LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.

International audienceAutosomal recessive LPIN1 mutations have been recently described as a novel cause of rhabdomyolysis in a few families. The purpose of the study was to evaluate the prevalence of LPIN1 mutations in patients exhibiting severe episodes of rhabdomyolysis in infancy. After exclusion of primary fatty acid oxidation disorders, LPIN1 coding sequence was determined in genomic DNA and cDNA. Among the 29 patients studied, 17 (59%) carried recessive nonsense or frameshift mutations, or a large scale intragenic deletion. In these 17 patients, episodes of rhabdomyolysis occurred at a mean age of 21 months. Secondary defect of mitochondrial fatty oxidation or respiratory chain was found in skeletal muscle of two patients. The intragenic deletion, c.2295-866_2410-30del, was identified in 8/17 patients (47%), all Caucasians, and occurred on the background of a common haplotype, suggesting a founder effect. This deleted human LPIN1 form was unable to complement ∆pah1 yeast for growth on glycerol, in contrast to normal LPIN1. Since more than 50% of our series harboured LPIN1 mutations, LPIN1 should be regarded as a major cause of severe myoglobinuria in early childhood. The high frequency of the intragenic LPIN1 deletion should provide a valuable criterion for fast diagnosis, prior to muscle biopsy

Respiratory Chain Defects May Present Only with Hypoglycemia

International audienceHypoglycemia occasionally results from oxidative phosphorylation deficiency, associated with liver failure. Conversely, in some cases of respiratory chain defect, the impairment in glucose metabolism occurs with normal hepatic function. The mechanism for this hypoglycemia remains poorly understood. We report here three unrelated children with hypoglycemia as the presenting symptom associated with oxidative phosphorylation deficiency but without liver dysfunction. Two patients had, respectively, complex III and complex IV deficiency and presented with long fast hypoglycemia. During a fasting test, the first patient showed evidence for impaired gluconeogenesis (progressive increase of plasma lactate and no decrease of alanine levels), whereas the second patient appeared to have impaired fatty acid oxidation (hypoketotic hypoglycemia with increased levels of non esterified fatty acids). The third patient presented with both long and short fast hypoglycemia related to complex IV deficiency. The mechanism of hypoglycemia for this patient may have been partly related to GH insufficiency, whereas impaired glycogen metabolism possibly accounted for short fast hypoglycemia. We suggest that hypoglycemia can be the presenting symptom for respiratory chain defects, through the possible reduction in cofactors resulting from oxidative phosphorylation deficiency, and that respiratory chain defects should therefore be considered in the differential diagnosis of hypoglycemia

Phenylbutyrate increases pyruvate dehydrogenase complex activity in cells harboring a variety of defects

OBJECTIVE: Deficiency of pyruvate dehydrogenase complex (PDHC) is the most common genetic disorder leading to lactic acidosis. PDHC deficiency is genetically heterogenous and most patients have defects in the X-linked E1-α gene but defects in the other components of the complex encoded by PDHB, PDHX, DLAT, DLD genes or in the regulatory enzyme encoded by PDP1 have also been found. Phenylbutyrate enhances PDHC enzymatic activity in vitro and in vivo by increasing the proportion of unphosphorylated enzyme through inhibition of pyruvate dehydrogenase kinases and thus, has potential for therapy of patients with PDHC deficiency. In the present study, we investigated response to phenylbutyrate of multiple cell lines harboring all known gene defects resulting in PDHC deficiency. METHODS: Fibroblasts of patients with PDHC deficiency were studied for their enzyme activity at baseline and following phenylbutyrate incubation. Drug responses were correlated with genotypes and protein levels by Western blotting. RESULTS: Large deletions affecting PDHA1 that result in lack of detectable protein were unresponsive to phenylbutyrate, whereas increased PDHC activity was detected in most fibroblasts harboring PDHA1 missense mutations. Mutations affecting the R349-α residue were directed to proteasome degradation and were consistently unresponsive to short-time drug incubation but longer incubation resulted in increased levels of enzyme activity and protein that may be due to an additional effect of phenylbutyrate as a molecular chaperone. INTERPRETATION: PDHC enzyme activity was enhanced by phenylbutyrate in cells harboring missense mutations in PDHB, PDHX, DLAT, DLD, and PDP1 genes. In the prospect of a clinical trial, the results of this study may allow prediction of in vivo response in patients with PDHC deficiency harboring a wide spectrum of molecular defects