Phosphoglycerate Mutase Deficiency Research Articles

Phosphoglycerate mutase deficiency with tubular aggregates in a patient from panama

Phosphoglycerate mutase deficiency (PGAM) is a rare metabolic myopathy that results in terminal block in glycogenolysis. Clinically, patients with PGAM deficiency are asymptomatic, except when they engage in brief, strenuous efforts, which may trigger myalgias, cramps, muscle necrosis, and myoglobinuria. An unusual pathologic feature of PGAM deficiency is the association with tubular aggregates. We report an African-American patient from Panama with partial deficiency of PGAM who presented with asymptomatic elevation of creatine kinase levels and tubular aggregates on muscle biopsy. Muscle biopsies showed subsarcolemmal and sarcolemmal tubular aggregates in type 2 fibers. Muscle PGAM enzymatic activity was decreased and gene sequencing revealed a heterozygous mutation in codon 78 of exon 1 of the PGAM2 gene, which is located on the short arm of chromosome 7. PGAM deficiency has been reported in 14 patients, 9 of whom were of African-American ethnicity, and in 5 (36%) tubular aggregates were seen on muscle biopsy. Contrary to previously reported cases, our patient was initially asymptomatic. This further expands the PGAM deficiency phenotype.

Decreased oxidative phosphorylation and PGAM deficiency in horses suffering from atypical myopathy associated with acquired MADD

Earlier research on ten horses suffering from the frequently fatal disorder atypical myopathy showed that MADD (multiple acyl-CoA dehydrogenase deficiency) is the biochemical derangement behind atypical myopathy. From five horses that died as a result of this disease and seven healthy control horses, urine and plasma were collected ante mortem and muscle biopsies were obtained immediately post-mortem (2 patients and 7 control horses), to analyse creatine, purine and carbohydrate metabolism as well as oxidative phosphorylation.In patients, the mean creatine concentration in urine was increased 17-fold and the concentration of uric acid approximately 4-fold, compared to controls.The highest degree of depletion of glycogen was observed in the patient with the most severe myopathy clinically. In this patient, glycolysis was more active than in the other patients and controls, which may explain this depletion. One patient demonstrated very low phosphoglycerate mutase (PGAM) activity, less than 10% of reference values.Most respiratory chain complex activity in patients was 20–30% lower than in control horses, complex II activity was 42% lower than normal, and one patient had severely decrease ATP-synthase activity, more than 60% lower than in control horses.General markers for myopathic damage are creatine kinase (CK) and lactic acid in plasma, and creatine and uric acid in urine. To obtain more information about the cause of the myopathy analysis of carbohydrate, lipid and protein metabolism as well as oxidative phosphorylation is advised.This study expands the diagnostic possibilities of equine myopathies.

Unusual presentation of phosphoglycerate mutase deficiency due to two different mutations in PGAM-M gene

Phosphoglycerate mutase (PGAM) deficiency causes a rare metabolic myopathy characterized by exercise-related myalgia and myoglobinuria. This disorder was described in 13 patients and five different mutations in the PGAM-M gene were identified. We report on a new patient with an unusual clinical presentation. As a youth, he participated in different sports without complaining of muscular symptoms, but at 44 years of age, after a brief, intense effort, he experienced lightheadedness without fainting. Serum CK was elevated and the ischemic exercise test showed a pathological lactate response. Muscle biopsy showed only mild abnormalities, but biochemical study revealed a defect of PGAM and genetic analysis showed two different mutations in the PGAM-M gene. Our case expands the clinical spectrum of PGAM deficiency and suggests that the frequency of this metabolic myopathy may be underestimated.

