RESUMO
Gallbladder cancer (GBC) is one of the most fatal malignancies of the biliary tract system and is ranked sixth among the neoplasms of the gastrointestinal tract. Gallstone disease (GSD) is considered the major risk factor for GBC. However, the underlying molecular mechanism of GBC pathogenesis from different stages of GSD is not yet clearly understood. We analyzed transcriptomic datasets of GBC with reference to GSD of three different follow-up periods, i.e.,GBC vs. GSD3 (1-3 years), GBCvs. GSD5 (5-10 years), andGBC vs. GSD10 (more than 10 years). We identified overlapping and specific molecular signatures in GBC compared with GSD at three different follow-up periods. Using integrative network biology approaches, such as protein-protein interaction network analysis, transcriptional regulatory network analysis, and miRNA-target gene network analysis, we have identified a few hub genes. The hub genes identified from GBC vs. GSD3, GBC vs. GSD5, and GBC vs. GSD10 were directly or indirectly associated with cancer progression and initiation from GSD. Functional enrichment analysis indicated significant correlation between GSD and GBC pathogenesis. The identified hub genes can be used for future targeted validation to develop potential diagnostic, prognostic, or therapeutic biomarkers in GBC.
Assuntos
Colelitíase , Neoplasias da Vesícula Biliar , MicroRNAs , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/patologia , Humanos , Nefropatias , MicroRNAs/genética , Doenças Musculares , Fosfoglicerato Mutase/deficiênciaRESUMO
BACKGROUND: Phosphoglycerate mutase (PGAM) deficiency is associated with a rare glycogen storage disease (glycogenosis type X) in humans caused by pathogenic variants in the PGAM2 gene. Several genes causing autosomal forms of glycogen storage disease (GSD) have been identified, involved in various forms of neuromuscular anomalies. METHODS: Targeted whole exome sequencing (WES) was performed on the DNA of single affected individual (IV-1) followed by Sanger sequencing confirmation of the identified variant in all available members of the family. RESULTS: In the present study, the affected individual, presenting mild features of glycogen storage disease type X. Targeted exome sequencing revealed a biallelic frameshift variant (c.687dupC; p. Met230Hisfs*6) in the PGAM2 gene located on chromosome 7p13. CONCLUSION: In short, we reported a novel homozygous frameshift variant as a cause of glycogen storage disease type X from Pakistani population. The work presented here proves significance of targeted WES in accurate diagnosis of known complex genetic disorders.
Assuntos
Nefropatias/genética , Doenças Musculares/genética , Fosfoglicerato Mutase/deficiência , Fosfoglicerato Mutase/genética , Adolescente , Mutação da Fase de Leitura , Homozigoto , Humanos , Nefropatias/patologia , Masculino , Doenças Musculares/patologia , Fosfoglicerato Mutase/químicaRESUMO
Lower glycolysis involves a series of reversible reactions, which interconvert intermediates that also feed anabolic pathways. 3-phosphoglycerate (3-PG) is an abundant lower glycolytic intermediate that feeds serine biosynthesis via the enzyme phosphoglycerate dehydrogenase, which is genomically amplified in several cancers. Phosphoglycerate mutase 1 (PGAM1) catalyzes the isomerization of 3-PG into the downstream glycolytic intermediate 2-phosphoglycerate (2-PG). PGAM1 needs to be histidine phosphorylated to become catalytically active. We show that the primary PGAM1 histidine phosphate donor is 2,3-bisphosphoglycerate (2,3-BPG), which is made from the glycolytic intermediate 1,3-bisphosphoglycerate (1,3-BPG) by bisphosphoglycerate mutase (BPGM). When BPGM is knocked out, 1,3-BPG can directly phosphorylate PGAM1. In this case, PGAM1 phosphorylation and activity are decreased, but nevertheless sufficient to maintain normal glycolytic flux and cellular growth rate. 3-PG, however, accumulates, leading to increased serine synthesis. Thus, one biological function of BPGM is controlling glycolytic intermediate levels and thereby serine biosynthetic flux.
