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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

Oil-red-O staining of skeletal muscle and myoblasts from our patient and a control.Images were taken with x20 magnification. 2A: Transverse cross-section of a left deltoid muscle biopsy of the patient shows the presence of numerous LDs, mainly in type 1 fibers, a: control, b: patient. 2B: Cytological oil-Red-O analysis of the patient myoblasts cultivated under basal (a) or pro-inflammatory conditions (TNFα+IL-1β) (b). LDs appear as red circular vacuoles in the cytoplasm. Treatment with dexamethasone alone (d) or combined with TNFα+IL-1β (c) reversed the LD phenotype. 2C: Relative knockdown of aldolase A expression in control and patient myoblasts. 2D: representative oil-red-O staining of mock-transfected control (a) and patient (c) cells, or aldolase A-siRNA-transfected control (b)and patient (d) myoblasts.
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pgen-1004711-g002: Oil-red-O staining of skeletal muscle and myoblasts from our patient and a control.Images were taken with x20 magnification. 2A: Transverse cross-section of a left deltoid muscle biopsy of the patient shows the presence of numerous LDs, mainly in type 1 fibers, a: control, b: patient. 2B: Cytological oil-Red-O analysis of the patient myoblasts cultivated under basal (a) or pro-inflammatory conditions (TNFα+IL-1β) (b). LDs appear as red circular vacuoles in the cytoplasm. Treatment with dexamethasone alone (d) or combined with TNFα+IL-1β (c) reversed the LD phenotype. 2C: Relative knockdown of aldolase A expression in control and patient myoblasts. 2D: representative oil-red-O staining of mock-transfected control (a) and patient (c) cells, or aldolase A-siRNA-transfected control (b)and patient (d) myoblasts.

Mentions: Microscopy showed an excessive lipid droplet (LD) accumulation, visualized with oil-red-O staining (Figure 2A), in the muscle biopsy from the patient (a) compared with control biopsies (b). However, the muscle tissue of the patient showed a well-preserved fascicular architecture with normal type 1 and type 2 fibers. In addition, the cytochrome c-oxidase and phosphorylase staining patterns were similar to controls.


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)

Oil-red-O staining of skeletal muscle and myoblasts from our patient and a control.Images were taken with x20 magnification. 2A: Transverse cross-section of a left deltoid muscle biopsy of the patient shows the presence of numerous LDs, mainly in type 1 fibers, a: control, b: patient. 2B: Cytological oil-Red-O analysis of the patient myoblasts cultivated under basal (a) or pro-inflammatory conditions (TNFα+IL-1β) (b). LDs appear as red circular vacuoles in the cytoplasm. Treatment with dexamethasone alone (d) or combined with TNFα+IL-1β (c) reversed the LD phenotype. 2C: Relative knockdown of aldolase A expression in control and patient myoblasts. 2D: representative oil-red-O staining of mock-transfected control (a) and patient (c) cells, or aldolase A-siRNA-transfected control (b)and patient (d) myoblasts.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004711-g002: Oil-red-O staining of skeletal muscle and myoblasts from our patient and a control.Images were taken with x20 magnification. 2A: Transverse cross-section of a left deltoid muscle biopsy of the patient shows the presence of numerous LDs, mainly in type 1 fibers, a: control, b: patient. 2B: Cytological oil-Red-O analysis of the patient myoblasts cultivated under basal (a) or pro-inflammatory conditions (TNFα+IL-1β) (b). LDs appear as red circular vacuoles in the cytoplasm. Treatment with dexamethasone alone (d) or combined with TNFα+IL-1β (c) reversed the LD phenotype. 2C: Relative knockdown of aldolase A expression in control and patient myoblasts. 2D: representative oil-red-O staining of mock-transfected control (a) and patient (c) cells, or aldolase A-siRNA-transfected control (b)and patient (d) myoblasts.
Mentions: Microscopy showed an excessive lipid droplet (LD) accumulation, visualized with oil-red-O staining (Figure 2A), in the muscle biopsy from the patient (a) compared with control biopsies (b). However, the muscle tissue of the patient showed a well-preserved fascicular architecture with normal type 1 and type 2 fibers. In addition, the cytochrome c-oxidase and phosphorylase staining patterns were similar to controls.

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