Phosphoglycerate mutase deficiency: case report of a manifesting heterozygote with a novel E154K mutation and very late onset

Phosphoglycerate mutase (PGAM) deficiency is a rare glycogen storage disease (glycogenosis type X) due to recessive mutations in the muscle-specific isoform PGAMM. We present a 67-year-old German patient with exercise-induced cramps and myalgia for 1 year but no attacks of rhabdomyolysis. CK was 2.5-folds increased and forearm exercise test was normal. Sections of the muscle biopsy stained with PAS showed moderate glycogen accumulation. Gomori-trichome and NADH showed subsarcolemmal depositions (0.01% of the fibres) suggesting tubular aggregates (Fig. 1). PGAM activity in muscle homogenate [4] was moderately reduced (141 U/g wet weight, normal 332 ± 88). Deficiencies of alpha-glucosidase, myophosphorylase, CPT and MAD were excluded biochemically. The PGAM-M gene was amplified [5] and directly sequenced. A novel G to A transition at nucleotide position 460, resulting in exchange of amino acid glutamic acid at codon 154 to lysine, was identified in heterozygous state. This was confirmed by reverse sequencing. RFLP analysis in 70 normal controls from the same ethnic origin did not show the mutation. There are several lines of evidence suggesting that the patient is a manifesting heterozygous carrier. The E154K mutation is considered pathogenic because: (1) the mutation was not identified in normal controls, (2) it affects a highly conserved amino acid (Fig. 2), (3) it results in changing of an acidic amino acid to a basic amino acid with larger side chain, (4) it was the only mutant change identified in the coding region and exon– intron boundaries of the PGAM-M gene. However, it cannot be excluded that the patient carries a large deletion or a deep intronic mutation on the second allele. The biochemical result with half the normal enzyme activity, however, seems consistent with just one mutant allele. Finally, glycogen storage and tubular aggregates in muscle (in very low degree, though) are typical findings of PGAM deficiency. These histological changes might be scarce, even in cases with two mutant alleles. We identified another case of PGAM deficiency (with the typical phenotype of exercise-induced myalgia with rhabdomyolysis starting at age 35 years) with moderate glycogen accumulation and very few fibres suggestive of tubular aggregates (0.02% of total fibres). This patient of African origin had very reduced PGAM activity (9.6 U/g wet weight, normal 332 ± 88) and carried the homozygous W78X stopmutation that was identified in several African patients with PGAM deficiency [3, 6]. The patient had incomplete raise of lactate in the forearm test, as described for PGAM deficiency [1, 3, 7]. The manifesting heterozygote patient, however, had normal forearm exercise test, suggesting that 50% residual activity is enough so that the metabolic impairment is undetectable in this test. In both of our patients electron microscopy was unable to identify fibres with tubular aggregates because they were very scarce and abnormal fibres were not seen in semi-thin sections because of the small piece of muscle that is analysed. P. R. Joshi M. Knape S. Zierz M. Deschauer Neurologische Universitatsklinik, Halle, Germany

Muscle Phosphoglycerate Mutase Deficiency Revisited

Phosphoglycerate mutase (PGAM) deficiency (glycogen storage disease type X) has been reported in 12 patients of whom 9 were African American. To describe 2 patients, 1 of Pakistani and 1 of Italian ethnic origin, with typical clinical and biochemical changes of glycogen storage disease type X and novel mutations in the gene encoding the muscle subunit of PGAM (PGAM2). Clinical, pathological, biochemical, and molecular analyses. Tertiary care university hospitals and academic institutions. Patients A 37-year-old Danish man of Pakistani origin who had exercise-related cramps and myoglobinuria and a 65-year-old Italian man who had exercise intolerance and myalgia but no pigmenturia and had undergone long-term statin therapy. Clinical course and biochemical and molecular features. Biochemical evidence showed severe isolated PGAM deficiency, and molecular studies revealed 2 novel homozygous mutations, a nonsense mutation and a single nucleotide deletion. Pathological studies of muscle showed mild glycogen accumulation but prominent tubular aggregates in both patients. We found that glycogen storage disease type X is not confined to the African American population, is often associated with sarcoplasmic reticulum (SR) proliferation, and is genetically heterogeneous.

Biochemical and molecular genetic identification of patients with phosphoglycerate mutase deficiency

Phosphoglycerate mutase (PGAM) deficiency is an autosomal recessive glycogenosis (type X) characterised by exercise induced cramps, myalgia, and myoglobinuria. Myohistological features are glycogen deposition and tubular aggregates. Biochemically there is low muscle PGAM activity (most patients below 10%) but few manifesting heterozygotes with 50% activity are reported. Molecular genetic investigations have revealed 4 mutations among 13 patients, so far. A nonsense mutation W78X is frequent in patients of African origin.

