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Objectives To estimate the frequency of and to characterize muscle excitability abnormalities in Machado-Joseph disease (MJD). Design Machado-Joseph disease is a common autosomal dominant cerebellar ataxia caused by an unstable CAG trinucleotide repeat expansion. Muscle cramps and fasciculations are frequent and sometimes disabling manifestations. However, their frequency and pathophysiological mechanisms remain largely unknown. Symptomatic patients with MJD (hereinafter MJD patients) with molecular confirmation were assessed prospectively. A standard questionnaire addressing clinical features of muscle cramps and fasciculations was used. The Cramps Disability Scale was used to quantify cramps-related disability. Patients underwent neurophysiological testing with routine techniques. F waves of the right median nerves were obtained, and persistence indexes were calculated. Four muscles (deltoid, first dorsal interossei, tibialis anterior, and vastus lateralis) were examined by needle electromyography. A semiquantitative scale (from 0 [no activity] to 4 [continuous activity]) was used to determine the frequency of rest fasciculations in each muscle. Results Fifty MJD patients (29 men) were included in the study. Their mean age at examination was 46.3 years, their mean age at onset of the disease was 35 years, and the mean duration of disease was 11.2 years. Abnormal CAG n varied from 59 to 75 repeats. Forty-one patients presented with muscle cramps; in 10, this was their first symptom. The frequency of cramps varied between 1 and 90 episodes a week. For 15 patients, cramps were the chief complaint, frequently disturbing sleep or work (Cramps Disability Scale score, 2 or 3). Lower limbs were affected in 37 individuals, but unusual regions, such as the face and abdominal muscles, were also involved. Fasciculations were found in 25 individuals; in 8 patients, they included facial muscles. However, fasciculations were not a significant complaint for any of these patients. The clinical and neurophysiological profile of MJD patients with and without cramps was not significantly different. However, MJD patients with fasciculations had more severe damage to their peripheral nerves. Conclusions Muscle excitability abnormalities were found in 41 MJD patients (82%), and they were the presenting complaint in 10 (20%). They are related to altered excitability of peripheral motor axons, but mechanisms underlying cramps and fasciculations are possibly distinct in MJD patients.

Background McArdle disease is a common metabolic disorder characterized by marked exercise intolerance, premature fatigue during exertion, myalgia, and cramps. Despite the wide knowledge of the molecular basis of McArdle disease, few studies have used a physiological approach or explored the possibility of improving the exercise capacity of these patients. Objectives To describe 3 unrelated patients with McArdle disease with a novel mutation in thePYGMgene and to assess the physical capacity in 1 of them. Design Using molecular genetic approaches, we identified the underlying molecular defect in 3 patients with McArdle disease. Physical performance was evaluated in 1 patient by means of an exercise tolerance test on a bicycle ergometer. Setting Two university hospitals. Exercise physiology studies were performed in a university department. Patients The 3 patients showed common features of McArdle disease. They were definitively diagnosed by histochemistry, biochemistry, or molecular genetic analysis. Results All of the 3 patients were genetic compounds for the common Arg50Stop mutation and a novel c.13_14delCT mutation in thePYGMgene. The peak oxygen uptake (VO2peak) of the patient who performed the exercise test was only 20.2 mL · kg−1 · min−1. Conclusions Together with the novel mutation, there is a markedly decreased exercise capacity in a patient with McArdle disease, which could account for the profound alteration in the capacity for performing normal activities of daily living in this subpopulation.

