Muscle phosphoglycerate mutase deficiency

A 52-year-old man complained since adolescence of cramps and pigmenturia after 15 to 30 minutes of intense exercise. There was no family history of neuromuscular diseases, and strength was normal. The rise of venous lactate after forearm ischemic exercise was abnormally low. Histochemical and ultrastructural studies of a muscle biopsy showed mild increase of glycogen, which was confirmed by biochemical analysis. Studies of anaerobic glycolysis in vitro showed decrease lactate formation with glycogen and with all hexosephosphate glycolytic intermediates, suggesting a defect below the phosphofructokinase reaction. Muscle phosphoglycerate mutase (PGAM) activity was 5.7% of the lowest control, while all other enzymes of glycolysis had normal activities. Electrophoretic, heat lability, and mercury inhibition studies showed that the small residual activity of PGAM in the patient's muscle was represented by the brain (BB) isoenzyme, suggesting a genetic defect of the M subunit that predominates in normal muscle. The prevalence of the BB isoenzyme in other tissues, including muscle culture, may explain why symptoms were confined to muscle.     

A non-ischemic forearm exercise test for the screening of patients with exercise intolerance.

BACKGROUND: The forearm exercise test is a common investigation that allows detection of some metabolic myopathies. It is not completely standardized and, when performed in ischemic conditions, may induce rhabdomyolysis in patients with glycogenosis. OBJECTIVE: To develop a standardized non-ischemic exercise test for a safe screening of patients with exercise intolerance. METHODS: Twenty-six healthy subjects and 32 patients with exercise intolerance performed an isometric exercise at 70% of the maximal voluntary contraction during 30 seconds in non-ischemic conditions. Blood concentrations of creatine kinase, lactate, and ammonia were analyzed. RESULTS: A nearly fourfold lactate rise was induced by exercise in healthy subjects. All patients with normal muscle biopsy showed values similar to those of healthy subjects. No significant lactate increase was observed in six patients with a myophosphorylase defect and one with a debrancher defect. Disparate lactate responses were observed in 14 patients with a mitochondrial myopathy. The blood lactate level at rest was abnormally high in four of these patients. The lactate surface normalized by the mechanical energy production was above the normal range in eight patients. CONCLUSIONS: The authors propose a standardized non-ischemic grip test that overcomes the main drawbacks of the classic ischemic forearm exercise test. It provides a specific, efficient, and safe screening test for patients with exercise intolerance. Its sensitivity was very good for patients with a glycogenolysis defect but remains partial in patients with a mitochondrial disorder.     

Effect of coenzyme Q10 in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): evaluation by noninvasive tissue oximetry

We evaluated the effect of coenzyme Q10 supplementation to two patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) by using noninvasive tissue oximetry with near-infrared spectra of hemoglobin from the quadriceps muscle during bicycle ergometer exercise. Patients showed distinct oxygen consumption patterns reflecting the defect in oxidative phosphorylation and the impairment in oxygen utilization during exercise. Based on the oxygen consumption pattern, we considered one patient as having severe mitochondrial disorder and another patient as having mild one. After coenzyme Q10 supplementation, the oxygen consumption pattern of the patient with the severe form shifted to the mild one, while that of the patient with mild form remained unchanged. The shift of the pattern to the mild form correlated well with reduction of the sum of the serum lactate and pyruvate content during exercise. Noninvasive tissue oximetry may be useful to evaluate the effect of coenzyme Q10 supplementation to patients with mitochondrial encephalomyopathy including MELAS.     

The effects of partial chronic denervation on forearm metabolism.

