Many neuromuscular conditions, particularly metabolic disorders of skeletal muscle, typically result in one or more of the following symptoms that limit exercise performance. Although these symptoms are often present from childhood, the diagnosis may be delayed for years or decades.

The underlying mechanism typically is a defect in one of the metabolic pathways that normally supplies energy to working muscle. A common complaint is that the patient feels that activity is limited because he or she just "runs out of gas". This is an apt analogy that draws attention to the fact that skeletal muscle is a sophisticated "machine" which is powered by a remarkable "engine" that is able to convert a variety of fuels to energy. Conventional medical evaluation of such complaints typically fails to arrive at a proper diagnosis so patients are told that they simply are "out of shape" or that their problems are "psychological".

Fatigue: Life long premature exert ional fatigue and weakenss with moderate exercise is typical of complete blocks in muscle glycogenolysis due to phosphorylase of PFK deficiency (whereas patients with partial glycolytic defects have relatively normal tolerance of moderate exercise).  As children they fatigue on family outings and can not keep up with their peers with brisk walking, running, cycling, or skating.  As Adults they tire  easily with modest exertion and adopt excuses - a need to tie a shoe, a desire to look in a shop window - to explain their need to stop and rest.  Impaired aerobic glycogenolysis due to muscle phosphorylase of PFK deficiency is associated with fluctuations in exercise capacity related to the availability of blood borne fuels.  They often have a "second wind" phenomenon in which, after a 'warm up' period, initially fatiguing exercise becomes much easier so the activity (walking, mowing the lawn, etc.) can be continued without further interruption.  The mechanism of the second wind is increased delivery of blood borne fuels to working muscle related to increase mobilization of extramuscular fuels, increased blood flow or both with resultant increase cellular capacity for oxidative phosphorylation.  The improvement in muscle oxidative capacity typically is associated with a steep drop in exercise heart rate.  Patients with PFK deficiency often experience the opposite - an 'out of wind' effect in which exercise which previously was tolerated causes fatigue.  The 'out of wind' phenomenon is attributable to a reduction in available oxidative fuel that typically is produced by a high carbohydrate meal.  The  enzymatic  block prevents the utilization of glucose and increased glucose causes an insulin-mediated fall in blood levels of free fatty acids, the major fuel available for PFK deficiency muscle.

Cramps:  Muscle cramps are triggered by activities that normally engage anaerobic glycogenolysis: 1)intense isometric exercise (e.g. arm wrestling, attempting pushups or pull ups, trying to push a stalled car) which may trigger symptoms after only brief effort; or 2) maximal dynamic exercise - e.g. maximal effort sprinting a distance of about 50 yards (as in running the bases in baseball).  The cramps are distinctive; the muscle is shortened, hard, usually intensely painful, and is unable to be lengthened for minutes to hours (the limb is 'locked-up').  These cramps are the direct consequence of exertions and are not to be confused with spontaneous cramps which occur at rest, often during sleep, or cramps which occur with over-shortening of a muscle without intense effort.  Unlike ordinary cramps, the muscle shortening is electrically silent implying that it relates not to recurrent sarcolemmal activation (as is typical of spontaneous cramps) but to persistent calcium mediated interactions of actin and myosin due to increased calcium sensitivity, increased cellular calcium concentration, or both.

Myoglobinuria:  Myoglobinuria usually is similarly triggered by brief maximal exercise (sprinting, wrestling, attempting to water ski) and pigmenturia noted within hours, often at the time of the first voiding after the injury-producing activity.  Despite virtually lifelong exercise intolerance, most patients first come to medical attention as a result of a sentinel clinical event - often an episode of severe rhabdomyolysis with markedly elevated serum CK and pigmenturia.  Myoglobinuria always raises the suspicion of metabolic abnormality, though in a large published series, only about half were found to have an underlying metabolic defect when screened for know glycolytic and lipid defects.  The most common metabolic cause of myoglobinuria were carnitine palmitoyl transferase deficiency (present in 50% of patients with an established metabolic defect) and glycolytic defects (found in 42% of those with enzyme defects).  The most common glycolytic defect was myophosphorylase deficiency.

Muscle Weakness:  Muscle weakness is the usual presentation of Debrancher deficiency ( and in that respect debrancher deficiency is atypical of the non lysosomal glycogenoses).  And, although exercise intolerance is the dominant manifestation of McArdle disease and PFK deficiency, about 25% of patients develop variable predominantly proximal weakness.  Usually this occurs later in life (5th decade and beyond), but occasionally younger patients are affected.  In some cases, the weakness may be profound and mimic a muscular dystrophy.  The pathogenesis of progressive muscle weakness in glycolytic disorders in unknown.  Proposed mechanisms include: 1) recurrent muscle injury that ultimately exhausts the regenerative capacity of skeletal muscle; 2) impaired protein metabolism attributable to the oxidation of amino acids - especially branched chain amino acids - as alternate energy substrates; 3) interference with muscle contractile function by excessive accumulation of muscle glycogen.  The finding of highly focal muscle injury and atrophy in some cases seems most consistent with the first mechanism.

Rhabdomyolysis; (muscle necrosis)

Myalgia; (muscle pain)

Ophthalmoplegia;  (paralysis of the eye muscles)