Background Classic Fabry disease, an X-linked recessive lysosomal storage disease due to the deficient activity of α-galactosidase A, typically presents in early childhood with acroparesthesias, angiokeratomas, hypohidrosis, and corneal dystrophy. The neuropathic pain presumably results from glycosphingolipid accumulation in the vascular endothelium and in small-caliber nerve fibers, and is treatable by enzyme replacement therapy. Later-onset variants with residual α-galactosidase A activity lack vascular endothelial involvement and classic symptoms, which lead to the development of cardiac and/or renal disease after the fourth decade of life. Objective To expand the later-onset Fabry phenotype to include cramp-fasciculation syndrome without small-fiber neuropathy. Methods A 34-year-old man who presented with chronic exercise-induced pain, fasciculations, and cramps of the feet and legs, and his similarly affected mother, were evaluated. Clinical, biochemical, and molecular studies were performed. Results Clinical evaluation suggested the diagnosis of Fabry disease, which was confirmed by reduced plasma and leukocyte α-galactosidase A activities (8.8% and 13.4% of normal, respectively) due to a missense A143T mutation. His mother was heterozygous for the A143T mutation. Conclusion The presentation of cramps and fasciculations without apparent small-fiber neuropathy expands the phenotype of later-onset Fabry disease.

A 29-year-old African American woman with an 8-year history of biopsy-proven renal sarcoidosis and end-stage renal disease requiring hemodialysis was admitted to the hospital with progressive weakness and shortness of breath for 2 months. Eight months prior to admission, she was prescribed 15 mg of prednisone twice a day and 200 mg of hydroxychloroquine sulfate twice a day for hypercalcemia and elevated angiotensin-converting enzyme level. As her laboratory abnormalities improved, the prednisone dose was gradually decreased, and hydroxychloroquine was continued. Six months earlier, she noticed numbness in her feet and progressive loss of muscle bulk in her feet and hands. She also noticed difficulty reaching overhead, getting out of a chair, and climbing stairs. She denied any pain or muscle cramps. Results of electrophysiological tests at that time, which included nerve conduction studies and needle electromyography, revealed moderately severe axonal sensorimotor polyneuropathy. Her weakness worsened and so she was admitted to the hospital and subsequently transferred to our facility for further management.

• Objective. —To define clinically an unusual acute paralytic syndrome with features distinctive from those of the Guillain-Barre syndrome and similar to those described in Chinese children and young adults. Design. —Case series. Setting. —University medical centers. Patients. —Three North American men (mean age, 29 years) who presented with acute symmetric weakness and muscle cramps after a preceding gastrointestinal tract illness. These patients had no sensory symptoms, developed no respiratory insuffiency or facial weakness, and had normal to brisk muscle stretch reflexes. Results. —Results of serial nerve conduction studies were normal except for low-amplitude motor potentials. Needle electromyography revealed diffuse denervation potentials. Cerebrospinal fluid showed an elevated protein level and, in one case, a mild pleocytosis. A sural nerve biopsy specimen in one patient was normal; muscle biopsy specimens showed denervation atrophy. Conclusions. —These cases resemble those described in Chinese children and young adults and may represent a postviral monophasic process affecting the anterior horn cell or distal motor nerve terminal. Further pathologic correlation will be required to identify the exact site of the lesion. Differentiation is important when considering modes of treatment.

• A family was studied in which four generations (16 of 41 members) suffered from painful recurrent muscle cramping. A clear pattern of autosomal dominant inheritance was noted. The cramping first developed during adolescence or early adulthood. Electromyographic analysis indicated a neurogenic origin. The cramps seemed to be due to dysfunction of the motor neurons. The mechanisms underlying this alteration are unclear and require further investigation.

