A single amino acid substitution (157 Gly----Val) in a phosphoglycerate kinase variant (PGK Shizuoka) associated with chronic hemolysis and myoglobinuria

Fujii, H.; Kanno, Hitoshi; Hirono, Akira; Shiomura, Tadahiko; Shiro, Motoo

doi:10.1182/blood.v79.6.1582.1582

Cited by 38 publications

(12 citation statements)

References 15 publications

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“…All nine patients complained of exercise intolerance, with cramps and myoglobinuria. Two more patients had hemolytic anemia53 or mild mental retardation140 in addition to myopathy. Molecular defects have been documented in three patients with pure myopathy,26, 64, 156 as well as in the two patients with myopathy‐plus 53, 139…”

Section: Glycogenoses Causing Exercise Intolerance Cramps and Myoglmentioning

confidence: 99%

Muscle glycogenoses

2001

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There are 11 hereditary disorders of glycogen metabolism affecting muscle alone or together with other tissues, and they cause two main clinical syndromes: episodic, recurrent exercise intolerance with cramps, myalgia, and myoglobinuria; or fixed, often progressive weakness. Great strides have been made in our understanding of the molecular bases of these disorders, all of which show remarkable genetic heterogeneity. In contrast, the pathophysiological mechanisms underlying acute muscle breakdown and chronic weakness remain unclear. Although glycogen storage diseases have been studied for decades, new biochemical defects are still being discovered, especially in the glycolytic pathway. In addition, the pathogenesis of polyglucosan deposition is being clarified both in traditional glycogenoses and in disorders such as Lafora's disease. In some conditions, combined dietary and exercise regimens may be of help, and gene therapy, including recombinant enzyme replacement, is being actively pursued.

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Section: Glycogenoses Causing Exercise Intolerance Cramps and Myoglmentioning

confidence: 99%

Muscle glycogenoses

2001

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“…Calculated range of disease Properties of deficient enzymes Number of References diseased minimum range of minimum enzyme unstable kinetic change in persons survival chronic normal activity variants change isoenzyme activity disease activity ? - Tanaka, 1990;Valentine, 1983;Board, 1978;Rijksen, 1983;Miwa, 1985;Paglia, 1981;Necheles, 1970Tanka, 1990Paglia, 1974;Zanella, 1980;Neubauer, 1990;Arnold, 1973Tanka, 1990Vora, 1983;Valentine, 1984 ;Fogelfeld, 1990Kishi, 1987Miwa, 1981 ;Valentine, 1984Eber, 1979Valentine, 1984;Rosa, 1985 ;Zanella, 1985Waller, 1974Tanaka, 1990Maeda, 1991 ;Fujii, 1980Fujii, , 1992Valentine, 1984Schroter, 1965Rosa, 1973Rosa, , 1978Buc, 1974;Rosa, 1989;Tanaka, 1990 Syllm- Rapoport, 1965…”

Section: Enzymementioning

confidence: 99%

“…During the past two decades, we have reached at an advanced level in the mathematical modelling of the main metabolic pathways of the human erythrocyte (Rapoport et al, 1976;Holzhutter et al, 1985;Schuster et al, 1988). These models have been successfully employed to describe stationary and time-dependent metabolic states of the cell under normal physiological conditions as well as in the presence of enzyme deficiencies of pyruvate kinase (Holzhutter et al, , 1990) and glucose 6-phosphate dehydrogenase (Schuster et al, 1989 Krietsch et al, 1977 (V,,,,, = 19-83%); Fujii et al, 1992 (V,-= 0.7%); Rosa et al, 1982 (V,,,,, = 2.7%). (C) Pymvate kinase deficiency.…”

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confidence: 99%

Use of Mathematical Models for Predicting the Metabolic Effect of Large‐Scale Enzyme Activity Alterations

