Desarrollo léxico formal

Many of the clinical features of the retinal dystrophy associated with the NRL

S50T mutation are similar to those observed in patients suffering from retinitis

pigmentosa due to mutations in rhodopsin, peripherin-RDS, or other, as yet

unidentified, genes. Classically the first symptom o f retinitis pigmentosa is nyctalopia, with later onset of problems relating to visual field loss, and lastly variable reduction of central vision. Visual field loss typically begins in the mid- rather than the far periphery. Peripheral intraretinal pigment migration is associated with RPE atrophy. With the exception of a limited number o f geographically limited forms of RP (sectorial RP), the scotopic ERG almost invariably becomes extinguished during the course of the disease.

Several features of the phenotype associated with the NRL S50T mutation

may, however, serve to distinguish it from other forms of RP:

1). In younger family members electrophysiology typically demonstrates a remarkable preservation of cone function at a time when rod fimction has already been completely extinguished.

2). The ‘negative’ waveform of the dark-adapted maximal (bright white flash) ERG response is well recognised in certain specific retinal dystrophies, such as X- linked retinoschisis, but is unusual amongst RP phenotypes. Since the a-wave is generated by the photoreceptors, whereas the b-wave arises in the inner retina, the relative preservation of the a-wave in this dystrophy is particularly interesting.

Whilst rods outnumber cones approximately 13 to 1, the cones account for around 15% of the full-field ERG response to single flashes of white light under dark- adapted conditions. Since the a wave amplitude in younger members of RP251 varies from 45-115pv, and a normal value would be in the 300-400pv range, it is possible

that these a waves represent isolated cone function. The relatively greater reduction in b wave amplitude suggests inner retinal dysfunction, and may represent a direct effect

of the NRL mutation, mediated by its expression in other cells o f the neural retina, or

an indirect effect due to loss of rods.

Histological studies of human retinas affected by retinitis pigmentosa have demonstrated that rods, amacrine cells and horizontal cells may all undergo neurite sprouting in regions with significant photoreceptor loss’. When neurite sprouting does occur, the majority of rod neurites bypass the dendrites o f horizontal and bipolar cells, the normal targets of rod axons in the outer plexiform layer, and directly contact the hypertrophied processes of Müller cells, which have undergone reactive gliosis in response to photoreceptor cell death, and the somata o f amacrine cells. These changes in retinal neuronal circuitry may contribute to the electroretinographic abnormalities observed in RP, and in some instances to the development o f an electronegative ERG.

3). The development of macular thickening appears to be a natural stage in the progression of this dystrophy. Whereas a proportion of RP patients with macular oedema usually respond to oral acetazolamide, there was no such response in any patient in this study (excluding patient IV:3 from family RP57, whose oedema may have been largely due to retinal telangiectasis).

4). A striking ‘Bull’s eye’ pattern of macular atrophy, with attendant loss of visual acuity, more typical o f that seen in cone-rod dystrophies, is observed in older individuals.

5). Peripapillary chorioretinal atrophy, similar to that seen in high myopia, but not a common feature of inherited retinal dystrophies, occurs with disease progression. Histological analysis of age-related peripapillary atrophy has demonstrated degeneration of the RPE-Bruch’s membrane complex, with concomitant

NRL Ser50Thr Mutation

loss of rod photoreceptors, which resembles the degeneration that may be found in the

macula and periphery of aging eyes (Curcio et al, 2000).

Atrophy is also observed in both the macula and the peripapillary region in myopia, and in the peripapillary region alone in chronic glaucoma. Progressive

peripapillary chorioretinal atrophy in patients with the NRL S50T mutation may,

therefore, be mirroring the atrophic changes occurring in their macula and retinal periphery.

Each of these features may well be found in isolation in patients with retinal dystrophies due to other genetic changes, but a combination of these features, especially if observed in several members o f a family, would be consistent with an

underlying NRL mutation.

6.10.1 Comparison with other RP phenotypes.

In all four pedigrees the RP phenotype is fully penetrant and exhibits only limited variation in expressivity. This is comparable with the phenotypes ascribed to

specific rhodopsin mutations and in contrast to the variable expressivity and

incomplete penetrance associated with the 7pl5.1-pl3 (Kim et al, 1995), 8q ll-ql3

(Jacobson et al, 2000) and 19ql3.4 (Al-Maghtheh et al, 1996) adRP loci

respectively.

Prior to the development o f molecular classifications, it was shown that adRP

could be classified according to the pattern of photoreceptor degeneration (Lyness et

al, 1985; Massof and Finkelstein, 1987; Kemp et al, 1988)”. Type-1 or diffuse adRP

is characterised by diffuse loss o f rod function with relative preservation of cone function in the early stages of the disease. Patients frequently present early, with night blindness evident before the age of 10 years. Further visual symptoms and retinal pigmentary changes may, however, be delayed for 10-20 years after the onset of