Chronic progressive external ophthalmoplegia in a patient presenting with both nuclear and mitochondrial genome variants

Aim of the Study Chronic progressive external ophthalmoplegia (CPEO), characterized by slowly progressive paralysis of the extra-ocular muscles, is a common clinical feature in mitochondrial disorders. Usually, CPEO is associated with the presence of single or multiple mitochondrial DNA deletions or point mutations. When transmitted in a Mendelian way, it includes both autosomal dominant and recessive forms. Here, we describe a patient presenting with isolated CPEO. She has a long, but slowly progressive clinical history.
Methods and Results To identify the molecular cause of the patient's mitochondrial myopathy, a genetic analysis was undertaken of both nuclear and mitochondrial genes. In the nuclear C10orf2 gene ,a novel variant was discovered at a highly conserved site. This variant was also seen in other affected family members. C10orf2, also known as Twinkle, is a replicative mitochondrial (mt) DNA helicase and a key protein of the mtDNA replisome. MtDNA analysis did not show any deletions or a depletion of the mt genome, but sequencing analysis of the MT-TL1 (tRNALeu(UUR)) gene revealed two heteroplasmic mtDNA variations. The tRNALeu(UUR) gene is a hotspot for pathogenic mt mutations with a marked phenotypic variability. The alterations are situated immediately adjacent of the common m.3243A>G mutation, which is a cause of both MELAS and CPEO. Using cloning experiments it became clear that both mutations were not situated on the same mtDNA molecule. Heteroplasmy levels, determined with restriction fragment analysis, showed a total mutation load of around 36% in muscle, while the variants were not detected in leukocytes.
Conclusions We described a patient with isolated CPEO carrying a nuclear C10orf2 and two heteroplasmic mitochondrial tRNALeu(UUR) gene alterations. This C10orf2 variant is located in a gene region prone to pathogenic mutations. Both mitochondrial aberrations have previously been associated with mitochondrial disorders, one patient presenting also with a CPEO picture. But, until now, both alterations were never reported in the same patient. In summary, this CPEO patient is a unique case study as both mt and nuclear genome variants might contribute to the phenotype.