A national epidemiological study of chronic progressive external ophthalmoplegia in the United Kingdom - molecular genetic features and neurological burden

Abstract

Purpose: Chronic progressive external ophthalmoplegia (CPEO) is a classical manifestation of mitochondrial disease characterised by slowly progressive limitation of eye movements and ptosis. CPEO can develop either in isolation or as the defining feature of a more severe multisystemic “CPEO plus” phenotype. As part of a national epidemiological study of mitochondrial diseases in the UK, we set out: (i) to derive a robust estimate of the prevalence of CPEO in the general population; (ii) to define the molecular spectrum of disease causing genes associated with CPEO; and (iii) to document the overall burden of neurological disease in this group of patients.

Methods: The Mitochondrial Disease Patient Cohort Study is a project that is nationally funded by the Medical Research Council (MRC) to collect clinical and molecular data on patients with confirmed mitochondrial disease in the UK. Patients with suspected CPEO were identified from the mitochondrial cohort database and their medical records were then reviewed by two independent investigators (PYWM and AC) to confirm the diagnosis.

Results: Out of a total of 631 patients registered on the mitochondrial cohort database, 255 patients (40.4%) were confirmed to have CPEO. The majority of patients (181/255, 71.0%) had typical ocular features of CPEO and the age of onset ranged from 1.0 to 76.0 years with a mean age of 29.9 years. Significant neurological deficits were present in 221 patients (86.7%) in particular myopathy (62.0%) and ataxia (51.0%). The minimum prevalence of CPEO was estimated at 3.39 per 100 000 inhabitants, about 1 in 30,000 of the general population. The most commonly identified genetic defect was a pathogenic mitochondrial DNA (mtDNA) point mutation (n = 80, 31.4%), followed by a single mtDNA deletion (n = 72, 28.2%), and a point mutation within nuclear-encoded CPEO genes (n = 70, 27.5%). The degree of ptosis and ophthalmoplegia was found to be more severe among patients harbouring single mtDNA deletions.

Conclusions: CPEO is a frequent cause of significant visual impairment among patients with confirmed mitochondrial disease and it is invariably associated with the development of debilitating neurological complications. The management of this group of patients therefore requires a multidisciplinary team approach to minimise long-term morbidity.

Keywords: 612 neuro-ophthalmology: diagnosis • 600 mitochondria • 522 eye movements