A novel mitochondrial tRNA^Ala gene variant causes chronic progressive external ophthalmoplegia in a patient with Huntington disease

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• 作者：Massimiliano Filosto^a ; ^{massimiliano.filosto@unibs.it" class="auth_mail" title="E-mail the corresponding author} ; Gaetana Lanzi^b ; Claudia Nesti^c ; Valentina Vielmi^a ; Eleonora Marchina^d ; Anna Galvagni^a ; Silvia Giliani^b ; Filippo M. Santorelli^c ; Alessandro Padovani^a
• 关键词：Mitochondrial diseases ; CPEO ; Huntington disease ; mtDNA ; tRNA
• 刊名：Molecular Genetics and Metabolism Reports
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：6
• 期：Complete
• 页码：70-73
• 全文大小：747 K

文摘

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.