title: Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion.
abstract: Twinkle is a mitochondrial replicative helicase, the mutations of which have been associated with autosomal dominant progressive external ophthalmoplegia (adPEO), and recessively inherited infantile onset spinocerebellar ataxia (IOSCA). We report here a new phenotype in two siblings with compound heterozygous Twinkle mutations (A318T and Y508C), characterized by severe early onset encephalopathy and signs of liver involvement. The clinical manifestations included hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, intractable epilepsy and elevation of serum transaminases. The liver showed mtDNA depletion, whereas the muscle mtDNA was only slightly affected. Alpers-Huttenlocher syndrome has previously been associated with mutations of polymerase gamma, a replicative polymerase of mtDNA. We show here that recessive mutations of the close functional partner of the polymerase, the Twinkle helicase, can also manifest as early encephalopathy with liver involvement, a phenotype reminiscent of Alpers syndrome, and are a new genetic cause underlying tissue-specific mtDNA depletion.
authors.affiliation: Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Finland.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Hakonen
authors.forename: Pirjo
authors.initials: P
authors.lastname: Isohanni
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Riitta
authors.initials: R
authors.lastname: Herva
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.forename: Tuula
authors.initials: T
authors.lastname: Lönnqvist
mesh_terms: D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D001927:Brain Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology; D017173:Caenorhabditis elegans; D004265:DNA Helicases / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics; D017809:Fatal Outcome; D017353:Gene Deletion; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008107:Liver Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D028361:Mitochondrial Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D004265:DNA Helicases; C431576:TWNK protein, human