Muscle Phosphofructokinase Deficiency Research Articles

Unique Exercise Lactate Profile in Muscle Phosphofructokinase Deficiency (Tarui Disease); Difference Compared with McArdle Disease.

Glycogen storage disease V (GSDV, McArdle disease) and GSDVII (Tarui disease) are the most common of the rare disorders of glycogen metabolism. Both are associated with low lactate levels on exercise. Our aim was to find out whether lactate response associated with exercise testing could distinguish between these disorders. Two siblings with Tarui disease, two patients with McArdle disease and eight healthy controls were tested on spiroergometric exercise tests with follow-up of venous lactate and ammonia. A late increase of lactate about three times the basal level was seen 10-30 min after exercise in patients with Tarui disease being higher than in McArdle disease and lower than in the controls. Ammonia was increased in Tarui disease. Our results suggest that follow-up of lactate associated with exercise testing can be utilized in diagnostics to distinguish between different GSD diseases.

Juvenile-onset permanent weakness in muscle phosphofructokinase deficiency

We describe a 41-year-old Moroccan woman with phosphofructokinase (PFK) deficiency who presented slowly progressive muscular weakness since childhood, without rhabdomyolysis episode or hemolytic anemia. Deltoid biopsy revealed massive glycogen storage in the majority of muscle fibers and polysaccharide deposits. PFK activity in muscle was totally absent. A novel homozygous non-sense mutation was detected in PFKM gene. Our observation suggests that juvenile-onset fixed muscle weakness may be a predominant clinical feature of PFK deficiency. Vacuolar myopathy with polyglucosan deposits remains an important morphological hallmark of this rare muscle glycogenosis.

Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII)

Muscle phosphofructokinase (PFKM) deficiency, a rare disorder of glycogen metabolism also known as glycogen storage disease type VII (GSDVII), is characterized by exercise intolerance, myalgias, cramps and episodic myoglobinuria associated with compensated hemolytic anaemia and hyperuricemia. We studied five patients with PFKM deficiency coming from different Italian regions. All probands showed exercise intolerance, hyperCKemia, cramps and myoglobinuria. One patient had a mild hypertrophic cardiomyopathy. Biochemical studies revealed residual PFK activity ranging from 1 to 5%. Molecular genetic analysis identified four novel mutations in the PFKM gene. In our series of patients, clinical and laboratory features were similar in all but one patient, who had an unusual phenotype characterized by 25years disease history, high CK levels, hypertrophic cardiomyopathy with paroxysmal atrial fibrillation without fixed muscle weakness.

P5.48 Infantile-onset permanent weakness in muscle phosphofructokinase deficiency

P5.48 Infantile-onset permanent weakness in muscle phosphofructokinase deficiency

Muscle Phosphofructokinase Deficiency With Neonatal Seizures and Nonprogressive Course

Muscle phosphofructokinase deficiency is known to cause childhood-onset exercise intolerance, muscle cramps, and myoglobinuria. Rarely, phosphofructokinase deficiency manifests in infancy as congenital myopathy and arthrogryposis with fatal outcome. Here, the authors report the case of a 2-year-old boy with infantile phosphofructokinase deficiency who presented on the third day of life with intractable seizures. Two of his sisters died in infancy with hypotonia, developmental delay, and seizure disorder of unclear etiology. On follow-up, he has had hypotonia and mild developmental delay. However, he continues to gain developmental milestones, and his seizures are now well controlled on carbamazepine. This presentation suggests expanding the phenotype of muscle phosphofructokinase deficiency to include early-onset neonatal seizures. It is also unusual in the relatively milder course of the infantile form of this disorder. The authors propose that this form of glycogen storage disease be considered in the differential diagnosis of neonatal seizures and early infantile nonprogressive muscle weakness.

G.P.1 08 Phenotype–genotype correlation in two families with muscle phosphofructokinase deficiency

Muscle phosphofructokinase deficiency (PFK) is a relatively rare glycogenosis characterized by mild proximal myopathy associated with compensated hemolytic anaemia and hyperuricemia. We report 2 unrelated families with PFK deficiency. Family 1: A 45-year-old man (pt1) complained of episodic diffuse myalgias, vomiting and dark urines after mild exercise. He had a mild hypertrophic cardiomyopathy. Neurological examination was unremarkable. Family history was negative but his older 12-year-old son showed elevated CK levels (max 600IU/l).

