title: A novel mitochondrial tRNA(Ala) gene variant causes chronic progressive external ophthalmoplegia in a patient with Huntington disease.
abstract: Chronic progressive external ophthalmoplegia is a mitochondrial disorder usually caused by single or multiple mitochondrial DNA (mtDNA) deletions and, more rarely, by maternally inherited mtDNA point mutations, most frequently in tRNA genes (MTT). We report on a patient presenting with a progressive eyelid ptosis with bilateral ophthalmoparesis, dysphagia, dysphonia and mild proximal limb weakness associate with a mild movement disorder characterized by abnormal involuntary movements involving head and limbs, imbalance and gait instability. Muscle biopsy demonstrated the presence of ragged red fibers and several cytochrome-C-oxidase negative fibers. Molecular analysis showed the novel m.5613T > C heteroplasmic mutation in the mitochondrial tRNA(Ala) gene (MTTA) which disrupts a conserved site and fulfills the accepted criteria of pathogenicity. Moreover, a 38 CAG trinucleotide repeat expansion was found on the huntingtin gene, thus configuring a singular CPEO/"reduced penetrance" Huntington disease "double trouble". With this novel MTTA point mutation, we extend the spectrum of provisional pathogenic changes in this gene, which is a very rare site of pathogenic mutation, and confirm that clinical expression of these mutations is hardly ever heterogeneous, including myopathy and CPEO. Mitochondrial involvement is an emerging key determinant in the pathogenesis of Huntington disease and it is well known that mutant huntingtin influences the mitochondrial respiratory complexes II and III. A synergist effect of the HTT and MTTA mutations on respiratory chain function may be hypothesized in our patient and should be regarded as a spur for further studies on the mtDNA/HTT reciprocal interactions.
authors.affiliation: Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital "Spedali Civili", Brescia, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Filosto
authors.affiliation: Institute of Molecular Medicine "A. Nocivelli", University Hospital "Spedali Civili", Brescia, Italy.
authors.forename: Gaetana
authors.initials: G
authors.lastname: Lanzi
authors.affiliation: Unit of Molecular Medicine, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Nesti
authors.affiliation: Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital "Spedali Civili", Brescia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vielmi
authors.affiliation: Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Marchina
authors.affiliation: Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital "Spedali Civili", Brescia, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Galvagni
authors.affiliation: Institute of Molecular Medicine "A. Nocivelli", University Hospital "Spedali Civili", Brescia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Giliani
authors.affiliation: Unit of Molecular Medicine, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.affiliation: Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital "Spedali Civili", Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
keywords: CPEO; Huntington disease; Mitochondrial diseases; mtDNA; tRNA