Effects of chronic denervation upon in vivo forearm metabolism were studied in six patients and six controls. The diagnosis was amyotrophic lateral sclerosis in four patients, the neuronal form of Charcot-Marie Tooth disease in one patient, and an unclassified chronic disease of the lower motor neurons in one patient. In all cases the forearm muscles showed clinical weakness and electrical evidence of denervation, while muscle biopsy from a proximal muscle of the upper limb showed typical denervation atrophy. At rest there was increased oxygen utilization and lactate output as well as a tendency for increased uptake of glucose and long chain fatty acids from arterial blood per 100 ml of forearm tissue. During exercise the abnormally high lactate output increased further. An increased arterial lactate concentration was present during rest and exercise. Oxidation of fatty acids was not impaired. It is suggested that these abnormalities are consistent with an augmented utilization of blood borne fuels at rest by denervated muscles. A concurrent regional ischemia of muscles during rest and exercise, possibly due to defective autoregulation of skeletal muscle blood flow, may explain the abnormally high lactate generation.     

An unusual metabolic myopathy: a malate-aspartate shuttle defect

Studies on a 27-year-old man with a 3-year history of exercise-induced muscle pain, passage of red urine and elevated serum creatine kinase are described. Histological examination of a biopsy from quadriceps revealed non-specific myopathic changes with occasional clusters of subsarcolemmal mitochondria. The phosphorylase stain was normal. Phosphorous nuclear magnetic resonance (NMR) spectroscopy studies of gastrocnemius and flexor digitorum superficialis muscles showed no abnormalities at rest. During aerobic exercise there was an abnormally rapid decrease in phosphocreatine concentration but the pH remained within the normal range. There was a build-up of phosphomonoester (probably glucose 6-phosphate), usually indicative of a block in glycolysis. However, a primary defect in the glycolytic pathway seemed unlikely because muscle acidified normally during ischaemic exercise. Recovery from exercise was unusual in that phosphocreatine resynthesis and inorganic phosphate disappearance followed similar prolonged time courses (in control subjects the rate of inorganic phosphate disappearance was about twice as fast as the rate of phosphocreatine resynthesis). The transport of inorganic phosphate into the mitochondria appeared to be delayed. These slow recovery data suggested that oxidative metabolism was impaired. However, with all substrates tested, isolated muscle mitochondria had rates of oxygen uptake that were similar to control values, thereby ruling out a primary defect in mitochondrial respiration. A system involving several mitochondrial transport systems, the malate-aspartate shuttle, was measured. The activity in the patient's isolated mitochondria was less than 20% of the activity present in samples from control subjects. This patient is the only one so far reported with a defect involving the malate-aspartate shuttle system.     

Benign mitochondrial myopathy with decreased succinate cytochrome C reductase activity

In most of the cases previously described, the defect on complex II was suggested by low activity of succinate cytochrome C reductase (SCCR). The clinical pattern of the previous 10 cases is heterogeneous and may be limited to one particular tissue or be of a more general nature. We report a 22-year-old-woman, daughter of consanguineous parents, with generalized muscle weakness, easy fatigability and benign course, who showed a decrease of SCCR activity in mitochondria of muscle fibers. Free carnitine (FC) concentration was decreased in muscle as well. The muscle biopsy showed a mild variation in fiber size, with fiber type I predominance, subsarcolemmal oxidative DPNH accumulations, excess of neutral lipids and abnormally large mitochondria with paracrystalline inclusions. A possible inheritance pattern is discussed. Coenzyme Q10 therapy in this patient induced a significant increase of global MRC index score and a decrease of the turns-mean amplitude ratio in the automatic analysis of the EMG.     

A case of mitochondrial myopathy,lactic acidosis and complex I deficiency

Summary A 34-year-old man affected by exercise intolerance, mild proximal weakness and severe lactic acidosis is described. Muscle biopsy revealed mitochondrial abnormalities and an increase of cytochrome c oxidase histochemical reaction. Biochemical investigations on isolated muscle mitochondria as well as polarographic studies revealed a mitochondrial NADH-CoQ reductase (complex I) deficiency. Mitochondrial dysfunction was confirmed by ³¹P nuclear magnetic resonance spectroscopy. Immunological investigation showed a generalized reduction of all complex I polypeptides. Genetic analysis did not reveal mitochondrial DNA deletions. The biochemical defect was not present in the patient's muscle tissue culture. Metabolic measurements and functional evaluation showed a reduced mechanical efficiency during exercise.     

