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A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia.

Mamoune A, Bahuau M, Hamel Y, Serre V, Pelosi M, Habarou F, Nguyen Morel MA, Boisson B, Vergnaud S, Viou MT, Nonnenmacher L, Piraud M, Nusbaum P, Vamecq J, Romero N, Ottolenghi C, Casanova JL, de Lonlay P - PLoS Genet. (2014)

Bottom Line: Myoglobinuria was always triggered by febrile illnesses.Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines, and reduced by dexamethasone.We also propose a treatment for this severe disease.

View Article: PubMed Central - PubMed

Affiliation: INSERM U781, Institut Imagine des Maladies Génétiques, Université Paris Descartes et Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker, AP-HP, Paris, France.

ABSTRACT
Aldolase A deficiency has been reported as a rare cause of hemolytic anemia occasionally associated with myopathy. We identified a deleterious homozygous mutation in the ALDOA gene in 3 siblings with episodic rhabdomyolysis without hemolytic anemia. Myoglobinuria was always triggered by febrile illnesses. We show that the underlying mechanism involves an exacerbation of aldolase A deficiency at high temperatures that affected myoblasts but not erythrocytes. The aldolase A deficiency was rescued by arginine supplementation in vitro but not by glycerol, betaine or benzylhydantoin, three other known chaperones, suggesting that arginine-mediated rescue operated by a mechanism other than protein chaperoning. Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines, and reduced by dexamethasone. Our results expand the clinical spectrum of aldolase A deficiency to isolated temperature-dependent rhabdomyolysis, and suggest that thermolability may be tissue specific. We also propose a treatment for this severe disease.

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Related in: MedlinePlus

1A: Family tree showing the 3 affected children.1B: Crystal structure of human muscle aldolase complexed with fructose 1,6-bisphosphate (isoenzyme A, PDB code 4ALD) superimposed with the tetrameric crystal structure of human brain aldolase (isoenzyme C, PDB code 1XFB), which is similar to the muscle isoenzyme. Chains A, B, C and D of isoenzyme C are shown in orange, light blue, light green and pink, respectively. Monomeric isoenzyme A is shown in grey and is superimposed on chain D of the tetrameric isoenzyme C. Fructose 1,6-bisphosphate co-crystallized with isoenzyme A is shown in yellow. The mutated residue described in this report (red arrow) and the mutated amino acids previously described are highlighted in the magnified structure. The structural and functional consequences of the mutations are described in Table 1. 1C: aldolase A, glucose-6-phosphate dehydrogenase (G6PD) and hexokinase activities in the erythrocytes of the parents, the healthy sibling and the 3 affected patients (*: patients 2, 3, 4). 1D: in vitro muscle study of anaerobic glycogenolysis and glycolysis (only patient 3); results of lactate production (µmol/g muscle in 30 minutes) after incubation with various substrates.
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pgen-1004711-g001: 1A: Family tree showing the 3 affected children.1B: Crystal structure of human muscle aldolase complexed with fructose 1,6-bisphosphate (isoenzyme A, PDB code 4ALD) superimposed with the tetrameric crystal structure of human brain aldolase (isoenzyme C, PDB code 1XFB), which is similar to the muscle isoenzyme. Chains A, B, C and D of isoenzyme C are shown in orange, light blue, light green and pink, respectively. Monomeric isoenzyme A is shown in grey and is superimposed on chain D of the tetrameric isoenzyme C. Fructose 1,6-bisphosphate co-crystallized with isoenzyme A is shown in yellow. The mutated residue described in this report (red arrow) and the mutated amino acids previously described are highlighted in the magnified structure. The structural and functional consequences of the mutations are described in Table 1. 1C: aldolase A, glucose-6-phosphate dehydrogenase (G6PD) and hexokinase activities in the erythrocytes of the parents, the healthy sibling and the 3 affected patients (*: patients 2, 3, 4). 1D: in vitro muscle study of anaerobic glycogenolysis and glycolysis (only patient 3); results of lactate production (µmol/g muscle in 30 minutes) after incubation with various substrates.

Mentions: Three patients from a Moroccan consanguineous family (Figure 1A) suffered from recurrent episodes of rhabdomyolysis that required numerous hospitalizations from 2 months of age. These acute episodes were invariably triggered by febrile illnesses. The presenting symptoms were an inability to walk and myalgia. During the acute episodes, plasma creatine phosphokinase (CK) levels were variable, ranging from markedly elevated (peak levels: 180,000–450,000 U/L, N<150) with overt myoglobinuria to milder elevations (3,000 U/L). The following tests were normal: hemoglobin, hematocrit, mean corpuscular volume, plateletcount, reticulocyte count, bilirubin, haptoglobin, ferritin, Coombs' test, urea, creatinine, blood gasses, plasma lactate, carnitine, blood acylcarnitine profile, plasma amino acids, and urinary organic acids. Electromyography, brain MRI, abdominal ultrasonography, and echocardiography were also normal. CK levels ranged from normal (<150 U/L) to elevated (up to 1,800 U/L) in all 3 patients between acute episodes. The clinical examination and muscle tests performed 2 months after an episode of rhabdomyolysis were normal for each patient, at ages 9, 10, and 11 years respectively. Family history revealed neither chronic hemolytic anemia, nor episodes of jaundice or blood transfusions. Two patients suffered from learning disabilities and required a special school.


A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia.

