Chronic Progressive External Ophthalmoplegia (CPEO/PEO) Panel

The accumulation of multiple mtDNA deletions can be a sign of the cell’s inability to maintain mitochondrial genome integrity. Multiple mtDNA deletions are typically seen in the skeletal muscle of patients affected by adult-onset chronic progressive external ophthalmoplegia (weakness of the extraocular muscles, referred to as CPEO or PEO), a disorder that is often accompanied by ptosis, oropharyngeal weakness, and proximal limb weakness (DiMauro and Hirano. 2011. PubMed ID: 20301382). Onset typically ranges between 20-40 years of age (Viscomi and Zeviani. 2017. PubMed ID: 28324239). In contrast to many other mitochondrial diseases, isolated CPEO is a relatively mild phenotype.

When patients display additional, often more severe phenotypes beyond those of the isolated form, this may be referred to as chronic progressive external ophthalmoplegia plus (CPEO+/PEO+). Additional symptoms are often multi-systemic and can include ataxia, psychiatric symptoms, sensory axonal neuropathy, hearing loss and/or optic atrophy, among others (Sommerville et al. 2014. PubMed ID: 27858775; Hanisch et al. 2015. PubMed ID: 25143630). At this time, genotype-phenotype correlation for this spectrum of disease is poorly understood.

Muscle biopsies of patients affected with CPEO are distinguished by the presence of ragged red fibers, a characteristic finding under modified Gomori trichrome staining that is explained by the accumulation of abnormal mitochondria within the subsarcolemmal space (DiMauro and Hirano. 2011. PubMed ID: 20301382; Viscomi and Zeviani. 2017. PubMed ID: 28324239). Patients generally present with decreased activities of the respiratory chain complexes, a consequence of reduced mitochondrial genome integrity, and histochemical staining for cytochrome c oxidase (COX, complex IV) is also either decreased or absent (Viscomi and Zeviani. 2017. PubMed ID: 28324239).

Chronic progressive external ophthalmoplegia (CPEO) can be caused by defects in one of a number of genes within the nuclear genome: DGUOK, DNA2, MGME1, OPA1, POLG, POLG2, RNASEH1, RRM2B, SLC25A4, SPG7, TK2, TWNK, or TYMP. Inheritance may be primarily autosomal dominant (POLG2, OPA1, DNA2, SLC25A4) or autosomal recessive (DGUOK, MGME1, RNASEH1, TK2, TYMP), while reports of both recessive and dominant inheritance have been documented for a subset of genes (POLG, RRM2B, TWNK, SPG7).

Please note that CPEO may also present in individuals who harbor de novo or maternally-inherited mtDNA deletions, or pathogenic single nucleotide variants in the mitochondrial genome (DiMauro and Hirano. 2011. PubMed ID: 20301382; Chinnery. 2014. PubMed ID: 20301403). Sequencing of the mitochondrial genome is not offered as part of this test, but could be considered in individuals who test negative for plausible causative variants in the nuclear genes associated with this disorder.

Based on a 2014 literature review by Sommerville et al., POLG and TWNK are likely the most common nuclear-encoded genes known to be responsible for chronic progressive external ophthalmoplegia; at the time of publishing, 258 and 143 patients, respectively, had been reported (Sommerville et al. 2014. PubMed ID: 27858775). TYMP, RRM2B, OPA1, and SLC25A4 were found in 30-50 patients each, while SPG7, MGME1, TK2, POLG2, DGUOK, DNA2, and MPV17 were less common causes of disease (<13 individuals each).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).