G.P.16.07. Biochemical and molecular genetic identification of patients with phosphoglycerate mutase deficiency

G.P.16.07. Biochemical and molecular genetic identification of patients with phosphoglycerate mutase deficiency

G.P.16.08. Two novel mutations associated with muscle phosphoglycerate mutase (PGAM) deficiency

G.P.16.08. Two novel mutations associated with muscle phosphoglycerate mutase (PGAM) deficiency

Exercise‐induced cramp, myoglobinuria, and tubular aggregates in phosphoglycerate mutase deficiency

We report two patients in whom phosphoglycerate mutase (PGAM) deficiency was associated with the triad of exercise-induced cramps, recurrent myoglobinuria, and tubular aggregates in the muscle biopsy. Serum creatine kinase (CK) levels were elevated between attacks of myoglobinuria. Forearm ischemic exercise tests produced subnormal increases of venous lactate. Muscle biopsies showed subsarcolemmal tubular aggregates in type 2 fibers. Muscle PGAM activities were markedly decreased (3% of the normal mean) and molecular genetic studies showed that both patients were homozygous for a described missense mutation (W78X). A review of 15 cases with tubular aggregates in the muscle biopsies from our laboratory and 15 cases with PGAM deficiency described in the literature showed that this clinicopathological triad is highly suggestive of PGAM deficiency.

Effect of Fuels on Exercise Capacity in Muscle Phosphoglycerate Mutase Deficiency

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. To investigate whether fuels that bypass the metabolic block can improve exercise capacity or whether exercise capacity improves during sustained exercise. Single-blind, placebo-controlled investigation of the effects of glucose, lactate, and intralipid on work capacity in patients with PGAMD. 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. 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. Whether a second wind occurs during exercise and whether fuels that bypass the metabolic block can improve exercise and oxidative capacity. 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. 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.

Muscle phosphoglycerate mutase deficiency with tubular aggregates: Effect of dantrolene

A patient with muscle phosphoglycerate mutase deficiency (PGAMD) and exercise-induced muscle cramps had tubular aggregates in muscle and increased muscle Ca2+-adenosine triphosphatase and calcium content. Two ischemic forearm exercise tests induced contractures in the patient. On dantrolene treatment, the patient became asymptomatic, and the ischemic test was performed without contracture. These findings suggest that cramps in muscle PGAMD are caused by a high calcium release from the sarcoplasmic reticulum relative to calcium re-uptake capacity.

Muscle phosphoglycerate mutase deficiency with tubular aggregates: Effect of dantrolene

Muscle phosphoglycerate mutase deficiency with tubular aggregates: Effect of dantrolene

Molecular genetic studies in muscle phosphoglycerate mutase (PGAM-M) deficiency.

Phosphoglycerate mutase (PGAM; EC 2.7.5.3) catalyzes the interconversion of 2-phosphoglycerate and 3-phosphoglycerate in the glycolytic pathway. Hereditary muscle PGAM deficiency has been identified in 9 patients with myopathy. All patients had exercise intolerance and 6 had myoglobinuria. Seven of the 9 patients were African-Americans: 5 of them were homozygous for a nonsense mutation, TGG(Trp) to TAG at codon 78; 1 was a compound heterozygote for the nonsense mutation and a missense mutation, GAG(Glu) to GCG(Ala) at codon 89; and 1 could not be tested. The only 2 Caucasian patients, a brother and sister, were homozygous for a different missense mutation, CGG(Arg) to TGG(Trp) at codon 90. Despite the small number of patients identified, these findings indicate that there is a common mutation in African-Americans while there may be molecular genetic heterogeneity in other ethnic groups.

Glycolytic defects in muscle: aspects of collaboration between basic science and clinical medicine.

The molecular heterogeneities of enzyme abnormality have been identified successfully since 1990 for major clinical entities of glycogenolytic and glycolytic defects in skeletal muscle. The interchange between clinical medicine and basic science, which enabled these achievements, has a long history. This review introduces several important examples of this interchange, which has borne much fruit in the comprehensive understanding of glycogenolysis-glycolysis in skeletal muscle and the related defects that cause various metabolic diseases. For instance, the presence of "glycogen synthase" was mainly suggested by the pathophysiology of McArdle's disease. Clinical manifestations of muscle phosphofructokinase (PFK) deficiency have indicated that there could be PFK isozymes under separate genetic control. Although glycolysis is a unidirectional pathway, enzyme defects at each step do not necessarily cause similar manifestations. Glycogen accumulation is mostly associated with enzyme defects in glycogenolysis and in the first stage of glycolysis. Since the original report of phosphoglycerate mutase deficiency in 1981, no newly recognized glycolytic defects have been presented. Glycolytic steps for which no enzyme deficiency has been identified seem to provide another important impetus for further study of "fail-safe" mechanisms in regard to monogenic disorders.

