The classic picture is one of exercise-induced painful muscle cramps, associated with myoglobinuria. The concomitant laboratory documentation of profound elevated serum CK levels and myoglobinuria strongly implicates either a carbohydrate or lipid enzymatic deficiency of inborn metabolism (Fig. 75-4; Table 75-3). Very rarely prolonged use of one extremity, in isolation, will uncover the presence of a previously unsuspected glycogen storage disease (GSD). Muscle phosphorylase deficiency, an inborn error of glycogen metabolism, is the most common of these GSD myopathies.

Table 75-3 Myopathies Presenting with Exercise Intolerance

Glycogenoses Respiratory Chain Defects Lipid Metabolism Disorders
Myophosphorylase deficiency (McArdle disease)—Type V Complex 1 deficiency Carnitine deficiency
Phosphofructokinase deficiency (Tauri disease)—Type VII Coenzyme Q10 deficiency Carnitine palmitoyltransferase deficiency
Phosphorylase B kinase deficiency—Type VIII Complex III deficiency Very long chain, long chain, medium chain, or short chain acyl CoA dehydrogenase deficiency
Phosphoglycerate kinase deficiency—Type IX Complex IV deficiency 3-Hydroxy Acyl-CoA dehydrogenase deficiency protein deficiency
Phosphoglycerate mutase deficiency—Type X Complex V deficiency Glutaric aciduria type II (electron-transferring flavoprotein and CoQ oxidoreductase deficiencies)
Lactate dehydrogenase deficiency—Type XI Combination of I to V Neutral lipid storage disease with myopathy; neutral lipid storage disease with ichthyosis
Beta enolase deficiency—Type XII    


Skeletal muscle function is extremely energy dependent. Normal muscle metabolism requires the presence of both circulating glucose and free fatty acids (Figs. 75-5 and 75-6). At rest, muscles use fatty acids for basal metabolic demands. When one first begins to vigorously exercise, usually within the first 10 minutes, the glycolysis of glycogen, already stored within muscle tissues, is the primary energy source as its breakdown produces glucose but for a relatively short time period. However, when the vigorous exercise is prolonged past these first few minutes, the body shifts to anaerobic glycolysis. This is manifested clinically by the second wind phenomenon. Here lipid stores, in the form of free fatty acids, are mobilized as the primary source of energy. Effective glycolysis is blocked in the various muscle glycogenoses. This essentially deprives muscle of the initial need for glucose, and consequently an accumulation of underutilized glycogen occurs within muscle. In essence, that is, these muscles are inappropriately stressed by what for most healthy persons is no more than strenuous exercise.

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