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.

ABSTRACT. Objective. Between October and November 2003, several infants with encephalopathy were hospitalized in pediatric intensive care units in Israel. Two died of cardiomyopathy. Analysis of the accumulated data showed that all had been fed the same brand of soy-based formula (Remedia Super Soya 1), specifically manufactured for the Israeli market. The source was identified on November 6, 2003, when a 5.5-month-old infant was admitted to Sourasky Medical Center with upbeat nystagmus, ophthalmoplegia, and vomiting. Wernicke's encephalopathy was suspected, and treatment with supplementary thiamine was started. His condition improved within hours. Detailed history revealed that the infant was being fed the same formula, raising suspicions that it was deficient in thiamine. The formula was tested by the Israeli public health authorities, and the thiamine level was found to be undetectable (<0.5 g/g). The product was pulled from the shelves, and the public was alerted. Thiamine deficiency in infants is very rare in developed countries. The aim of this study was to report the epidemiology of the outbreak and to describe the diagnosis, clinical course, and outcome of 9 affected infants in our care.Methods. After the index case, an additional 8 infants were identified in our centers by medical history, physical examination, and laboratory testing. The group consisted of 6 male and 3 female infants aged 2 to 12 months. All were assessed with the erythrocyte transketolase activity assay, wherein the extent of thiamine deficiency is expressed in percentage stimulation compared with baseline (thiamine pyrophosphate effect [TPPE]). Normal values range from 0% to 15%; a value of 15% to 25% indicates thiamine deficiency, and >25% indicates severe deficiency. Blood lactate levels (normal: 0.5-2 mmol/L) were measured in 6 infants, cerebrospinal fluid lactate in 2 (normal: 0.5-2 mmol/L), and blood pyruvate in 4 (normal: 0.03-0.08 mmol/L). The diagnostic criteria for thiamine deficiency were abnormal transketolase activity and/or unexplained lactic acidosis. Treatment consisted of intramuscular thiamine 50 mg/day for 14 days combined with a switch to another infant formula.Results. Early symptoms were nonspecific and included mainly vomiting (n ‫؍‬ 8), lethargy (n ‫؍‬ 7), irritability (n ‫؍‬ 5), abdominal distension (n ‫؍‬ 4), diarrhea (n ‫؍‬ 4), respiratory symptoms (n ‫؍‬ 4), developmental delay (n ‫؍‬ 3), and failure to thrive (n ‫؍‬ 2). Infection was found in all cases. Six infants were admitted with fever. One patient had clinical dysentery and group C Salmonella sepsis; the others had mild infection: acute gastroenteritis (n ‫؍‬ 2); upper respiratory infection (n ‫؍‬ 2); and bronchopneumonia, acute bronchitis, and viral infection (n ‫؍‬ 1 each). Two infants were treated with antibiotics. Three infants had neurologic symptoms of ophthalmoplegia with bilateral abduction deficit with or without upbeat nystagmus. All 3 had blood lactic acidosis, and 2 had high cerebrospinal fluid lactate levels. Patient 1, our index case, wa...

Table 1 contains errors in the ''Genotype'' column. The mutation of patient L.R. should be described as c.2401C/T, R801X. The mutation of patient D.A. should be described as c.192þ2T/C leading to the deletion of the last 106 nt of exon 2, and the mutation of patient P.N. should be described as c.1441þ2T/C leading to the skipping of exon 9 (exon and nucleotide numbering according to NM_145693). A corrected version of the table is included below. The authors regret these errors.