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.

Free Mg2+ concentration in the calf muscle of glycogen phosphorylase and phosphofructokinase deficiency patients assessed in different metabolic conditions by 31P MRS.

BackgroundThe increase in cytosolic free Mg2+ occurring during exercise and initial recovery in human skeletal muscle is matched by a decrease in cytosolic pH as shown by in vivo phosphorus magnetic resonance spectroscopy (31P MRS). To investigate in vivo to what extent the homeostasis of intracellular free Mg2+ is linked to pH in human skeletal muscle, we studied patients with metabolic myopathies due to different disorders of glycogen metabolism that share a lack of intracellular acidification during muscle exercise.MethodsWe assessed by 31P MRS the cytosolic pH and free magnesium concentration ([Mg2+]) in calf muscle during exercise and post-exercise recovery in two patients with McArdle's disease with muscle glycogen phosphorylase deficiency (McArdle), and two brothers both affected by Tarui's disease with muscle phosphofructokinase deficiency (PFK).ResultsAll patients displayed a lack of intracellular acidosis during muscle exercise. At rest only one PFK patient showed a [Mg2+] higher than the value found in control subjects. During exercise and recovery the McArdle patients did not show any significant change in free [Mg2+], while both PFK patients showed decreased free [Mg2+] and a remarkable accumulation of phosphomonoesters (PME). During initial recovery both McArdle patients showed a small increase in free [Mg2+] while in PFK patients the pattern of free [Mg2+] was related to the rate of PME recovery.Conclusioni) homeostasis of free [Mg2+] in human skeletal muscle is strongly linked to pH as shown by patients' [Mg2+] pattern during exercise;ii) the pattern of [Mg2+] during exercise and post-exercise recovery in both PFK patients suggests that [Mg2+] is influenced by the accumulation of the phosphorylated monosaccharide intermediates of glycogenolysis, as shown by the increased PME peak signal.iii) 31P MRS is a suitable tool for the in vivo assessment of free cytosolic [Mg2+] in human skeletal muscle in different metabolic conditions;

Impaired aerobic glycolysis in muscle phosphofructokinase deficiency results in biphasic post-exercise phosphocreatine recovery in 31P magnetic resonance spectroscopy

Using 31P magnetic resonance spectroscopy, energy metabolism in calf muscles of two patients with biochemically and genetically proven muscular phosphofructokinase deficiency, and an asymptomatic heterozygote was monitored during isometric foot plantarflexion performed under aerobic and anaerobic conditions and in the aerobic recovery phases. In the heterozygote only a moderate alteration from normal was found in terms of an elevated ATP demand during exercise. In the homozygote, hexose phosphates, indicated as phosphomonoesters, increased dramatically during contraction. Phosphomonoester accumulation resulted in consumption of free inorganic phosphate (P i). During ischemic exercise the absence of glycolytic ATP formation resulted in a linear time course of phosphocreatine breakdown and a moderate alkalinization. During the recovery, phosphocreatine resynthesis showed a biphasic time course, indicating that mitochondrial function itself was not directly affected. At first glance, the early depletion of P i below initial resting levels and the rate of phosphate splitting from sugar phosphates seemed to become the limiting factor for the rate of the oxidative phosphorylation and creatine kinase reaction. However, the actual concentrations of P i and ADP estimated at the onset of delay were too high to exclusively explain the dramatic delay in PCr resynthesis. For this reason, a reduced turnover of the citric acid cycle was assumed, which was caused by the complete absence of glycolysis in PFK deficiency patients. Furthermore, results from PFK deficiency patients were compared with previous findings from myophosphorylase deficiency patients in the literature.

Sympathetic activation in exercise is not dependent on muscle acidosis. Direct evidence from studies in metabolic myopathies.

