LOS MEDIOS DE COMUNICACIÓN

Before addressing how mitochondrial dysfunction, widely expressed in all tissues studied, might result in a tissue specific clinical condition, one must first consider which particular cell types are primarily affected in LHON. Most of the limited histopathological reports available have supported a primary neuronal degeneration of the retinal ganglion cells and their projections, the optic nerve, with secondary degenerative changes in other parts of the visual system (Kwittken and Barest, 1958; Wilson, 1963; Hume Adams et al. 1966). However

all reports are from cases with established optic atrophy due to LHON. Secondary degenerative changes may have taken place, so any conclusions regarding which cells are primarily affected are by necessity speculative. Demyelination confined to the optic nerve, with secondary neuronal loss and gliosis, or a primary vascular or inflammatory process cannot be excluded from these studies. Abnormalities on fundoscopy or in visual evoked potentials in asymptomatic/pre-symptomatic family members (Nikoskelainen at al. 1977;

1982) have been demonstrated, but are non-specific. Pathological data from the visual pathways shortly preceding the onset of significant symptoms, or during the acute phase would be more informative in this respect.

The most recent post mortem study (Kerrison at al. 1995) reported

swollen mitochondria with disrupted cristae in the ganglion cells of a woman from the Queensland family with the 14,484 and 4,160bp mutations with isolated blindness. Similar changes are often found in the muscle of patients with mitochondrial myopathies (Fukuhara at al. 1980), in whom there is less

doubt regarding the significance of MRC dysfunction in disease pathogenesis. These findings might represent non-specific post mortem changes, as the authors conceded considerable autolysis had taken place. However calcium containing double-membrane bound inclusions, with rudimentary cristae were also documented in these LHON ganglion cells. These were not found in control tissues, and were thought to represent calcified mitochondrial inclusions resulting from mitochondrial dysfunction. Intracellular calcium accumulation is believed to be a crucial step in cell death induced by excitatory amino acids such as glutamate, and neuronal damage induced by cellular energy depletion may also involve activation of excitatory glutamate receptors (reviewed by Ludolph et al. 1993). Kerrison at al. (1995) suggest that such mechanisms may

also be contributing to cell death in LHON, although clearly this is speculative at present.

Assuming the optic nerves are the cells of primary importance in LHON, if MRC dysfunction is of pathogenetic significance in their demise, the question of how some form of complex I dysfunction, expressed in all tissues, might result in the selective death of the optic nerve cells? Either optic nerve cells are particularly susceptible to some dysfunction of complex I that is of less significance in other tissues, or an additional biochemical defect is expressed as a tissue specific phenomenon in these cells.

In considering the first of these possibilities, as the primary LHON mutations identified at positions 11,778, 14,484 and 3,460 are all in genes encoding complex I subunits, it is probable that complex I is in some way involved in disease pathogenesis. Defects in complex I function as demonstrated in 3,460 LHON, the more subtle abnormalities proposed in

11,778 LHON, and potentially present in 14,484 LHON in whom only limited studies have been reported, might differ in detail but all share a secondary common final pathway which results in optic nerve cell death. Discussion on the nature of such secondary mechanisms is purely speculative, but might for instance involve local oxidative stress and/or excitotoxic damage as implicated

in other cell specific neurodegenerations such as Parkinson's disease (Schapira, 1994b), Alzheimer's disease (Mecocci et al. 1994) and Huntington's

disease (Beal at al. 1993). Most of the work in this field to date concentrates on

Parkinson's disease (PD) in which complex I dysfunction has been implicated (reviewed by Schapira, 1994c). PD is characterized by the selective loss of a very specific cell population in the substantia nigra zona compacta, and although the complex I defect is also most pronounced in this brain region it must also involve the more numerous non-neuronal cells in this region to be readily detected. Controversial evidence has also been presented that this occurs on a background of more widespread MRC dysfunction in PD subjects, as a milder complex I defect has also been identified in platelets (Krige at al.

1992) and in muscle (Cardellach at al. 1993; Blin at al. 1994) from PD patients.

Local factors particular to the substantia nigra in PD are believed to be contribute to the tissue specificity of this functional defect. These include abnormalities in local oxidative defences with excess free radical production (Jenner at al. 1992; Schapira, 1994b), the local accumulation pro-oxidant

substances such as iron and melanin (Good at al. 1992; Mann at al. 1994), and

local accumulations by neurotransmitter uptake mechanisms of endogenous or exogenous toxins e.g. catecholamine derivatives (Liptrot at al. 1993) or the

opiate derivative MPTP (Adams and Odunze, 1991). Clearly LHON and PD are quite different conditions, and pedigree analyses support a different genetic basis, so whilst their respective aetiological mechanisms are likely to be distinct, one can speculate that a widely expressed functional defect, in the case of LHON consequent upon a mtDNA mutation, might only have pathological consequences in optic nerve cells due to the presence of similar additional local factors. One feature common to both the substantia nigra and the retina is the presence of pigment, implicated in the differential susceptibility of substantia nigra cells in PD by binding metal ions (Hirsch at al. 1988; Good at al. 1992),

which in turn contribute to oxidative damage (reviewed by Schapira, 1994b). It is also interesting to note in this context that another extrapyramidal disease

(dystonia) has been associated with LHON in families with a severe complex I defect and a complex I mtDNA mutation at 14,459bp (Shoffner et al. 1995).

The local factor(s) that might render the optic nerve differentially susceptible to minor abnormalities of MRC dysfunction are as yet unidentified, They could be related to a nuclear gene, as pedigree studies would suggest, but environmental agents may equally be involved. A single report of identical twins with the 11,778 mutation, of whom only one is clinically affected and the other remains asymptomatic 6.5 years later, implies that non-genetic factors are involved in the clinical expression of LHON (Johns et al. 1994). The second

twin may yet develop visual impairment, but at the very least non-genetic factors such as alcohol intake, smoking and nutrition, must have influence on the age of onset. A mtDNA mutation resulting in tissue specific susceptibility to a normally non-toxic environmental agent has been proposed in Chinese families with aminoglycoside induced deafness. Symptoms in affected individuals occur at low doses of aminoglycosides that would not normally be toxic, associated with a mitochondrial rRNA mutation at position 1555 (Prezant et al. 1993). Prior to the interest surrounding mtDNA mutations and LHON

environmental toxins had been proposed as contributory aetiological agents (Hume Adams et al. 1966; Wilson et al. 1971), and perhaps this is an area that

should now be re-addressed as studies of MRC function alone have not unravelled the pathogenetic mechanisms in LHON.

A final possibility in this category is that a tissue specific threshold effect exists, such that a reduction of at most 50 - 80% in complex I function in LHON cells is below the threshold at which physiological cell function is impaired in muscle, skin and brain, but in optic nerve cells the threshold is lower and cell death ensues. Differences between tissues in their ability to tolerate specific enzyme defects before oxygen consumption is impaired have been reported, as discussed in chapter 6 5.2.4, although studies in this field are as yet limited in number.