The clinical manifestations and molecular mechanisms of mitrochondrial neuro-opthalmological disorders

Abstract

Autosomal dominant optic atrophy (DOA) classically presents with bilateral, symmetric visual failure in early childhood, with the pathological hallmark being the selective loss of retinal ganglion cells (RGCs). In the first population-based epidemiological study of DOA, we were able to estimate its minimum prevalence at 1 in 35,000 in the North of England. In independent case series from Northern Europe and North America, the majority of families with DOA harboured pathogenic OPA1 mutations (50.0-57.6%), and large-scale OPA1 rearrangements were present in only a small subgroup (11.1-12.9%). We also confirmed that OPA3 mutations were very rare in non-syndromal DOA cases. Visual deterioration was observed in over half (54.2-67.4%) of all patients during long term follow-up, and the rate of visual decline varied markedly both between and within families. In a large multi-centre study of 104 OPA1-positive patients from 45 independent families, we established that additional neuromuscular complications are common in OPA1 disease, affecting up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and chronic progressive external ophthalmoplegia (CPEO) from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. Patients with these syndromal disease variants (DOA+) had a worse visual prognosis, and this was associated with a more pronounced reduction in retinal nerve fibre layer thickness compared to patients with pure DOA. Interestingly, there was a two- to three-fold increased risk of developing DOA+ features with missense OPA1 mutations and those located within the GTPase domain.