A new metabolic muscle disease due to abnormal hexokinase activity.

A 34 year old man presented with an 8 year history of mild muscle pain and stiffness on exertion especially in the cold. Clinical examination was normal. Apart from a mild persistent leucocytosis, his routine investigations were normal including creatine kinase activity, electromyography and nerve conduction studies. An ischaemic exercise test produced a slow and incomplete rise in lactate. Histological examination showed non-specific myopathic changes in some quadriceps femoris muscle fibres. Investigation of muscle metabolism by spectrofluorometric analysis of muscle enzyme activity and by muscle fibre incubation studies revealed a severe defect in glucose phosphorylation, associated with an electrophoretically abnormal hexokinase. Further metabolic studies suggest that the block in glucose metabolism is by-passed via an enhanced phosphorylation of fructose by the abnormal hexokinase.     

Serum enzyme levels in patients with myasthenia gravis after aerobic and ischaemic exercise

This study was designed to test the hypothesis that there is a myopathic component in myasthenia gravis. Serum enzyme analyses and lactate and pyruvate assays were undertaken before and after exercise in order to detect possible leakage from defective muscle membrane. A patient and a control group were exercised under (1) aerobic conditions, (2) ischaemic conditions, and (3) aerobic conditions under the influence of edrophonium chloride. The patient group showed a higher resting level of lactate in the aerobic state than did the controls. In addition, the average change in SGOT values in the patient group after one minute of aerobic exercise under the influence of edrophonium chloride exceeded that of the control group. Both these findings suggest possible leakage of enzyme and metabolite from the myasthenic muscle due to a membrane defect and support the hypothesis that there may be a myopathic component in myasthenia gravis. However, the two groups showed no significant differences in CPK values, which are often elevated in primary muscle diseases.     

Chronic fatigue and myalgia syndrome: mitochondrial and glycolytic studies in skeletal muscle.

Clinical and biochemical findings in skeletal muscle in 11 patients with chronic fatigue myalgia syndromes of unknown aetiology are reported. All patients had severe asthenia for from one to 10 years with greatly limited exercise capacity and protracted exhaustion after minor exercise. Diffuse myalgia was prominent and was exacerbated for hours to days after exercise. Assay of skeletal muscle carnitine, phosphorylase, all glycolytic enzymes and the mitochondrial marker enzymes monoamine oxidase, isocitrate dehydrogenase and cytochrome oxidase were normal. These findings lend no support to the presence of a major defect in muscle intermediary energy pathways in this syndrome.     

Hypoxanthine and Mcardle disease: a clue to metabolic stress in the working forearm

Forearm exercise in a patient with myophosphorylase deficiency resulted in abnormally high levels of hypoxanthine in the venous blood. The post-exercise hypoxanthine response may reflect ATP depletion in the muscle and provides a useful screening test in muscle diseases with abnormal energy metabolism.     

Ca2+-ATPase deficiency in a patient with an exertional muscle pain syndrome.

31P Magnetic resonance spectroscopy studies were carried out in vivo on skeletal muscle of a patient with verapamil-responsive, chronic, progressive post-exertional muscle pain. A sister suffered from a similar complaint. The results showed that the muscle: (1) decreased its high energy phosphate content more rapidly than normal during exercise, indicating either increased utilisation or decreased production of ATP; (2) acidified more rapidly than normal during exercise suggesting an increased glycolytic rate; (3) continued in some studies to acidify markedly during the first minute after exercise, indicating that glycolysis remained active into the recovery period; (4) had phosphocreatine and ADP recovery rates consistent with normal rates of oxidative phosphorylation. On the basis of these results, it was proposed that the patient suffers from a defect in Ca2+ handling in the muscle. Subsequently, direct measurement of Ca2+-ATPase activity in the sarcoplasmic reticulum fraction from a muscle biopsy sample showed that the activity of this enzyme was reduced by about 90%.     

A mitochondrial encephalomyopathy with a partial cytochrome c oxidase deficiency of muscle.

