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Next-generation sequencing facilitates the diagnosis in a child with twinkle mutations causing cholestatic liver failure.

I n many disorders, overlapping clinical phenotypes and locus heterogeneity can significantly hamper making a clinical or molecular diagnosis. In both acute and cholestatic liver failure, making such a diagnosis has significant potential to alter the direction of therapy. In several large series, the majority of children with acute liver failure have no identifiable cause. It is the hope that new technologies may allow for rapid detection of all of the genetic causes of liver failure (1). Mitochondria are essential for the survival of eukaryotic cells. Their major function is to generate adenosine triphosphate, the energy for supporting cellular activities. Mitochondria contain their own DNA and machinery for transcription and translation. The replication, repair, transcription, and translation of mitochondrial DNA (mtDNA) depend on the protein components encoded by the nuclear genome (2,3). The C10orf2 gene encodes the mtDNA helicase TWINKLE, which is one of the proteins essential for mtDNA maintenance. Dominant mutations cause multiple mtDNA deletions and progressive external ophthalmoplegia (Online Mendelian Inheritance in Man no. 609286), and recessive mutations can lead to mtDNA depletion and infantile onset spinocerebellar ataxia (IOSCA) (Online Mendelian Inheritance in Man no. 271245). The clinical features of IOSCA include hypotonia, athetosis, ataxia, ophthalmoplegia, hearing deficit, sensory neuropathy, and epileptic encephalopathy. Previous cases have described patients with either homozygous (Y508C) or compound heterozygous (Y508C and A318T) TWINKLE mutations. A 20-year follow-up on 23 patients with IOSCA demonstrated that the common symptoms include refractory status epilepticus, migraine-like headaches, and severe psychiatric symptoms (4). We report on a child with compound heterozygous recessive TWINKLE mutations who presented at an early age with acute liver failure, subsequent neurologic decompensation, and Fanconi syndrome.