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PLoS Genet. 2014 Nov 13;10(11):e1004711. doi: 10.1371/journal.pgen.1004711. eCollection 2014 Nov.

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

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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.
Département de Génétique, Hôpitaux Universitaires Henri-Mondor, Créteil, AP-HP, France.
"Mitochondria, Metals and Oxidative Stress" group, Jacques Monod Institute, UMR7592 CNRS, Paris Diderot University, Paris, France.
Metabolic biochemistry and INSERM U1124, University Paris Descartes, Hospital Necker Enfants Malades, Paris, France.
Clinique Universitaire de Pédiatrie, Hôpital couple enfant, CHU de Grenoble, France.
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, United States of America; Unité Institut National de la Santé et de la Recherche Médicale U980, Laboratory of Human Genetics of Infectious Diseases, Imagine Institute; and Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, University Paris Descartes, Paris, France.
Département de Biochimie, Toxicologie et Pharmacologie, CHU de Grenoble, Centre de Référence Rhône-Alpes des Maladies NeuroMusculaires, Grenoble, France.
Université Pierre et Marie Curie, UM 76, INSERM U974, CNRS UMR 7215, Institut de Myologie, GHU Pitié-Salpêtrière, AP-HP, Centre de Référence des Maladies Neuromusculaires, Paris, France.
Laboratoire Maladies Héréditaires du Métabolisme, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France.
Banque de Cellules, Hôpital Cochin, APHP, Paris, France.
INSERM et Laboratoire de Biochimie et Biologie Moléculaire, HMNO, CBP, CHRU Lille, Lille, France.
Clinique Universitaire de Pédiatrie, Hôpital couple enfant, CHU de Grenoble, France; Howard Hughes Medical Institute, New York, New York, United States of America.


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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