A 16 year old girl showed delayed psychomotor development. In infancy, exercise intolerance, cerebellar signs, deteriorated with increasing intercurrent infections, and disturbances of breathing and cardiac rhythm became manifest. From the age of 7 years there was chronic progressive psychomotor deterioration, with hypotonia, a bilateral pyramidal and cerebellar syndrome, and mild epilepsy. CSF pyruvate and lactate levels were elevated, and lactate content was elevated in the urine. There was an abnormally high rise of lactate levels on moderate exercise and an abnormal response to pyruvate loading. Quadriceps muscle biopsies obtained at age 10 and 16 years showed ragged-red fibres, and a decreased cytochrome c oxidase activity and cytochrome aa3 content. Cytochrome c oxidase activity in fibroblasts was normal. Clinical signs and symptoms in association with a disturbance of mitochondrial energy metabolism led us to diagnosis of probable Leigh syndrome.     

Progression of neuropathy in peripheral arterial disease

Atherosclerotic peripheral arterial disease (PAD) can cause muscle denervation, but whether it is associated with more severe peripheral nerve disease is not clear. Equally unclear is the effect of exercise training on the neuromuscular aspects of this disease. We performed serial electrophysiologic studies (nerve conduction studies and quantitative electromyography) and muscle strength assessment on 16 patients with moderately severe PAD. Seven of the patients were assigned to a natural history (control) group and 9 to and exercise training group. Over study periods ranging from 3 to 23 months, 6 to 7 patients in the control group and 8 of 9 patients in the exercise training group showed progression of multifocal neuropathic disease in their ischemic legs. For equivalent lengths of time, the degree of neuropathic progression was not significantly different between the control and exercise training group. There was a significant decline in muscle strength for the control group but not for the exercise training group. These results demonstrate that PAD can be associated with the development of a multifocal predominantly motor neuropathy, which is most likely ischemic in etiology. Furthermore, exercise training does not pose an additional risk for the development of neuropathy in patients with moderately severe PAD. © 1995 John Wiley & Sons, Inc.     

Muscle-eye-brain disease (MEB)

Clinical features of a rare congenital myopathy, muscle-eye-brain (MEB) disease, are described in 19 patients. The pedigree data suggest an autosomal recessive inheritance. The patients presented with congenital hypotonia and muscle weakness. Serum CK was elevated, EMG was myopathic and muscle biopsy showed slight or moderate changes compatible with muscular dystrophy. Ophthalmological findings included severe visual failure and uncontrolled eye movements associated with severe myopia. The flash VEPs were exceptionally high, whereas non-corneal ERG was unrecordable. The EEG showed progressive abnormalities after the age of 6 months. Psychomotor development was slow during the first years of life, and mental retardation was severe. Most patients began to deteriorate around age 5 years. This change included spasticity and joint contractures. CT scans showed ventricular dilatations and abnormally low white matter density in several patients. Spasticity, high VEPs and ocular manifestations differentiate MEB from the Fukuyama type congenital muscular dystrophy.     

Improvement of abnormal pyruvate metabolism and cardiac conduction defect with coenzyme Q10 in Kearns-Sayre syndrome

In a patient with Kearns-Sayre syndrome, concentration of coenzyme Q10, a component of the mitochondrial electron transport system, was decreased in serum and in the mitochondrial fraction of skeletal muscle. Serum concentrations of lactate and pyruvate were abnormally high, especially after exercise or oral glucose loading. Levels of folic acid in plasma and CSF were decreased. ECG showed a first-degree atrioventricular block. After administration of coenzyme Q10 60 to 120 mg daily for 3 months, serum levels of lactate and pyruvate became normal, with improvement of atrioventricular block and ocular movements.     

