Recurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number.

Mutations in SLC25A4 encoding the mitochondrial ADP/ATP carrier AAC1 are well-recognized causes of mitochondrial disease. Several heterozygous SLC25A4 mutations cause adult-onset autosomal-dominant progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions, whereas recessive SLC25A4 mutations cause childhood-onset mitochondrial myopathy and cardiomyopathy. Here, we describe the identification by whole-exome sequencing of seven probands harboring dominant, de novo SLC25A4 mutations. All affected individuals presented at birth, were ventilator dependent and, where tested, revealed severe combined mitochondrial respiratory chain deficiencies associated with a marked loss of mitochondrial DNA copy number in skeletal muscle. Strikingly, an identical c.239G>A (p.Arg80His) mutation was present in four of the seven subjects, and the other three case subjects harbored the same c.703C>G (p.Arg235Gly) mutation. Analysis of skeletal muscle revealed a marked decrease of AAC1 protein levels and loss of respiratory chain complexes containing mitochondrial DNA-encoded subunits. We show that both recombinant AAC1 mutant proteins are severely impaired in ADP/ATP transport, affecting most likely the substrate binding and mechanics of the carrier, respectively. This highly reduced capacity for transport probably affects mitochondrial DNA maintenance and in turn respiration, causing a severe energy crisis. The confirmation of the pathogenicity of these de novo SLC25A4 mutations highlights a third distinct clinical phenotype associated with mutation of this gene and demonstrates that early-onset mitochondrial disease can be caused by recurrent de novo mutations, which has significant implications for the application and analysis of whole-exome sequencing data in mitochondrial disease.

Late presentation of massive pleural effusion from intrathoracic migration of a ventriculoperitoneal shunt catheter: case report and review of the literature.

We report an unusual case of ventriculoperitoneal (VP) shunt intrathoracic migration, associated with massive symptomatic hydrothorax. The VP shunt was inserted 10 years before presentation, after hemorrhagic hydrocephalus caused by prenatal intraventricular hemorrhage. The pleural fluid was drained via tube thoracostomy and the shunt was externalized, with full resolution of symptoms and signs. The patient was subsequently managed with shunt revision with drainage into the abdominal cavity. We review the 10 pediatric cases of cerebrospinal fluid hydrothorax reported in the literature and discuss the mechanism of shunt tip migration. Pleural effusion secondary to VP shunt insertion is a rare and potentially life-threatening occurrence, and it should be suspected in any patient with a VP shunt and respiratory distress.