Assuntos
Ácidos Glicéricos/metabolismo , Fosfoglicerato Mutase/metabolismo , Serina/metabolismo , Humanos , Fosfoglicerato Mutase/deficiência , Células Tumorais CultivadasRESUMO
Phosphoglycerate mutase enzyme deficiency in muscle causes a metabolic myopathy (glycogen storage disease X) characterized by exertional muscle contractures, weakness, hyperCKemia, and myoglobinuria. Six different autosomal recessive variants in PGAM-M have been described thus far (Salameh et al., 2013). In this case report, we report a novel disease-causing variant. A 52-year-old African-American woman presented with exertional muscle contractures, myalgias, and weakness since childhood including an episode of rhabdomyolysis. Neurologic examination and EMG were normal. CK was mildly elevated at rest and over 20,000 U/L during her episode of rhabdomyolysis. Muscle biopsy revealed subsarcolemmal collections suggestive of tubular aggregates. Phosphoglycerate mutase activity was 8% of the reference value. PGAM-M sequencing showed compound heterozygous variants: c.233G>A, which has been found only in African-Americans with this disease, and a novel variant, c.278G>A. This case expands the genetic spectrum of phosphoglycerate mutase deficiency.
Assuntos
Nefropatias/genética , Doenças Musculares/genética , Fosfoglicerato Mutase/deficiência , Fosfoglicerato Mutase/genética , Éxons , Feminino , Heterozigoto , Humanos , Nefropatias/enzimologia , Nefropatias/patologia , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Doenças Musculares/enzimologia , Doenças Musculares/patologia , MutaçãoRESUMO
Apart from addressing humanity's growing demand for fuels, pharmaceuticals, plastics and other value added chemicals, metabolic engineering of microbes can serve as a powerful tool to address questions concerning the characteristics of cellular metabolism. Along these lines, we developed an in vivo metabolic strategy that conclusively identifies the product specificity of glycerate kinase. By deleting E. coli's phosphoglycerate mutases, we divide its central metabolism into an 'upper' and 'lower' metabolism, each requiring its own carbon source for the bacterium to grow. Glycerate can serve to replace the upper or lower carbon source depending on the product of glycerate kinase. Using this strategy we show that while glycerate kinase from Arabidopsis thaliana produces 3-phosphoglycerate, both E. coli's enzymes generate 2-phosphoglycerate. This strategy represents a general approach to decipher enzyme specificity under physiological conditions.
Assuntos
Escherichia coli/genética , Escherichia coli/metabolismo , Ácidos Glicéricos/metabolismo , Engenharia Metabólica , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Arabidopsis/enzimologia , Escherichia coli/enzimologia , Deleção de Genes , Fosfoglicerato Mutase/deficiência , Fosfoglicerato Mutase/genética , Especificidade por SubstratoRESUMO
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Cãibra Muscular/patologia , Debilidade Muscular/patologia , Músculo Esquelético/patologia , Fosfoglicerato Mutase/deficiência , Adulto , Humanos , Masculino , Cãibra Muscular/enzimologia , Cãibra Muscular/genética , Debilidade Muscular/enzimologia , Debilidade Muscular/genética , Músculo Esquelético/enzimologia , Fosfoglicerato Mutase/genética , Fosfoglicerato Mutase/metabolismoAssuntos
Erros Inatos do Metabolismo dos Carboidratos/patologia , Miopatias Mitocondriais/patologia , Metabolismo dos Carboidratos/fisiologia , Erros Inatos do Metabolismo dos Carboidratos/classificação , Erros Inatos do Metabolismo dos Carboidratos/genética , Frutose-Bifosfato Aldolase/deficiência , Frutose-Bifosfato Aldolase/genética , Glicogênio/deficiência , Glicogênio/metabolismo , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/metabolismo , Doença de Depósito de Glicogênio Tipo III/genética , Doença de Depósito de Glicogênio Tipo III/metabolismo , Doença de Depósito de Glicogênio Tipo IV/genética , Doença de Depósito de Glicogênio Tipo IV/metabolismo , Doença de Depósito de Glicogênio Tipo V/genética , Doença de Depósito de Glicogênio Tipo V/metabolismo , Doença de Depósito de Glicogênio Tipo VII/genética , Doença de Depósito de Glicogênio Tipo VII/metabolismo , Doença de Depósito de Glicogênio Tipo VIII/genética , Doença de Depósito de Glicogênio Tipo VIII/metabolismo , Humanos , L-Lactato Desidrogenase/deficiência , Miopatias Mitocondriais/classificação , Miopatias Mitocondriais/genética , Fosfoglicerato Quinase/deficiência , Fosfoglicerato Mutase/deficiência , Fosfoglicerato Mutase/genética , Fosforilase b/deficiênciaRESUMO
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.