Newly recognized congenital myasthenic syndrome associated with high conductance and fast closure of the acetylcholine receptor channel

We describe here a new congenital myasthenic syndrome associated with a kinetic abnormality of the acetylcholine receptor (AChR) channel. The propositus had poor suck and cry after birth. Subsequently, she had intermittent ocular symptoms and fatigued abnormally on exertion. At age 9 years, significant weakness was detected only in the frontalis, levator palpebrae, and neck flexor muscles. Electromyography showed no decrement in limb muscles but single-fiber examination of the facial muscles was consistent with a neuromuscular transmission defect. The ocular symptoms responded partially to pyridostigmine, but the abnormal fatigability did not. Tests for anti-AChR antibodies were negative. A younger sister had elements of the same disease. An intercostal muscle specimen was obtained from the propositus at age 9 years for endplate studies. The quantal content of the endplate potential was normal. Miniature endplate currents were abnormally large and their decay time constant was abnormally short. AChR channel properties were studied by analysis of acetylcholine-induced current noise. The mean single-channel conductance was increased 1.7-fold and the mean channel open time was 30% shorter than normal. The number of AChR per endplate was normal. Electron microscopy of most endplates showed no abnormality, but a few were degenerating or simplified. The channel abnormality may stem from a point mutation in an AChR subunit affecting a single amino acid residue lining the pore of the AChR channel. The mechanism by which the physiological abnormality produces clinical symptoms is not known, but possible explanations are considered.     

A case of skeletal muscle type very-long-chain-acyl CoA dehydrogenase(VLCAD) deficiency with repeated rhabdomyolysis]

We experienced a 24-year-old male patient with myalgia and myoglobuinuria followed by severe exercise from childhood. In 18 years old, he had severe myaglia after a long time-night trip by bus. He was diagnosed as acute renal failure induced by rhabdomyolysis and treated with hemodialysis. In 24 years old, he was admitted to our hospital because of repeated rhabdomyolysis. We performed muscle biopsy from right quadriceps femoris, however histological and immunohistochemistological studies were normal. Ischemic forearm exercise test showed the elevation of lactic acid in serum. Therefore, we performed the analysis of acylcarnitine in serum, and the measurement of enzyme in beta-oxidation in muscle and white blood cells. These showed the lack of very-long-chain-acyl coA dehydrogenase (VLCAD) activity. He was diagnosed as skeletal muscle type VLCAD deficiency. Under the guidance of high carbohydrate and low fat diet, creatine kinase was controlled around 400 IU/l. VLCAD deficiency is important to make a differential diagnosis of young cases with recurrent elevation of creatine kinase.     

Complex mitochondriopathy associated with 4 mtDNA transitions

In a 33-year-old man, mitochondriopathy was diagnosed upon short stature, auditory impairment, gynaecomastia, hypogonadism, vertical ophthalmoplegia, cerebral atrophy, leucencephalopathy, cataract, hypertrabeculated left ventricle, hypothyroidism, diabetes mellitus, glomerulonephritis necessitating kidney transplantation, general wasting, polyneuropathy, abnormally high lactate levels on exercise, partially reduced cytochrome-c oxidase staining and abnormally structured mitochondria on muscle biopsy. Mitochondrial DNA (mtDNA) analysis revealed 1 novel (A15662G) and 3 known mtDNA transition(s) (T3398C, T4216C, G15812A) affecting the cytb and ND1 gene, respectively. Three of the patient's transitions were also detected in blood leukocytes of the patient's maternal grandmother, mother and brother. Mutant mtDNA was heteroplasmic at >75% in the patient's skeletal muscle.     

HyperCKemia as the only sign of McArdle's disease in a child

An asymptomatic 13-year-old boy, who never complained of exercise intolerance or myalgia, was found to have markedly elevated serum creatine kinase (CK) levels during a routine check-up. General physical and neurologic examinations were normal. Surprisingly, histochemical and biochemical analysis of muscle showed myophosphorylase deficiency and genetic analysis showed that the patient was homozygous for the most common mutation encountered in McArdle's disease (R49X). This case illustrates the fuzzy correlation between molecular defect and clinical phenotype in patients with McArdle's disease, and suggests that a thorough study of the muscle biopsy is important in patients with idiopathic hyperCKemia for correct diagnosis and careful follow-up.