Mamoune A, Bahuau M, Hamel Y, Serre V, Pelosi M, Habarou F, Nguyen Morel MA, Boisson B, Vergnaud S, Viou MT, Nonnenmacher L, Piraud M, Nusbaum P, Vamecq J, Romero N, Ottolenghi C, Casanova JL, de Lonlay P - PLoS Genet. (2014)

1A: Family tree showing the 3 affected children.1B: Crystal structure of human muscle aldolase complexed with fructose 1,6-bisphosphate (isoenzyme A, PDB code 4ALD) superimposed with the tetrameric crystal structure of human brain aldolase (isoenzyme C, PDB code 1XFB), which is similar to the muscle isoenzyme. Chains A, B, C and D of isoenzyme C are shown in orange, light blue, light green and pink, respectively. Monomeric isoenzyme A is shown in grey and is superimposed on chain D of the tetrameric isoenzyme C. Fructose 1,6-bisphosphate co-crystallized with isoenzyme A is shown in yellow. The mutated residue described in this report (red arrow) and the mutated amino acids previously described are highlighted in the magnified structure. The structural and functional consequences of the mutations are described in Table 1. 1C: aldolase A, glucose-6-phosphate dehydrogenase (G6PD) and hexokinase activities in the erythrocytes of the parents, the healthy sibling and the 3 affected patients (*: patients 2, 3, 4). 1D: in vitro muscle study of anaerobic glycogenolysis and glycolysis (only patient 3); results of lactate production (µmol/g muscle in 30 minutes) after incubation with various substrates.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230727&req=5

pgen-1004711-g001: 1A: Family tree showing the 3 affected children.1B: Crystal structure of human muscle aldolase complexed with fructose 1,6-bisphosphate (isoenzyme A, PDB code 4ALD) superimposed with the tetrameric crystal structure of human brain aldolase (isoenzyme C, PDB code 1XFB), which is similar to the muscle isoenzyme. Chains A, B, C and D of isoenzyme C are shown in orange, light blue, light green and pink, respectively. Monomeric isoenzyme A is shown in grey and is superimposed on chain D of the tetrameric isoenzyme C. Fructose 1,6-bisphosphate co-crystallized with isoenzyme A is shown in yellow. The mutated residue described in this report (red arrow) and the mutated amino acids previously described are highlighted in the magnified structure. The structural and functional consequences of the mutations are described in Table 1. 1C: aldolase A, glucose-6-phosphate dehydrogenase (G6PD) and hexokinase activities in the erythrocytes of the parents, the healthy sibling and the 3 affected patients (*: patients 2, 3, 4). 1D: in vitro muscle study of anaerobic glycogenolysis and glycolysis (only patient 3); results of lactate production (µmol/g muscle in 30 minutes) after incubation with various substrates.
Mentions: Three patients from a Moroccan consanguineous family (Figure 1A) suffered from recurrent episodes of rhabdomyolysis that required numerous hospitalizations from 2 months of age. These acute episodes were invariably triggered by febrile illnesses. The presenting symptoms were an inability to walk and myalgia. During the acute episodes, plasma creatine phosphokinase (CK) levels were variable, ranging from markedly elevated (peak levels: 180,000–450,000 U/L, N<150) with overt myoglobinuria to milder elevations (3,000 U/L). The following tests were normal: hemoglobin, hematocrit, mean corpuscular volume, plateletcount, reticulocyte count, bilirubin, haptoglobin, ferritin, Coombs' test, urea, creatinine, blood gasses, plasma lactate, carnitine, blood acylcarnitine profile, plasma amino acids, and urinary organic acids. Electromyography, brain MRI, abdominal ultrasonography, and echocardiography were also normal. CK levels ranged from normal (<150 U/L) to elevated (up to 1,800 U/L) in all 3 patients between acute episodes. The clinical examination and muscle tests performed 2 months after an episode of rhabdomyolysis were normal for each patient, at ages 9, 10, and 11 years respectively. Family history revealed neither chronic hemolytic anemia, nor episodes of jaundice or blood transfusions. Two patients suffered from learning disabilities and required a special school.

Bottom Line: Myoglobinuria was always triggered by febrile illnesses.Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines, and reduced by dexamethasone.We also propose a treatment for this severe disease.

View Article: PubMed Central - PubMed

Affiliation: INSERM U781, Institut Imagine des Maladies Génétiques, Université Paris Descartes et Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker, AP-HP, Paris, France.

ABSTRACT
Aldolase A deficiency has been reported as a rare cause of hemolytic anemia occasionally associated with myopathy. We identified a deleterious homozygous mutation in the ALDOA gene in 3 siblings with episodic rhabdomyolysis without hemolytic anemia. Myoglobinuria was always triggered by febrile illnesses. We show that the underlying mechanism involves an exacerbation of aldolase A deficiency at high temperatures that affected myoblasts but not erythrocytes. The aldolase A deficiency was rescued by arginine supplementation in vitro but not by glycerol, betaine or benzylhydantoin, three other known chaperones, suggesting that arginine-mediated rescue operated by a mechanism other than protein chaperoning. Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines, and reduced by dexamethasone. Our results expand the clinical spectrum of aldolase A deficiency to isolated temperature-dependent rhabdomyolysis, and suggest that thermolability may be tissue specific. We also propose a treatment for this severe disease.

Show MeSH
Related in: MedlinePlus