Assuntos
Creatina , Doenças dos Cavalos/metabolismo , Deficiência Múltipla de Acil Coenzima A Desidrogenase/complicações , Fosforilação Oxidativa , Fosfoglicerato Mutase/deficiência , Condicionamento Físico Animal , Rabdomiólise/metabolismo , Animais , Aspartato Aminotransferases/sangue , Sequência de Bases , Creatina/urina , Creatina Quinase/sangue , Primers do DNA/genética , Feminino , Cavalos , L-Lactato Desidrogenase/sangue , Malonatos/urina , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Dados de Sequência Molecular , Deficiência Múltipla de Acil Coenzima A Desidrogenase/sangue , Deficiência Múltipla de Acil Coenzima A Desidrogenase/urina , Fosfoglicerato Mutase/genética , Rabdomiólise/etiologia , Análise de Sequência de DNA , Succinatos/urina , Ácido Úrico/urinaRESUMO
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.
Assuntos
Doenças Musculares/genética , Mutação/genética , Fosfoglicerato Mutase/deficiência , Fosfoglicerato Mutase/genética , Adolescente , Adulto , Análise Mutacional de DNA/métodos , Feminino , Humanos , Masculino , Doenças Musculares/enzimologia , Adulto JovemRESUMO
Glycolysis is one of the principle pathways of ATP generation in cells and is present in all cell tissues; in erythrocytes, glycolysis is the only pathway for ATP synthesis since mature red cells lack the internal structures necessary to produce the energy vital for life. Red cell deficiencies have been detected in all erythrocyte glycolytic pathways, although their frequencies differ owing to diverse causes, such as the affected enzyme and severity of clinical manifestations. The number of enzyme deficiencies known is endless. The most frequent glycolysis abnormality is pyruvate kinase deficiency, since around 500 cases are known, the first of which was reported in 1961. However, only approximately 200 cases were due to mutations. In contrast, only one case of phosphoglycerate mutase BB type mutation, described in 2003, has been detected. Most mutations are located in the coding sequences of genes, while others, missense, deletions, insertions, splice defects, premature stop codons and promoter mutations, are also frequent. Understanding of the crystal structure of enzymes permits molecular modelling studies which, in turn, reveal how mutations can affect enzyme structure and function.
Assuntos
Isomerases/genética , Mutação , Transferases/genética , Anemia Hemolítica/enzimologia , Anemia Hemolítica/genética , Anemia Hemolítica Congênita não Esferocítica , Animais , Bisfosfoglicerato Mutase/deficiência , Bisfosfoglicerato Mutase/genética , Eritrócitos/enzimologia , Glucose-6-Fosfato Isomerase/genética , Glicólise , Humanos , Isomerases/deficiência , Fosfoglicerato Quinase/deficiência , Fosfoglicerato Quinase/genética , Fosfoglicerato Mutase/deficiência , Fosfoglicerato Mutase/genética , Piruvato Quinase/deficiência , Piruvato Quinase/genética , Transferases/deficiência , Triose-Fosfato Isomerase/deficiência , Triose-Fosfato Isomerase/genéticaAssuntos
Doença de Depósito de Glicogênio/genética , Fosfoglicerato Mutase/deficiência , Fosfoglicerato Mutase/genética , Idade de Início , Idoso , Sequência de Aminoácidos , Sequência Conservada , Análise Mutacional de DNA , Doença de Depósito de Glicogênio/patologia , Heterozigoto , Humanos , Dados de Sequência Molecular , Músculos/patologia , Mutação de Sentido Incorreto , Fosfoglicerato Mutase/químicaRESUMO
