The first description of optic atrophy in FRDA was made by Sjögren, in 1940, in 12% of his patients . Four decades later, Harding identified optic atrophy in 30% of cases: only 5.2% with severely and 13% with mildly reduced visual acuity, the remaining being asymptomatic . Deafness was present in 7.8%, ranging from severe (0.9%) to mild (5.2%) .
Across the years, a few studies have demonstrated that subclinical involvement of visual and auditory systems is much more frequent than severe blindness and deafness [5,6,7]. Reduced visual acuity has been identified in 3.1–13% [4, 6, 8], and increased latency of visual evoked potentials in a much higher percentage of individuals: 34–70% [5, 6, 9]. In a study conducted by Fortuna et al., all the 26 individuals had thinning of the retinal nerve fibre layer on optical coherence tomography, in spite of only five having reduced visual acuity . Involvement of posterior visual pathways was also present in these patients, with significantly higher apparent diffusion coefficients on diffusion-weighted MRI of the optic radiations . Hearing loss of variable severity has been reported in 10–39% [4, 6, 8], with abnormal conduction in central pathways identified in 61–100% [6, 8, 10]. Impaired speech-understanding at levels of everyday background noise has been reported in up to 90% of patients, developing as soon as early-school years [7, 10].
Notwithstanding the relative frequency of subclinical visual and auditory impairment, co-occurrence of severe blindness and deafness are rather uncommon, but may be clustered with diabetes . Critical vision loss resembling LHON has been described in very few patients, most being compound heterozygotes, with large expanded alleles, long duration and advanced disease [5, 11, 12]. The patient here reported had a catastrophic and rapidly progressive optic neuropathy, while hearing loss had a protracted course over 11 years until reaching a stage of critical deafness. Opposed to what has been described he was not a compound heterozygote, but a large expansion and long disease duration could partly account for such a severe phenotype.
Underlying pathophysiological mechanisms are incompletely understood. Current lines of evidence suggest anterior and posterior visual pathways degeneration; whereas in auditory function, the cochlea appears to be spared and central auditory brainstem is affected [5, 7]. A study on a mouse model, specifically addressing retinal ganglion cell death, suggested that optic atrophy was a consequence of increased sensitivity to oxidative stress, due to impaired intra-cellular iron regulation . Frataxin deficiency may impact the respiratory chain, leading to mitochondrial iron deposition and dysfunction with consequent increased cellular susceptibility to oxidative stress [5, 13].
With this report we wish to (1) further contribute to the characterization of optic and auditory involvement in FRDA, (2) stress the need to better understand the underlying mechanisms, as well as their genetic and epigenetic modifying factors (including somatic heterogeneity); and (3) increase awareness for this rare extreme phenotype. Improved healthcare services and longer survival of early-onset patients will probably increase the frequency of these devastating manifestations.