Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways. Using homozygosity mapping, we identified six deleterious mutations in the LPIN1 gene in patients who presented at 2-7 years of age with recurrent, massive rhabdomyolysis. The LPIN1 gene encodes the muscle-specific phosphatidic acid phosphatase, a key enzyme in triglyceride and membrane phospholipid biosynthesis. Of six individuals who developed statin-induced myopathy, one was a carrier for Glu769Gly, a pathogenic mutation in the LPIN1 gene. Analysis of phospholipid content disclosed accumulation of phosphatidic acid and lysophospholipids in muscle tissue of the more severe genotype. Mutations in the LPIN1 gene cause recurrent rhabdomyolysis in childhood, and a carrier state may predispose for statin-induced myopathy.
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We gratefully acknowledge the collaboration of the patients' families and the dedicated assistance of Yehudit Karp. We thank Arnold Munnich and Ron Wanders for creating the international collaborations, George M. Carman for kindly providing S. cerevisiae strains and plasmids, Jan Smeitink and Richard Rodenburg for kindly providing the disease control muscle samples, and Saul Yedgar for fruitful discussions. This work was supported by grants of the Prinses Beatrix Fonds (grant number WAR05-0126) and Barth syndrome foundation to F.M.V. and by Fondation pour la Recherche Médicale to P.d.L.