BACKGROUND: Phosphoglycerate mutase (PGAM) deficiency (glycogen storage disease type X) has been reported in 12 patients of whom 9 were African American. OBJECTIVE: 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). DESIGN: Clinical, pathological, biochemical, and molecular analyses. SETTING: 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. MAIN OUTCOME MEASURES: Clinical course and biochemical and molecular features. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/metabolismo , Fosfoglicerato Mutase/deficiência , Adulto , Idoso , Creatina Quinase/sangue , Doença de Depósito de Glicogênio/fisiopatologia , Humanos , Itália , Masculino , Paquistão , Fosfoglicerato Mutase/genéticaRESUMO
Phosphofructokinase deficiency (Tarui disease) was the first disorder recognized to directly affect glycolysis. Since the discovery of the disease, in 1965, a wide range of biochemical, physiological and molecular studies have greatly contributed to our knowledge concerning not only phosphofructokinase function in normal muscle but also on the general control of glycolysis and glycogen metabolism. Studies on phosphofructokinase deficiency vastly enriched the field of glycogen storage diseases, making a relevant improvement also in the molecular genetic area. So far, more than one hundred patients have been described with prominent clinical symptoms characterized by muscle cramps, exercise intolerance, rhabdomyolysis and myoglobinuria, often associated with haemolytic anaemia and hyperuricaemia. The muscle phosphofructokinase gene is located on chromosome 12 and about 20 mutations have been described. Other glycogenoses have been recognised in the distal part of the glycolytic pathway: these are infrequent but some may induce muscle cramps, exercise intolerance and rhabdomyolysis. Phosphoglycerate Kinase, Phosphoglycerate Mutase, Lactate Dehydrogenase, beta-Enolase and Aldolase A deficiencies have been described as distal glycogenoses. From the molecular point of view, the majority of these enzyme deficiencies are sustained by "private" mutations.
Assuntos
Doença de Depósito de Glicogênio Tipo VII/diagnóstico , Doença de Depósito de Glicogênio Tipo VII/genética , Anemia Hemolítica/genética , Tolerância ao Exercício , Frutose-Bifosfato Aldolase/deficiência , Doença de Depósito de Glicogênio/enzimologia , Doença de Depósito de Glicogênio Tipo VII/complicações , Doença de Depósito de Glicogênio Tipo VII/enzimologia , Humanos , Hiperuricemia/genética , L-Lactato Desidrogenase/deficiência , Cãibra Muscular/genética , Mutação , Mioglobinúria/genética , Fosfofrutoquinases/deficiência , Fosfofrutoquinases/genética , Fosfoglicerato Quinase/deficiência , Fosfoglicerato Mutase/deficiência , Fosfopiruvato Hidratase/deficiência , Rabdomiólise/genéticaRESUMO
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.
Assuntos
Tolerância ao Exercício/genética , Músculo Esquelético/enzimologia , Doenças Musculares/enzimologia , Mioglobinúria/enzimologia , Fosfoglicerato Mutase/deficiência , Adolescente , Adulto , Negro ou Afro-Americano/genética , Biópsia , Creatina Quinase/sangue , Análise Mutacional de DNA , Teste de Esforço , Feminino , Humanos , Corpos de Inclusão/enzimologia , Corpos de Inclusão/genética , Corpos de Inclusão/patologia , Isquemia/enzimologia , Isquemia/genética , Isquemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Cãibra Muscular/enzimologia , Cãibra Muscular/genética , Cãibra Muscular/fisiopatologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Mutação de Sentido Incorreto , Mioglobinúria/genética , Mioglobinúria/fisiopatologia , Fosfoglicerato Mutase/genética , Retículo Sarcoplasmático/enzimologia , Retículo Sarcoplasmático/patologiaRESUMO
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.
