Mitochondrial Chronic Progressive External Ophthalmoplegia

Abstract

Background: Chronic progressive external ophthalmoplegia (CPEO) is a rare disorder that can be at the forefront of several mitochondrial diseases. This review overviews mitochondrial CPEO encephalomyopathies to enhance accurate recognition and diagnosis for proper management.

Methods: This study is conducted based on publications and guidelines obtained by selective review in PubMed. Randomized, double-blind, placebo-controlled trials, Cochrane reviews, and literature meta-analyses were particularly sought.

Discussion: CPEO is a common presentation of mitochondrial encephalomyopathies, which can result from alterations in mitochondrial or nuclear DNA. Genetic sequencing is the gold standard for diagnosing mitochondrial encephalomyopathies, preceded by non-invasive tests such as fibroblast growth factor-21 and growth differentiation factor-15. More invasive options include a muscle biopsy, which can be carried out after uncertain diagnostic testing. No definitive treatment option is available for mitochondrial diseases, and management is mainly focused on lifestyle risk modification and supplementation to reduce mitochondrial load and symptomatic relief, such as ptosis repair in the case of CPEO. Nevertheless, various clinical trials and endeavors are still at large for achieving beneficial therapeutic outcomes for mitochondrial encephalomyopathies.

Key messages: Understanding the varying presentations and genetic aspects of mitochondrial CPEO is crucial for accurate diagnosis and management.

Keywords: CPEO; chronic progressive external ophthalmoplegia; mitochondrial diseases.

Figure 1

The diverse clinical outcomes of mitochondrial encephalomyopathies necessitate thorough screening of patients under suspicion.

Figure 2

This diagram shows the proteins involved in the maintenance of mitochondrial DNA and the pathways involved. The mitochondrial nucleotide salvage pathway (1) is shown and is responsible for salvaging deoxyribonucleosides (dNs) and converting them into deoxyribonucleotide triphosphates (dNTPs) used in mtDNA replication. Along this pathway, Thymidine kinase 2 (TK2) and deoxyguanosine kinase (DGK) convert dNs into deoxyribonucleotide monophosphates (dNMPs) that later convert into deoxyribonucleoside diphosphates(dNDPs) by nucleotide monophosphate kinase (NMPK), then into dNTPs by nucleotide diphosphate kinase (NDPK). The cytosolic nucleotide metabolism pathway (2) includes thymidine phosphorylase (TP), which converts thymidine into thymine, and ribonucleotide reductase (RNR), which converts NDPs into dNDPs, supplying the nucleotide salvage pathway. RNR consists of two catalytic and two R2 or p53-induced small subunits. The nucleotide transport proteins (3) supply the nucleotide salvage pathway from the cytosol. MPV17 protein supplies dNTPs, while adenine nucleotide transporter (ANT1) supplies ADPs with the assistance of acylglycerol kinase (AGK), which are later converted to deoxyadenosine diphosphate (dADPs) feeding into the dNDPs. Mitochondrial DNA synthesis (4) requires the enzymes TWINKLE, a helicase, and the synthesis initiator, DNA polymerase gamma (POLG), which needs an RNA primer that is supplied by mitochondrial transcription factor A (TFAM). POLG consists of one catalytic subunit and two subunits encoded from POLG2. (5) The removal of RNA primers and flap intermediates is then achieved via ribonuclease H1 (RNase H1), DNA helicase/nuclease 2 (DNA2), and mitochondrial genome maintenance exonuclease 1 (MGME1). (6) Mitochondrial fusion is mediated by the proteins optic atrophy 1 (OPA1), F-box and leucine-rich repeat 4 (FBXL4), mitofusin 1 and 2 (MFN 1 and 2).

Figure 3

Patient A, diagnosed with mitochondrial encephalomyopathy, presents with chronic progressive external ophthalmoplegia with limited eye movements in all gazes and cerebellar signs (intention tremor in finger-to-nose test and tandem walking), in addition to areas of pigment hyperplasia on fundoscopy. The yellow discoloration shown in the image is from fluorescein eye staining.

Figure 4

Patient B is a 27-year-old male with a recent diagnosis of a homozygous pathogenic variant of MGME1, presenting with chronic progressive external ophthalmoplegia (limitation with horizontal and vertical gazes), refractory errors, pigmentary retinopathy, exercise intolerance, myopathy, fatigue, attention-deficit/hyperactivity disorder, and right bundle branch block. He underwent ptosis repair at the ages of 15 and 17, but ptosis recurred over time. He has a long family history of consanguinity and a similar clinical phenotype presented in his cousin and past uncles.

Figure 5

A summary of the proposed diagnostic pathway by Watson et al., where invasive testing is preceded by genetic sequencing, the gold standard of diagnosis. The green line indicates a yes, while the red line indicates no.