Clinical examination and FAF imaging in MIDD revealed a typical pattern with areas of irregular increased FAF adjacent to and between the areas of RPE atrophy (Rath PP, et al.
IOVS 2002;43:ARVO E-Abstract 4345)
(Figs. 3 4) . The electrophysiological data revealed nonuniform central retinal dysfunction consistent with abnormalities suggested by FAF imaging. Only two patients demonstrated Ganzfeld ERG abnormalities suggestive of generalized retinal dysfunction, consistent with previous reports describing normal electrophysiology in most patients.
10 11 12 13 22 The Ganzfeld ERG, however, is a mass response and is thus unaffected by localized dysfunction such as a pure maculopathy.
The PERG and the mfERG are measures of central retinal function. A marked reduction in the amplitude of the PERG P50 component suggests dysfunction anterior to the ganglion cells in the visual pathway.
14 The PERG within the normal range in some of the patients is in keeping with localized retinal dysfunction surrounding the macular and sparing the fovea, as revealed both in fundus examination and FAF imaging. In other patients, there was sufficient retinal dysfunction to cause absolute abnormalities in the PERG.
The mfERG provides spatial information about the central retinal cones and their postreceptoral cells not readily available in the Ganzfeld ERG.
15 The mfERG has been used for investigation for a variety of macular diseases.
15 23 24 25 26 The present mfERG analysis in MIDD reveals reduction of peak amplitudes whereas the implicit times were normal in all but one eye. These findings are compatible with loss of cone photoreceptor outer segments as hypothesized by Hood.
15 One patient demonstrated a normal PERG, although the central hexagon of the mfERG showed reduced peak amplitudes. The mfERG may occasionally reveal subtle early changes in macular function that are not enough to produce an abnormal PERG.
In addition to the ring group analysis, we compared the mfERG results with FAF findings. With the 61-hexagon stimulus, mfERG responses were recorded over the optic nerve head. This is not an artifact. The hexagons do not fall completely on the optic disc, and light-scattering may contribute to the almost normal responses over the optic nerve head.
27 Qualitative analysis revealed no substantial peak amplitude reduction in the central element. Amplitude changes in the mfERG superimposed onto the FAF image corresponded well with the area of abnormality seen with FAF imaging
(Fig. 3) .
It is thought that an increased FAF signal is the result of a high metabolic turnover of photoreceptor outer segments leading to lipofuscin accumulation in RPE cells.
28 Both the electrophysiological and imaging data suggest restricted photoreceptor damage in MIDD rather than generalized retinal dysfunction. In histologic study of patients with A3243G mutation and Kearns-Sayre or MELAS syndrome, investigators reported atrophic photoreceptor outer segments and abnormal mitochondria in the inner retinal segments. Ultrastructural changes were present in RPE cells together with enlarged mitochondria.
7 8 9 It was postulated that photoreceptor outer segments are stressed both from the RPE and from photoreceptor inner segments, which contain 90% of the retina’s mitochondria.
9 29
Although the FAF pattern in MIDD is specific, the changes have similarities with the pattern described in patients with geographic atrophy due to age-related macular degeneration.
16 It is known that mitochondrial alterations are not only described in maternal inherited diseases but also appear in any aging postmitotic cell,
30 so that there may be a common pathogenic pathway in the development of atrophy of the RPE. Mitochondria are involved in a number of metabolic processes including the generation of chemical energy in form of adenosine triphosphate (ATP).
30 They are the main source of reactive oxygen species formation and important control centers for apoptosis.
30 31 32 Thus, it is no surprise that mitochondrial DNA shows a high mutation rate and that mutations accumulate with age.
33 Furthermore, defective mitochondria may be not properly autophagocytosed. Their components may undergo further oxidative modification within the lysosomes, resulting in the formation of additional undegradable material, such as lipofuscin in RPE cells, and progressively less mitochondrial recycling. Consequently, compensatory mechanisms may fail with time, followed by dysfunction and cell death, particularly in relation to postmitotic tissues with high energy demand, such as photoreceptors and RPE cells.
31
Age-dependent somatic selection favors the persistence of mitochondria carrying the mutation in many mitochondrial diseases and symptoms may appear only later in life. This is in keeping with the slow progression and localized damage in our patients and in patients with other mitochondrial diseases.
34
Rod photoreceptor dysfunction may be predicted in patients with MIDD, as much of the generated energy in rods supports the ionic pumps that keep the cell in a response-ready state (i.e., for photoreceptor outer segment disc turnover and for the phototransduction cascade).
35 If rods were the first location susceptible to the effects of the A3243G mutation, it would explain the striking location of retinal changes, as histologic data describe a maximum rod density at 4 to 6 mm from the fovea.
36 Nevertheless, global rod system ERG abnormalities in the Ganzfeld ERG were observed in only one patient.
The results clearly demonstrate a nonuniform retinal damage and suggest damage to the cone photoreceptor outer segments in MIDD. The results support further the hypothesis that both photoreceptor outer segments and RPE cells are involved in the pathogenesis of MIDD, consistent with histologic data. However, whether the two cell layers are equally susceptible to the effects of the A3243G mutation or the photoreceptor damage is a consequence of the disease principally involving the RPE is yet to be ascertained.
The authors thank Alaric Smith for the referral of patients.