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Diagnostic investigations of patients with chronic progressive external ophthalmoplegia
  1. Patrick Yu-Wai-Man1,2,
  2. Grainne S Gorman2,3,
  3. Robert W Taylor2,
  4. Douglass M Turnbull2,3
  1. 1Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
  2. 2Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK
  3. 3Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
  1. Correspondence to Dr Patrick Yu-Wai-Man, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK; Patrick.Yu-Wai-Man{at}ncl.ac.uk

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We read with great interest the article by Roefs and colleagues on the use of orbicularis oculi muscle biopsies sampled at the time of ptosis surgery to reach a molecular diagnosis for patients exhibiting classical features of chronic progressive external ophthalmoplegia (CPEO).1 All three cases included in this report were sporadic and no additional neurological features were present. Histochemical analysis of the orbicularis oculi muscle revealed pathological hallmarks suggestive of an underlying mitochondrial disease process with ragged red fibres and isolated clusters of cytochrome c oxidase (COX)-deficient fibres. Long-range PCR analysis was performed on extracted orbicularis oculi muscle DNA and single, large-scale mitochondrial DNA (mtDNA) deletions of varying sizes were identified in all three patients, confirming the clinical diagnosis. We fully agree with Roefs and colleagues that orbicularis oculi muscle, if available, can prove a useful tissue for investigating patients with suspected CPEO, as we have shown recently with extraocular muscle resections.2 However, only a subgroup of patients will develop functionally disabling ptosis that would benefit from surgical intervention, and even if warranted, it is not uncommon for patients to decline the procedure after having been informed about the possible risks.

Newcastle is one of three specialist centres in the UK that provide an integrated clinical and diagnostic service for patients with mitochondrial disease (http://www.mitochondrialncg.nhs.uk/, accessed 28 August 2012). In our experience, a skeletal muscle biopsy remains an essential element in the investigations of patients with mitochondrial ocular myopathies, especially in cases of diagnostic uncertainty. Not all patients will manifest the typical, bilateral, symmetrical ptosis and restriction of eye movements associated with CPEO,3 and in over half of all cases, referred to as CPEO+, prominent extraocular features, such as ataxia, peripheral neuropathy and a more generalised myopathy are also evident.4 By preserving the surrounding tissue architecture, which is not possible with the sparse fibres in an orbicularis muscle sample, a skeletal muscle biopsy can provide important additional pathological clues: for example, fibre-type grouping on myofibrillar ATPase staining clearly indicates denervation of the peripheral nerves; and the presence of dystrophic changes with basophilic-rimmed cytoplasmic vacuoles is highly suggestive of oculopharyngeal muscle dystrophy—a known clinical mimicker of CPEO.5

Genetic counselling is a key element in the multidisciplinary management of patients with mitochondrial disease and predicting the risk of transmission to the next generation with certainty requires a firm molecular diagnosis to be made. Single, large-scale mtDNA deletions are a common cause of sporadic CPEO, but an increasing number of patients are found to have multiple mtDNA deletions in skeletal muscle, which are secondary to a nuclear genetic defect affecting mtDNA maintenance, replication or repair.4 In up to a third of these cases, the cause remains unknown and the advent of whole exome-capture and next-generation sequencing promises to clarify the genetic diagnosis in this group of patients. The application of these new genetic tools require sufficient amount of high-quality genomic material, which can be a limiting factor with small-volume ocular tissue specimens.

We currently employ a percutaneous needle skeletal muscle biopsy approach, usually from the vastus lateralis (quadriceps) or tibialis anterior region. This procedure has a very good safety profile and it is well tolerated when carried out by properly trained health professionals under aseptic conditions.6 The diagnostic evaluation of patients with suspected mitochondrial ocular myopathies, either presenting in isolation or in combination with other multisystemic neurological features, can be complex requiring access to specialist clinical services and research facilities. The molecular investigations need to be tailored to each individual presentation and ophthalmologists should seek specialist advice to adequately plan the confirmatory studies needed to reach a genetic diagnosis for their patients.

Acknowledgments

RWT and DMT are funded by a Wellcome Trust Strategic Award, the Medical Research Council (UK), and the UK NHS Highly Specialised Services Group. PYWM is an MRC Clinician Scientist.

References

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Footnotes

  • Contributors All authors contributed to this paper through each of the following: (1) conception and design, analysis and interpretation of data; (2) drafting the article and revising it critically for important intellectual content; and (3) giving final approval for the version to be published.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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