Muscle acidosis has been implicated as a major determinant of reflex sympathetic activation during exercise. To test this hypothesis we studied sympathetic exercise responses in metabolic myopathies in which muscle acidosis is impaired or augmented during exercise. As an index of reflex sympathetic activation to muscle, microneurographic measurements of muscle sympathetic nerve activity (MSNA) were obtained from the peroneal nerve. MSNA was measured during static handgrip exercise at 30% of maximal voluntary contraction force to exhaustion in patients in whom exercise-induced muscle acidosis is absent (seven myophosphorylase deficient patients; MD [McArdle's disease], and one patient with muscle phosphofructokinase deficiency [PFKD]), augmented (one patient with mitochondrial myopathy [MM]), or normal (five healthy controls). Muscle pH was monitored by 31P-magnetic resonance spectroscopy during handgrip exercise in the five control subjects, four MD patients, and the MM and PFKD patients. With handgrip to exhaustion, the increase in MSNA over baseline (bursts per minute [bpm] and total activity [%]) was not impaired in patients with MD (17+/-2 bpm, 124+/-42%) or PFKD (65 bpm, 307%), and was not enhanced in the MM patient (24 bpm, 131%) compared with controls (17+/-4 bpm, 115+/-17%). Post-handgrip ischemia studied in one McArdle patient, caused sustained elevation of MSNA above basal suggesting a chemoreflex activation of MSNA. Handgrip exercise elicited an enhanced drop in muscle pH of 0.51 U in the MM patient compared with the decrease in controls of 0.13+/-0.02 U. In contrast, muscle pH increased with exercise in MD by 0.12+/-0.05 U and in PFKD by 0.01 U. In conclusion, patients with glycogenolytic, glycolytic, and oxidative phosphorylation defects show normal muscle sympathetic nerve responses to static exercise. These findings indicate that muscle acidosis is not a prerequisite for sympathetic activation in exercise.

Paradoxically enhanced glucose production during exercise in humans with blocked glycolysis caused by muscle phosphofructokinase deficiency.

Muscle phosphofructokinase deficiency (PFKD) is characterized by exercise intolerance due to the enzymatic block in muscle glycolysis. Glucose infusion increases exertional fatigue in these patients, probably by decreasing the availability of free fatty acids (FFA) and ketones, which play a crucial role in ATP production during exercise in PFKD. This suggests that a lower than normal hepatic glucose production would be appropriate during exercise in PFKD. To investigate glucoregulation in PFKD, we measured glucose turnover and hormonal and metabolic responses to 20 minutes of cycle exercise at near maximal effort in three patients with PFKD and in healthy matched controls studied at the same absolute (A, 15 to 30 Watts) and relative (R, 35 to 80 Watts, matched heart rates) work load as the patients. During exercise, mean glucose production was higher in all patients versus controls (30 +/- 4 versus A: 18 +/- 2 and R: 20 +/- 1 mumol.min-1.kg-1). Mean glucose utilization during exercise was similar in patients and controls working at the same relative work load and higher than in controls at the low work load. Exercise-induced increases in arterialized blood were higher in all patients for glucose, FFA, growth hormone, glucagon, and norepinephrine. Plasma alanine and lactate always decreased during exercise in patients and consistently increased in controls. In conclusion, an enhanced neuroendocrine response and a paradoxically exaggerated mobilization of glucose occurs during exercise in PFKD. The responses are probably initiated by neural feedback elicited by disturbances in local muscle metabolism. The responses promote delivery of oxidizable fat to muscle, but at the expense of accumulation and futile cycling of glucose.

Muscle phosphofructokinase deficiency in two generations

Phosphofructokinase (PFK) is the key regulatory enzyme of glycolysis. Patients lacking the muscular isoform of PFK typically present with myopathy and compensated hemolysis (glycogenosis type VII or Tarui's disease). Since 1965 about 30 cases of muscular PFK deficiency have been reported. In most cases family history suggests a recessive inherited trait. We describe a family of Ashkenazi Jewish origin with two members in subsequent generations suffering from muscular PFK deficiency. The propositus, a 19-year-old male patient, presented with weakness, myalgias and exercise intolerance since early infancy. His father also had early fatigue on exercise with myalgias; the mother and a 12-year-old brother were asymptomatic. Muscle biopsy of both the propositus and his father showed increased glycogen storage and absent histochemical stain for PFK. Biochemical studies of muscle revealed a markedly decreased PFK activity and DNA analysis of the muscle PFK gene revealed compound heterozygosity in both cases. This is the first description of proven muscle PFK deficiency (glycogenosis type VII) in two subsequent generations.