Schuster

Holzhütter

1995

European Journal of Biochemistry

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There are numerous examples showing that the metabolism of cells can be severely impaired if the activity of only one of the participating enzymes undergoes large-scale alterations, resulting, for example, from spontaneous mutations (inherited or aquired enzymopathies), the administration of toxic drugs or self-inactivation of enzymes during cell aging. However, a quantitative relationship between the degree of enzyme deficiency and the extent of metabolic dysfunction is very difficult to establish by experimental means. An alternative is to tackle this problem by mathematical modelling. Our approach is based on a comprehensive mathematical model of the energy and redox metabolism for human erythrocytes. We calculate stationary states of the cell metabolism, varying the activity of each of the participating enzymes by several orders of magnitude. The metabolic states are then evaluated in terms of a performance function which relates the metabolic variables to the overall functional fitness of the cell. The performance function for the erythrocyte takes into account the homeostasis of three essential metabolic variables : the energetic state (ATP), the reductive capacity (reduced glutathione), and the osmotic state. Based on the behaviour of the performance function at varying enzyme activities, we estimate those ranges of enzyme activities, in which the metabolic alterations should be either tolerable, associated with non-chronic or chronic diseases, or letal. For most enzymopathies, the experimental and clinical observations can be satisfactorily rationalized by the computational results. Moreover, a surprisingly high correlation is found between the range of the activity range where disease is predicted by the model and the observed number of diseased probands.Another objective of our study was to contribute to the theory of metabolic control. The well-elaborated concept of the metabolic control theory is restricted to (infinitely) small activity alterations. In order to quantify the metabolic effect of finite (large-scale) changes in the activity of an enzyme, we propose, as a control measure, the effective activity Em, defined as the relative activity of an enzyme (with respect to the activity in a reference state) required to bring about a change in the stationary value of a metabolic variable by the (finite) factor a. We demonstrate that none of the existing extrapolation methods using the conventional control coefficient is capable to provide reliable predictions of the effective activities for all enzymes of erythrocyte metabolism.

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“…PGK deficiency was confirmed by enzyme assays as well as by the sequence of the patient's PGK1 gene. To screen initially for enzyme deficiencies related to haemolytic anaemia, RBC enzymatic analysis was performed as described previously (Fujii et al, 1992). All the substrates used to measure RBC enzyme activities were purchased from Boehringer Mannheim (Mannheim, Germany).…”

Section: Methodsmentioning

confidence: 99%

A novel missense mutation (1060G → C) in the phosphoglycerate kinase gene in a Japanese boy with chronic haemolytic anaemia, developmental delay and rhabdomyolysis

et al. 2003

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Summary. We report the case of a 3‐year‐old Japanese boy with phosphoglycerate kinase 1 (PGK1) deficiency (Online Mendelian Inheritance in Man entry 311800). The patient had anaemia and jaundice at birth, necessitating exchange transfusions for 2 d. After one red blood cell transfusion at age 2 months, his Hb level was 8–9 g/dl, his reticulocyte counts were 300–500 × 109/l, and his total bilirubin level was 25·65–42·75 µmol/l. The patient suffered two episodes of respiratory infection‐associated haemolytic crisis and rhabdomyolysis during early infancy. At age 3·0 years, his developmental milestones (developmental quotients measured using the Tsumori–Inage methods) score was 49% (normal 74–131%), and his height was below average by −2·0 standard deviations. The diagnosis of PGK1 deficiency was made based on his remarkably low (< 10% of normal) erythrocyte PGK enzyme activity level and the identification of a novel missense (1060G→C) PGK1 gene mutation. This mutation results in the Ala‐353Pro amino acid substitution, which has been designated PGK Kyoto. The patient developed the full clinical symptoms of PGK1 deficiency including haemolytic anaemia, myopathy, central nervous system disorder and growth retardation, which is unusual.

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A single amino acid substitution (157 Gly----Val) in a phosphoglycerate kinase variant (PGK Shizuoka) associated with chronic hemolysis and myoglobinuria

Cited by 38 publications

References 15 publications

Muscle glycogenoses

Muscle glycogenoses

Use of Mathematical Models for Predicting the Metabolic Effect of Large‐Scale Enzyme Activity Alterations

A novel missense mutation (1060G → C) in the phosphoglycerate kinase gene in a Japanese boy with chronic haemolytic anaemia, developmental delay and rhabdomyolysis

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