Background Muscle phosphoglycerate mutase deficiency (PGAMD) is a rare, recessively inherited metabolic myopathy that affects one of the last steps of glycolysis. Clinically, PGAMD resembles muscle phosphorylase deficiency (McArdle disease) and phosphofructokinase deficiency (PFKD). However, it is unknown whether PGAMD is associated with a second-wind phenomenon during exercise, as in McArdle disease, and whether patients with PGAMD, like patients with PFKD and McArdle disease, benefit from supplementation with fuels that bypass the metabolic block. Objective To investigate whether fuels that bypass the metabolic block can improve exercise capacity or whether exercise capacity improves during sustained exercise. Design Single-blind, placebo-controlled investigation of the effects of glucose, lactate, and intralipid on work capacity in patients with PGAMD. Setting National University Hospital, University of Copenhagen, and Neuromuscular Center, Institute for Exercise and Environmental Medicine. Patients Two unrelated men (21 and 26 years old) with PGAMD who since their teens had experienced muscle cramps, muscle pain, and episodes of myoglobinuria provoked by brief vigorous exercise, 4 patients with McArdle disease (mean ± SD age, 32 ± 5 years) with 0% residual phosphorylase activity in muscle, and 6 healthy, untrained male volunteers (mean ± SD age, 23 ± 1 years) were studied. Interventions Using constant and variable workload protocols on a cycle ergometer, it was investigated whether a spontaneous second wind occurs during exercise in patients with PGAMD, and using a constant workload protocol followed by an incremental load to exhaustion, it was tested whether infusion of lactate, glucose, or intralipid alters the exercise tolerance in PGAMD. Main Outcome Measures Whether a second wind occurs during exercise and whether fuels that bypass the metabolic block can improve exercise and oxidative capacity. Results In contrast to patients with McArdle disease, with whom they share many clinical features, in patients with PGAMD, cycle exercise and oxidative capacity are virtually normal, a second wind does not occur, and lipid and lactate supplements do not improve exercise capacity. Conclusion Although the clinical manifestations of PGAMD mimic McArdle disease with respect to the presence of exertional muscle cramps, rhabdomyolysis, and myoglobinuria, this study shows that cycle exercise responses are strikingly different.

To the Editor. —Tubular aggregates in skeletal muscle have been described in an increasing variety of disorders, including periodic paralysis; muscular dystrophies; inflammatory myopathies; chronic alcoholism; familial neuromuscular disease characterized by myalgia; and a variety of drug exposures, including anticonvulsants. 1-7 We report the observation of tubular aggregates in skeletal muscle from a patient with neoplastic disease and suggest that a pathogenetic relationship may exist between the development of tubular aggregates and the disturbance in calcium metabolism and regulation that frequently occurs in neoplastic disease. Report of a Case. —A 73-year-old man with no prior history of myalgias, muscle cramps, or muscle weakness presented with a 3-month history of orthostatic hypotension with occasional syncope, night sweats, and a 7-kg weight loss. His blood pressure was 120/60 mm Hg supine, with a pulse rate of 90 beats per minute. On standing, his blood pressure dropped to 70/42 mm Hg, with a

• Three patients from two families had an unusual phenotypical variant of late-onset hexosaminidase-A deficiency. The clinical picture was dominated by spinal motor neuron involvement mimicking juvenile-onset spinal muscular atrophy. Atypical features included prominent muscle cramps, postural and action tremor, recurrent psychosis, incoordination, corticospinal and corticobulbar involvement, and dysarthria. The presence of these atypical features in patients whose lower motor neuron involvement would otherwise be consistent with juvenileonset spinal muscular atrophy should raise the suspicion of the presence of hexosaminidase-A deficiency and GM 2 gangliosidosis that can be proved by appropriate enzyme assays.

• Phenytoin sodium has been used to treat muscle cramps of diverse causes, and is known to increase insulin sensitivity during long-term use. We have previously described a syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy with continual muscle cramping. The effect of 300 mg/d of phenytoin (Dilantin) on muscle cramping and carbohydrate economy was studied in three affected patients and four control subjects. Oral glucose tolerance tests, euglycemic insulin infusion studies, and monocyte insulin binding tests were conducted before and after phenytoin administration. All three patients had notable improvement in muscle cramps. In response to phenytoin, metabolic improvements were variable, with improvement characteristically better in patients with less severe baseline metabolic abnormalities. Patient 1, with the mildest degree of glucose intolerance, had decreased fasting insulin and blood glucose levels, improved glucose tolerance, and insulin-mediated glucose disposal, associated with an increase in monocyte insulin receptors. Patient 2 had reduced fasting plasma glucose and insulin levels and improved oral glucose tolerance, suggesting a beneficial effect on carbohydrate metabolism. Patient 3, with the most severely impaired carbohydrate economy, showed no metabolic improvement despite marked lessening of muscle pain. These clinical characteristics were unaffected in control subjects. We conclude that phenytoin is of value in the therapy of muscle cramps and glucose intolerance in patients with this syndrome.