Myogenic hyperuricemia: what can we learn from metabolic myopathies?

The association of muscle glycogenosis with hyperuricemia led to the identification of a unique purine disorder. Myogenic hyperuricemia is ascribed to excessive degradation of muscle purine nucleotides, secondary to impaired ATP generation. Although this pathophysiological condition has been observed not only in glycolytic defects but also in mitochondrial diseases affecting lipid and carbohydrate oxidation, it is most common and prominent in muscle phosphofructokinase deficiency, in which neither glycogen nor glucose can be used as metabolic fuels. The first key reaction of muscle purine degradation is catalysis by AMP deaminase. Numerous studies have indicated that AMP deaminase may play an important role in energy metabolism in contracting muscle. Arguments against this hypothesis have emerged through analyses on muscle AMP deaminase deficiency. According to a recent study, the mutant allele is extremely frequent among Caucasians and African-Americans, suggesting that many individuals with this enzyme defect may be clinically asymptomatic. Further study is required to explain the significance of muscle purine degradation in energy metabolism.

Various classes of mutations in patients with phosphofructokinase deficiency (Tarui's disease).

Muscle phosphofructokinase (PFK-M) deficiency (glycogenosis type VII, Tarui's disease) is characterized by intolerance to vigorous exercise, often accompanied by myoglobinuria. The disease is inherited as an autosomal recessive trait. The clinical manifestations are similar to those in myophosphorylase deficiency (McArdle's disease), and the diagnosis required demonstration of the enzyme defect in muscle biopsy. In the Western hemisphere PFK deficiency appears to be prevalent among people of Ashkenazi Jewish descent. To define the molecular basis of this myopathy, we have studied 11 Ashkenazi and 2 non-Ashkenazi families with the disease. Ashkenazi patients share two common pathogenic mutations, a splicing defect and a nucleotide deletion, which account for approximately 95% of mutant alleles. The molecular diagnosis is now possible in this population by using simple PCR-based tests to screen for these mutations.

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.

A New Variant of Muscle Phosphofructokinase Deficiency in a Japanese Case with Abnormal RNA Splicing

A genetic defect was investigated in a newly diagnosed Japanese case with muscle type phosphofructokinase (PFK-M) deficiency. Polymerase chain reaction (PCR) amplification of patient cDNA revealed an in-frame truncation of 165 bases. This was compatible to the complete deletion of exon 19. The rest of the sequence was identical to that of the normal PFK-M cDNA. Sequencing of PCR amplified genomic DNA of the patient revealed a point mutation from G to A at the 5′donor site of intron 19. This mutation resulted in the skipping of exon 19 in the patient mRNA. Homozygosity of this patient was confined by allele specific amplification of the genomic DNA. Donor mutations in intron 15 and intron 5 associated with different splicing errors were previously reported to cause this disease. Thus, the human PFK-M gene mutations are heterogeneous, however, the donor mutations and splicing errors would represent one of the frequent causes of this disease.

Muscle metabolism during lactate infusion in human phosphofructokinase deficiency

We studied the effect of intravenous infusion of sodium lactate (La) on muscle high-energy phosphate metabolism, pH, and venous effluent [NH3] in three patients with muscle phosphofructokinase (PFK) deficiency and three healthy subjects during maximal-effort rhythmic handgrip exercise (5 s of contraction alternated with 5 s of rest) performed for 3 min. Healthy subjects were matched to PFK-deficient patients for gender and maximal handgrip strength. Force production was recorded and during lactate infusion was matched to that without lactate. 31P-magnetic resonance spectroscopy was used to measure intracellular phosphocreatine (PCr), orthophosphate (Pi), ATP, and pH in the flexor digitorum profundus of the exercising forearm. La infusion had no effect on healthy subjects or patients during rest. In healthy subjects, La infusion had no effect on depletion of PCr; accumulation of Pi, ADP, or venous effluent NH3; or decline in pH in exercising muscle. In contrast, during exercise in PFK-deficient patients, [PCr] was higher (17.9 +/- 1.9 vs. 13.1 +/- 1.4 mmol/kg) and [phosphomonoester] (11.4 +/- 1.3 vs. 6.5 +/- 1.4 mmol/kg), [Pi] (9.2 +/- 1.8 vs. 5.0 +/- 0.7 mmol/kg), [ADP] (60.4 +/- 7.0 vs. 37.9 +/- 9.9 mumol/kg), and venous effluent [NH3] (335 +/- 136 vs. 176 +/- 61 mM) were lower (P < 0.05) during La infusion than in control conditions. The effects of La infusion on intracellular [PCr], [Pi], [phosphomonoester], [ADP], and [NH3] in PFK-deficient patients are consistent with the hypothesis that exogenous La augments the rate of oxidative phosphorylation in active muscle by bypassing the enzymatic block at PFK.