Assuntos
Exercício Físico , Glucose/administração & dosagem , Lactase/administração & dosagem , Músculo Esquelético/efeitos dos fármacos , Fosfoglicerato Mutase/deficiência , Adulto , Teste de Esforço/métodos , Glicogênio Fosforilase Muscular/deficiência , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Método Simples-Cego , Fatores de Tempo , Resultado do TratamentoRESUMO
Ischemic forearm exercise invariably causes muscle cramps and pain in patients with glycolytic defects. We investigated an alternative diagnostic exercise test that may be better tolerated. Nine patients with McArdle disease, one with the partial glycolytic defect phosphoglycerate mutase deficiency, and nine matched, healthy subjects performed the classic ischemic forearm protocol and an identical protocol without ischemia. Blood was sampled in the median cubital vein of the exercised arm. Plasma lactate level increased similarly in healthy subjects during ischemic (Delta5.1 +/- 0.7mmol L(-1)) and non-ischemic (Delta4.4 +/- 0.3) tests and decreased similarly in McArdle patients (Delta-0.10 +/- 0.02 vs Delta-0.40 +/- 0.10mmol L(-1)). Postexercise peak lactate to ammonia ratios clearly separated patients and healthy controls in ischemic (McArdle, 4 +/- 2 [range, 1-12]; partial glycolytic defect phosphoglycerate mutase deficiency, 6; healthy, 33 +/- 4 [range, 17-56]) and non-ischemic (McArdle, 5 +/- 1 [range, 1-10]; partial glycolytic defect phosphoglycerate mutase deficiency, 5; healthy, 42 +/- 3 [range, 35-56]) protocols. Similar differences in lactate to ammonia ratio between patients and healthy subjects were observed in two other work protocols using intermittent handgrip contraction at 50% and static handgrip exercise at 30% of maximal voluntary contraction force. All patients developed pain and cramps during the ischemic test, and four had to abort the test prematurely. No patient experienced cramps in the non-ischemic test, and all completed the test. The findings indicate that the diagnostic ischemic forearm test for glycolytic disorders should be replaced by an aerobic forearm test.
Assuntos
Teste de Esforço , Exercício Físico , Antebraço/fisiopatologia , Doença de Depósito de Glicogênio Tipo V/diagnóstico , Adulto , Amônia/sangue , Teste de Esforço/efeitos adversos , Feminino , Antebraço/irrigação sanguínea , Doença de Depósito de Glicogênio Tipo V/sangue , Doença de Depósito de Glicogênio Tipo V/complicações , Força da Mão , Humanos , Isquemia/fisiopatologia , Ácido Láctico/sangue , Masculino , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Cãibra Muscular/etiologia , Dor/etiologia , Fosfoglicerato Mutase/deficiência , Valores de Referência , Fluxo Sanguíneo RegionalRESUMO
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.
Assuntos
Dantroleno/uso terapêutico , Músculos/metabolismo , Doenças Musculares/tratamento farmacológico , Doenças Musculares/metabolismo , Fosfoglicerato Mutase/deficiência , Adulto , Exercício Físico/fisiologia , Humanos , Masculino , Microscopia Eletrônica , Músculos/ultraestrutura , Doenças Musculares/fisiopatologiaRESUMO
We report here findings in a 51-year-old Japanese man with non-insulin-dependent diabetes mellitus who complained of exercise-induced cramps. Muscle biopsy showed scattered regenerating fibers, small angular fibers and increased PAS positive particles. Electron microscopic examination revealed an abnormal accumulation of glycogen particles in subsarcolenmmal areas and between myofibrils while chemical studies showed an increased glycogen concentration and decreased phosphoglycerate mutase (PGAM), 46.9% of the normal mean value. Thus, partial PGAM deficiency, insulin resistance and mild diabetic sensory-motor polyneuropathy can induce severe cramps.
Assuntos
Neuropatias Diabéticas/enzimologia , Fosfoglicerato Mutase/deficiência , Biópsia , Cromossomos Humanos Par 7 , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/patologia , Teste de Esforço/efeitos adversos , Glicogênio/metabolismo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Cãibra Muscular/etiologia , Cãibra Muscular/metabolismo , Cãibra Muscular/patologia , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Miofibrilas/metabolismo , Miofibrilas/ultraestrutura , Fosfoglicerato Mutase/genética , Mutação Puntual , Tomografia Computadorizada por Raios XRESUMO
Human muscle phosphoglycerate mutase (PGAM-M) deficiency is associated with exercise intolerance, muscle cramps, chronic serum CK elevation, and recurrent episodes of myoglobinuria. Ten patients have been described: 7 African Americans, 1 African, and 2 Caucasians from the Italian kindred described here. Molecular genetic analysis has revealed three different mutations in the PGAM-M gene. The propositus of the Italian family was homozygous for a unique point mutation at codon 90 in exon 1, a C-to-T transition converting an encoded arginine to tryptophan. His sister, who had similar complaints, was also homozygous for this mutation while the paternal grandfather, both parents, a brother and a nephew of the propositus were heterozygous for the mutation. Our studies exclude that PGAM-M deficiency is limited to African Americans, and suggest that the molecular heterogeneity of this rare disorder may be due to a "founder effect" in different ethnic groups.