IN 1951, McArdle 1 described a 30-year-old man who suffered from severe muscle cramps and weakness following exertion. The symptoms were relieved by rest, and results of neurological examination were entirely normal. A disorder of glycogen breakdown was presumed on the basis of the failure of the patient's blood lactate level to rise following exercise under ischemicconditions. It was shown in subsequent similar cases 2-5 that there was an absence of muscle phosphorylase, the initial enzyme of glycolysis reacting directly with branched glycogen. Findings from muscle biopsies 2-5 demonstrated abnormal aggregates of glycogen within the muscle, both in the form of subsarcolemmal "blebs" and in more central regions of the fibers. These findings were confirmed by electronmicroscopy. 6,7 Subsequently, other examples of myopathy associated with different abnormalities of glycogen metabolism have been presented. These have included the absence of the enzymes α-glucosidase (amylo-1,4-glucosidase), 8-11 amylo-1,6-glucosidase (debrancher), 12-14 phosphohexoisomerase, 15

MUSCLE phosphofructokinase (PFK) deficiency in man was first described by Tauri et al1in a biochemical investigation in 1965. In 1967, Layzer et al2reported additional biochemical and immunologic studies in a second family with this disease. This disorder may be regarded as a fourth type of muscle glycogenosis3in addition to deficiencies of phosphorylase, amylo-1,6-glucosidase (debrancher) and amylo-1,4-glucosidase (acid maltase). The PFK catalyzes the conversion of fructose-6-phosphate (F-6-P) to fructose-1,6-diphosphate (F-1,6-PP); in the absence of this enzyme, glycogen cannot be broken down to lactic acid (Fig 1). The clinical features of this disease are identical to muscle phosphorylase deficiency (McArdle's disease) and include muscle cramps, exercise intolerance, contracture following ischemic work, and myoglobinuria.4 At the present time, phosphorylase deficiency can be detected by histochemical means prior to biochemical studies,5,11but a histochemical method for the detection of muscle PFK deficiency is not

• A family with a disorder characterized by muscle cramps that cause painful posturing of the hands and feet was studied. Three generations are affected and the trait is transmitted by autosomal dominant inheritance. The disorder begins in childhood and does not seem to be progressive. A primary abnormality in the motor neuron is suspected on the basis of electrophysiological studies.

We present a family with dominantly inherited myotonia congenita and painful, electrically silent muscle contractions after exertion. In two family members, painful muscle contractions occurred coincident with hypothyroidism, and improved after thyroid replacement therapy. It is probable that this family represents a disease that is similar to but distinct from the dominant form of myotonia congenita.

• Tubular aggregates of muscle are distinctive structures seen in a wide variety of disorders. We reviewed 1,500 consecutive muscle biopsy specimens for the presence of tubular aggregates. Fifteen biopsy specimens (1.0%) were found with this abnormality. All patients were male, and seven had specific diagnoses based on clinical, biochemical, morphologic, and electrophysiologic criteria: hypokalemic periodic paralysis (two patients); hyperkalemic periodic paralysis (one patient); myotonia congenita (one patient); inflammatory myopathies (three patients). The remaining eight patients had a syndrome characterized predominantly by muscle pain and/or cramps, not necessarily precipitated by exercise. Although tubular aggregates constituted the predominant abnormality on muscle biopsy specimens in these cases, other mild, nonspecific changes were noted.

• One year after a gunshot wound in the popliteal fossa, a 30-year-old man began to experience cramps and myokymia in the left gastrocnemius muscle. Myokymia was characterized by vermicular fibrillary movements localized to the gastrocnemius muscle and accompanied by plantarflexion and dorsiflexion of the toes. Neurologic examination, nerve conduction velocities, electromyograms, and muscle biopsy findings showed affection of left common peroneal and posterior tibial nerves. The myokymia disappeared during sleep, spinal anesthesia, and treatment with carbamazepine.

