The phenotype of the multifocal pattern dystrophy described in this report is caused by autosomal dominant inheritance of mutations in the peripherin/RDS
gene, with variable expressivity and a reduced penetrance. The type and distribution of the flecks in this pattern dystrophy strongly resembled the flecks observed in the fundus flavimaculatus phenotype of STGD1, an autosomal recessive retinal dystrophy caused by mutations in the ABCA4
This resemblance was evident on ophthalmoscopy as well as on AF and OCT.42,43,44,45,46
All probands demonstrated a variable number of irregularly shaped yellow–white flecks scattered throughout the posterior pole and around the retinal vascular arcades. These yellowish flecks were preceded either by typical macular pattern dystrophy or by non‐specific pigmentary changes in the fovea. The lesions were best defined by AF imaging. Discrete retinal abnormalities were also easily identified with this technique in several asymptomatic family members carrying the same peripherin/RDS mutation as the proband. Extensive atrophy of the central retina tends to occur with increasing age as demonstrated by the four probands who were over 60 years of age. The fact that multifocal pattern dystrophy, like many other “macular” dystrophies, may involve the peripheral retina is demonstrated by the abnormal photopic and scotopic ERGs in almost half of the probands and an abnormal EOG in the majority of the probands.
Of the nine different mutations that were identified, there were five different frameshift mutations and one nonsense mutation, which led to a premature termination by a stop codon. This may lead to either a shorter protein product or it may induce degradation of the mRNA by nonsense‐mediated decay. The mechanism of pathogenicity of the mutation may be haploinsufficiency in case of the frameshift mutations, the nonsense mutation and the splice site mutation. In case of the two missense mutations that were found, a dominant negative effect may also be possible, although there is plausible evidence that these mutations may also lead to haploinsufficiency.47,48
The frameshift mutation p.P147fsX4 has been previously described in patients with central areolar choroidal dystrophy.39
This p.P147fsX4 mutation was found in two unrelated probands, patients D and E. Both patients had multifocal pattern dystrophy, but in patient D the phenotype progressed to a panretinal dystrophy resembling retinitis pigmentosa, with widespread involvement of the rod and cone system. The missense mutation p.D157N has been reported previously in patients with pattern dystrophy,38
while the p.P210R missense mutation was found in patients with adult‐onset foveomacular vitelliform dystrophy.27,40
In our study, a genotype–phenotype correlation could not be established. The present study again demonstrates the highly divergent phenotypes in family members who carry identical peripherin/RDS
mutations. The retinal abnormalities range from minor foveal abnormalities to multifocal pattern dystrophy and even retinitis pigmentosa. This remarkable clinical heterogeneity precludes a straightforward genotype–phenotype correlation even with larger patient series.5,8,10,12,16,18,20,29,49
Obviously, modifying factors besides the specific mutation in the peripherin/RDS
gene exert an important influence on the resulting phenotype.
Zhang et al.
reported the histopathological findings in a patient with butterfly‐shaped pattern dystrophy with Stargardt‐like flecks caused by a p.C213Y substitution in peripherin/RDS
Adjacent to a central area of atrophy, the RPE cells were greatly distended by lipofuscin. This is in accordance with the predominantly increased AF signal of the lesions described in the present study. The same accumulation of lipofuscin in RPE cells has been demonstrated for STGD1.50,51,52
It is likely that the lipofuscin accumulation in multifocal pattern dystrophy is less pronounced in view of the better visual prognosis as well as the absence of choroidal blockage on the fluorescein angiogram. The small adjacent zones with a decreased AF signal, which were seen in association with the majority of flecks, are probably caused by RPE atrophy. This is reflected in the predominant hyperfluorescence of the flecks on the fluorescein angiogram. As the disease progresses, the flecks tend to evolve towards a confluent atrophic area which shows larger zones of decreased AF intensity. The multifocal nature of this pattern dystrophy may be explained by local differences in cell interactions, distribution, morphology and metabolism.53
Autosomal dominant multifocal pattern dystrophy should not be confused with autosomal recessive STGD1 and infrequent autosomal dominant retinal disorders such as STGD3 (ELOVL4
gene) and STGD4.54,55,56
Clinical findings that may help to distinguish this pattern dystrophy from STGD1 are the autosomal dominant pattern of inheritance, the relatively late age of onset (fifth decade), the comparatively good and stable visual acuity and the absence of a “dark choroid”. However, the incomplete penetrance (10% in this study) and the variable expression may mask the dominant inheritance pattern. Conversely, due to the high carrier frequency of ABCA4
mutations, STGD1 patients may have relatives with some form of retinal dystrophy.57
Three of the probands in this study received the proper diagnosis only after analysis of the peripherin/RDS
gene in a group of 15 patients with presumed STGD1, but without detectable mutations in the ABCA4
gene. Therefore, an analysis of the peripherin/RDS
gene should be considered in the absence of ABCA4
mutations, especially when confronted with the aforementioned phenotype.