• Asmaa Mamoune, Michel Bahuau, Yamina Hamel, Valérie Serre, Michele Pelosi, Florence Habarou, Marie-Ange Nguyen Morel, Bertrand Boisson, Sabrina Vergnaud, Mai Thao Viou, Luc Nonnenmacher, Monique Piraud, Patrick Nusbaum, Joseph Vamecq, Norma Romero, Chris Ottolenghi, Jean-Laurent Casanova, and Pascale de Lonlay.
• 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.
• PLoS Genet. 2014 Nov 1;10(11):e1004711.

AbstractAldolase 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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