To the Editor.— I think a novel and heretofore undescribed disorder of movement peculiar to trapshooters seems to be worthy of comment. As a neurologist and amateur trapshooter, I have long been cognizant of a problem that occurs in fellow competitors. It is restricted to participants in the sport who have a background of years of relatively uninterrupted competition. I believe that the disorder must be another example of that poorly understood collection of acquired motor afflictions, which have been variously named "writer's cramp," "scrivener's palsy," "habit spasm," "craft palsy," "occupational neurosis," "telegrapher's hand," and "violinist's cramp." 1-5 By definition, these disorders are affections of specific learned, highly coordinated, skilled motor movements. They occur after years of extensive execution of a particular muscular activity. Manifestations are varied, but the individual will note a slowing of performance or inability to initiate the act. There is usually an associated spasm of the

The clinical hallmarks of muscle phosphorylase deficiency (McArdle's disease) are muscle cramps and exercise intolerance, contracture following ischemic work, and episodic myoglobinuria. We have encountered a patient with all these symptoms who proved to lack muscle phosphofructokinase (PFK) rather than phosphorylase. This paper describes the results of biochemical and immunological characterization of the metabolic abnormality. Phosphofructokinase deficiency was first described in a detailed biochemical study by Tarui et al, 1 the only previous report. Phosphofructokinase catalyzes the conversion of fructose-6-phosphate to fructose 1 , 6-diphosphate (Fig 1). This enzymatic step is one of the main rate-limiting steps of glycolysis, 2 and there is evidence that the regulation of glycolysis by aerobic metabolism (the Pasteur effect) is mediated by factors regulating the activity of PFK. 3-5 Since glycogen accumulates in excessive amounts in muscle, PFK deficiency can be regarded as a fourth type of muscle glycogenosis, along with deficiencies of phosphorylase, amylo-1, 6-glucosidase

NEUROMUSCULAR disorders in the course of hyperthyroidism are recognized 1-3 and presently include exophthalmic ophthalmoplegia, 4 thyrotoxic myopathy, 5-10 myasthenia gravis, 3,11,12 and periodic paralysis. 13,14 Chronic thyrotoxic myopathy is most common but the mechanism of muscular dysfunction is obscure. The clinical features of chronic thyrotoxic myopathy are due to progressive weakness, more pronounced in proximal muscles. Disability may be mild or severe. Muscular wasting is frequently seen, and muscle cramps also occur occasionally. 15 McArdle 16 described a patient with a lifelong history of cramps after muscular exercise and postulated that this disorder was due to a defect in muscle glycogen break-down. Subsequently, Schmid et al, 17 Mommaerts et al, 18 and Pearson et al 19 found that muscle phosphorylase was lacking in similar patients. Since then, absence of muscle phosphorylase in additional cases has been confirmed. 20,21 Recently, Tarui et al, 22 and Layzer et al, 23 described

IN 1951, McArdle1described a patient whose major symptom was limitation of vigorous activity because of cramps after exercise. When electromyographic examination was performed during a cramp, electrical silence was found despite maximum shortening of the affected muscle; this could be considered a contracture (shortening of muscle without propagated action potential2). McArdle recognized the similarity of this event to the classical experiments of Lundsgaard3in which muscle poisoned by iodoacetate was able to contract without formation of lactic acid. When the patient exercised forearm muscles under ischemic conditions, in contrast to a normal person, there was no rise in venous lactic acid. McArdle therefore postulated that the disorder was due to a defeat of muscle glycogen breakdown. The nature of the enzymatic abnormality was clearly established by Schmid and his colleagues in one family,4and by Pearson, Mommaerts, and their colleagues in another.5Inability