Metabolic causes of myoglobinuria

To evaluate the proportion of cases of myoglobinuria that can be ascribed to specific metabolic defects, we have studied eight enzymes--phosphorylase, phosphorylase kinase, phosphofructokinase (PFK), phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGAM), lactate dehydrogenase (LDH), carnitine palmitoyltransferase (CPT), and myoadenylate deaminase (MAD)--in muscle biopsy specimens from 77 consecutive patients with myoglobinuria (documented in 44, suspected in 33). Enzyme defects were found in 36 patients: CPT deficiency in 17, phosphorylase deficiency in 10, phosphorylase kinase deficiency in 4, MAD deficiency in 3, PGK deficiency in 1, and a combined defect of CPT and MAD in 1. Exercise was the main precipitating factor, both in patients with and in those without detectable enzymopathies. Thirty patients had specific enzymopathies without myoglobinuria: 14 had phosphorylase deficiency, 9 had MAD deficiency, 3 had phosphorylase kinase deficiency, 3 had PFK deficiency, and 1 had PGAM deficiency. Systematic biochemical evaluation of muscle biopsy specimens revealed specific enzymopathies in about half of the patients with idiopathic myoglobinuria. The rest may have blocks of metabolic pathways not yet studied routinely, such as beta oxidation, or genetic defects of the sarcolemma, such as Becker's muscular dystrophy.

Physiologic assessment of phosphoglycerate mutase deficiency

A third case of phosphoglycerate mutase (PGAM) deficiency, a metabolic myopathy involving terminal glycolysis, was identified in a 24-year-old black man with episodic, exercise-induced myoglobinuria since age 13. To better understand the physiologic consequences of PGAM deficiency, incremental exercise testing was performed. Results were compared with those of two patients having myophosphorylase deficiency and five normals. In contrast to the patients with phosphorylase deficiency, the PGAM-deficient patient achieved near-normal levels of maximal exercise and produced a normal peak lactate after exercise. The mechanisms underlying the asymptomatic performance of such strenuous exercise in this case are uncertain, but the data suggest that unidentified factors are operative in precipitating attacks of myoglobinuria in patients with some metabolic myopathies. Despite similar clinical histories, patients with different glycolytic enzyme deficiencies can have striking differences in exercise tolerance.

Effect of phosphoglycerate mutase deficiency on heterotrophic and autotrophic carbon metabolism of Alcaligenes eutrophus.

Mutants of Alcaligenes eutrophus were isolated on the basis of their inability to grow on succinate as the sole source of carbon and energy. The mutants also failed to grow on other gluconeogenic substrates, including pyruvate, acetate, and citrate. Simultaneously, they had lost their capability for autotrophic growth. The mutants grew, but slower than the wild type, on fructose or gluconate. Growth retardation on gluconate was more pronounced. The mutants lacked phosphoglycerate mutase activity, and spontaneous revertants of normal growth phenotype had regained the activity. The physiological characteristics of the mutants indicate the role of phosphoglycerate mutase in heterotrophic and autotrophic carbon metabolism of A. eutrophus. Although the enzyme is necessary for gluconeogenesis during heterotrophic growth on three- or four-carbon substrates, its glycolytic function is not essential for the catabolism of fructose or gluconate via the Entner-Doudoroff pathway. The enzyme is required during autotrophic growth as a catalyst in the biosynthetic route leading from glycerate 3-phosphate to pyruvate. It is suggested that the mutants accomplish the complete degradation of fructose and gluconate mutase lesion. The catabolically produced triose phosphates are converted to fructose 6-phosphate which is rechanneled into the Entner-Doudoroff pathway. This carbon recycling mechanism operates less effectively in mutant cells growing on gluconate.