Low glucose-1, 6-bisphosphate and high fructose-2, 6-bisphosphate concentrations in muscles of patients with glycogenosis types VII and V

The level of glucose-1, 6-bisphosphate, a potent allosteric activator of phosphofructokinase, was markedly decreased in muscles of patients with glycogenosis type VII (muscle phosphofructokinase deficiency) and type V (muscle phosphorylase deficiency). Glucose-1-phosphate kinase activity in muscle was virtually absent in a patient with glycogenosis type VII, whereas it was normal in a patient with type V blycogenosis. Glucose-1-phosphate level was increased in type VII glycogenosis, whereas it was decreased in type V glycogenosis. Another activator of phosphofructokinase, fructose-2, 6-bisphosphate was increased in muscles of patients with both types of glycogenosis although it was much higher in type VII than in type V. This finding may be partly related to the difference of fructose-6-phosphate concentrations. The results suggest that phosphofructokinase would contribute to the major glucose-1-phosphate kinase activity in normal human muscle and would also form a kind of self-activating system.

Apparent absence of glycogen branching enzyme activity in phosphofructokinase deficiency

A 30-year-old woman with clinical features and biochemical findings of muscle phosphofructokinase deficiency was found to have a very low level of alpha-1,4-glucan:alpha-1,4-glucan-6-transglucosylase (branching enzyme, EC 2.4.1.18) activity in muscle. In contrast, branching enzyme activity in the leukocytes was in the range of control values. After sedimentation of the glycogen from muscle homogenates by centrifugation at 105,000 g, branching enzyme activity in muscle of the patient was similar to that of control subjects. This patient illustrates the possibility of falsely diagnosing branching enzyme deficiency when muscle glycogen content is elevated. It is likely that such an artefact may also cause a false positive diagnosis of branching enzyme deficiency in other metabolic diseases associated with glycogen accumulation.

Abnormal high-energy phosphate metabolism in human muscle phosphofructokinase deficiency

We studied the pattern of high-energy phosphate metabolism in five patients with phosphofructokinase deficiency (PFKD) and five healthy subjects (HS) during graded rhythmic handgrip performed for 5 min at 17, 33, 50, and 100% of maximal voluntary contraction (MVC). The range of MVC was similar in both groups. Force production was recorded, and intracellular concentrations of phosphorus compounds and pH were measured in the flexor digitorum profundus of the active forearm. At exercise intensities greater than or equal to 50% MVC, changes in concentrations of high-energy phosphate metabolites were abnormal in PFKD. During maximal effort, [ADP], calculated from the creatine kinase reaction, was 64.3 +/- 13.5 (SE) mumol/kg in PFKD vs. 25.7 +/- 4.0 in HS (P less than 0.05). Ammonia (NH3), a product of AMP deamination and an index of muscle [AMP], increased approximately twofold more in venous effluent during maximal forearm exercise in PFKD than in HS (P less than 0.05). Phosphocreatine concentration was 9.4 +/- 1.3 (SE) mmol/kg in HS and 13.0 +/- 1.7 in PFKD (P less than 0.05). Inorganic phosphate concentration was 15.8 +/- 1.4 mmol/kg in HS and 7.4 +/- 0.5 in PFKD (P less than 0.05). During strenuous exercise, PFKD patients exhibit an impairment in the rephosphorylation of ADP related to a subnormal oxidative capacity, an absence of glycolysis, and an attenuated breakdown of phosphocreatine.