Thorburn 13 was the first to describe a peculiar posture of the upper extremities following an injury to the cervical spine. It was characterized by abduction of the arms and flexion of the forearms with complete paralysis below the C5 level. Although this posture is not rare in clinical medicine, we have found only a few subsequent reports. That the posture results from paralysis of one segmentally innervated group of muscles with unopposed action of antagonists has become generally accepted. 8 There are situations where the abnormal posture persists in the absence of volition, or when the overactive muscles cannot be contracted by willed effort. For such states no more satisfactory explanation has been offered since Thorburn first reported the condition. In this communication, we present a clinical and pathologic study of 3 cases with an abnormal posture in one or more extremities, review other reports, and offer an explanation

A 16-year-old boy was seen for severe episodic muscle cramps and generalized myokymia, consistent with Isaacs's syndrome. Bilateral calf hypertrophy (46-cm calf circumference) and ankle areflexia were noted. He was treated with phenytoin sodium, 300 mg/day. Within three months there was marked decrease in myokymia, total relief of cramps, return of ankle reflexes, and 6-cm reduction in calf circumference. We suggest that the excess muscle activity in Isaacs's syndrome may be responsible for the associated phenomena of muscle hypertrophy and areflexia.

• In two patients, the skin over both hypothenar eminences underwent intermittent, spontaneous, irregular, dimpling contractions. The dimpling was benign, and was the result of spontaneous discharge of motor units in the palmaris brevis muscle. Electrophysiological investigations localized the site of origin of the discharge to the ulnar nerve, possibly at the wrist, but there was no clinical or physiological evidence of neuropathy or of nerve compression. In many respects, the clinical and electrophysiological features of hypothenar dimpling resemble hemifacial spasm.

• Two cases of an acute myopathy without muscle pain, tenderness, or swelling are described in alcoholic patients. Both were associated with severe hypokalemia and were largely reversible with potassium repletion. Hypokalemia may be the cause of some cases of acute myopathy in alcoholism, particularly those in which muscle cramps are absent.

We describe six adult patients (five men and one woman) out of 364 whose muscle biopsy specimens disclosed muscle adenylate deaminase deficiency. Two men had an associated dermatomyositis and another man had an associated progressive systemic sclerosis. Although the patients were different clinically, all complained of muscular weakness or poor exercise tolerance. The occurrence of muscle adenylate deaminase deficiency in both sexes suggests a possible autosomal mode of inheritance.

To the Editor.— In the past two years, we have seen four patients with muscle cramps after each patient underwent a subtotal gastrectomy. Our patients' ages ranged from 43 to 64 years. Painful exertional muscle cramps began from four to six years after each patient underwent a subtotal gastrectomy for a peptic ulcer. All of the patients were men. Cramps involved the upper and lower extremities in every case, as well as the abdominal wall in two cases. Cramps were sustained for several minutes with visible and palpable contraction of muscles (Figure, A). Electromyographically, irregular bursts of muscle action potentials were recorded from the affected muscle (Figure, B). Reflexes were hyperactive in three patients. Fasciculations and mild muscle atrophy were noted in two patients. In one patient, the cramps were induced by repetitive tapping of the muscle tendon, as well as by strong voluntary contractions. In another patient, manual muscle

Hypokalemic, 1 hyperkalemic, 2 and normokalemic 3 types of familial periodic paralysis have been reported. We studied a woman whose clinical syndrome and serum potassium changes were compatible with the hyperkalemic type of paralysis. In contrast to most of the previously described patients, her family did not demonstrate the pedigree pattern of an autosomal dominant gene with complete or almost complete penetrance. 2 In addition, she had a low serum calcium and carbon dioxide combining power during an attack. Only one other report describes hypocalcemia during an attack. 4 Our patient may represent a heretofore unreported variant of familial periodic paralysis or, possibly a similar but new metabolic defect. Report of Case A 35-year-old, married, Caucasian female secretary complained of episodic weakness and paralysis of her legs and arms. These attacks began when she was 18 months old. A typical attack was characterized by gradual weakness of the arms and