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Keywords:

  • Usher syndrome;
  • USH3;
  • retinitis pigmentosa;
  • phenotype−genotype correlation;
  • visual field deterioration;
  • functional vision score

Abstract.

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Purpose: To evaluate visual impairment in Finnish Usher syndrome type 3 (USH3) and compare this with visual impairment in Usher syndrome types 1b (USH1b) and 2a (USH2a).

Methods: We carried out a retrospective study of 28 Finnish USH3 patients, 24 Dutch USH2a patients and 17 Dutch USH1b patients. Cross-sectional regression analyses of the functional acuity score (FAS), functional field score (FFS*) and functional vision score (FVS*) related to age were performed for all patients. The FFS* and FVS* were calculated using the isoptre V-4 test target instead of the usual III-4 target. Statistical tests relating to regression lines and Student's t-test were used to compare between USH3 patients and the other genetic subtypes of Usher syndrome.

Results: Cross-sectional analyses revealed significant deterioration in the FAS (1.3% per year), FFS* (1.4% per year) and FVS* (1.8% per year) with advancing age in the USH3 patient group. At a given age the USH3 patients showed significantly poorer visual field function than the USH2a patients.

Conclusions: The rate of deterioration in visual function in Finnish USH3 patients was fairly similar to that in Dutch USH1b or USH2a patients. At a given age, visual field impairment in USH3 patients was similar to that in USH1b patients but poorer than in USH2a patients.


Introduction

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Usher syndrome, an eponym of the Scottish ophthalmologist Charles Usher (1865−1942), is an autosomal recessive disorder characterized by the combination of progressive retinitis pigmentosa (RP) and sensorineural hearing impairment (SNHI) (Usher 1916). Usher syndrome is estimated to occur in 3.5−6.2 of 100 000 people, making it the most common cause of deaf-blindness worldwide (Spandau & Rohrschneider 2002). Usher syndrome is divided into three clinical types (1−3) on the basis of audiovestibular features and 13 corresponding genotypes (Van Camp & Smith 2004).

Usher syndrome type 1 (USH1a−g) is characterized by congenital, profound SNHI, RP and vestibular areflexia. Usher syndrome type 2 (USH2a−c) shows moderate to severe congenital high frequency SNHI, RP and intact vestibular responses. Usher syndrome type 3 (USH3) shows a highly variable type and degree of progressive SNHI, RP and variable vestibular responses (Plantinga et al. 2005). The genetic subtypes USH1b and USH2a account for about 75–80% of all Usher syndrome patients worldwide, whereas Usher syndrome type 3 is rare (Pennings et al. 2002). However, Usher syndrome type 3 is common in the Scandinavian countries and especially in Finland. Pakarinen et al. (1995) concluded that USH3 accounts for 40% of all Finnish Usher syndrome patients.

A Finnish founder mutation is associated with the high prevalence of USH3 in the Finnish Usher syndrome population (Peltonen et al. 1999). This mutation in the USH3A gene on chromosome 3q21-q25 was designated Finmajor (c.300 T > G; c.528 T > G according to the new nomenclature) and leads to a premature stop codon for a tyrosine at amino acid position 176 (Y176X, previously Y100X) (Joensuu et al. 2001; Adato et al. 2002). It has currently been identified in over 44 Finnish families as the cause of USH3 (Sankila, unpublished 2005). The change in nomenclature is the result of a newly identified exon discovered by Adato et al. (2002). Another associated mutation is the Finminor mutation (c.131 T > A, now c.359 T > A), resulting in M120K (previously M44K) (Joensuu et al. 2001; Adato et al. 2002).

Retinitis pigmentosa leads to impaired dark adaptation, progressive visual field constriction and reduction in visual acuity (VA) in all types of Usher syndrome and may even result in blindness. Patients with USH3 have been reported to have hypermetropia with astigmatism as opposed to hypermetropia without astigmatism in USH1 and myopic refractive errors in USH2 (Pakarinen et al. 1996). Overall, 50% of patients with Usher syndrome at some point develop posterior subcapsular cataract that may severely hamper vision (Auffarth et al. 1997).

Pakarinen et al. (1996) presented a report on the ophthalmological course of Usher syndrome in type 3 patients. However, it only included VA data for analysis and comparison between the different clinical types of Usher syndrome. At that time, the different genotypes in Usher syndrome had scarcely been identified. The VA and visual field measurements of genetically confirmed Finnish USH3 patients were re-analysed in the present study and compared to similar analyses for Dutch USH1b and USH2a patients, identified by mutations in the MYO7A and USH2A genes, respectively (Pennings et al. 2004).

Methods

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Subjects

This study included 28 patients (25 Finmajor/Finmajor and three Finmajor/Finminor) with clinically and genetically confirmed diagnoses of Usher syndrome type 3 (Joensuu et al. 2003; unpublished data). Routine ophthalmological examination included external eye examination, corrected VA measurements, testing of refraction, Goldmann perimetry, biomicroscopy and ophthalmoscopy. We included only those patients whose VA scores and visual fields had been evaluated at least once. Data and patients were collected retrospectively after a previous nationwide epidemiological study of Usher syndrome type 3 in Finland conducted during 1989–92. Medical records were obtained in accordance with local ethics committees and in co-operation with the Finnish Ministry of Health, to include as many VA and visual field measurements as possible. Data on visual function were accepted without a priori criteria, provided that functions had been reliably measured and data sufficiently documented. The patients enrolled in this study were not selected according to VA or visual field findings.

Evaluation of visual acuity and visual field deterioration

Visual acuity was measured by using standard Snellen E-charts. Best corrected measurements of both eyes were used for further evaluation. The VA measurement for each eye was converted into a VA score (VAS) according to Weber−Fechner's law. The functional acuity score (FAS) was determined by the equation FAS  = (3 × VASboth eyes + VASleft eye+ VASright eye) / 5 (American Medical Association 2001).

Visual field size was evaluated by Goldmann perimetry in both eyes. The visual field score (VFS), as defined by the American Medical Association (2001), is related to the III-4 target. Unfortunately, the available Finnish USH3 visual field data mainly involved the V-4 target and the III-4 target had hardly been used. For this reason, visual field scores were quantified by plotting the V-4 isopter instead of the III-4 isopter; the derived (V-4) scores are marked with an asterisk to designate the different isopter. The corresponding visual field scores (VFS*) for each eye separately and both eyes combined were obtained by drawing 10 meridians in the visual field examination form; two in each upper quadrant (at 25, 65, 115 and 155 degrees) and three in each lower quadrant (at 195, 225, 255, 285, 315 and 345 degrees). These VFS*s were converted to a functional field score (FFS*) using a similar equation as for the conversion of the VAS. Finally, the functional vision score (FVS*) was determined by the FAS and the FFS* based on the equation FVS* = (FFS* × FAS) / 100 (American Medical Association 2001).

To allow for a correct comparison of functional vision scores between the present Finnish USH3 patient group and the previously published Dutch USH1b and USH2a patient groups (Pennings et al. 2004), the field scores for the V-4 target (FFS* and FVS*) were derived in the latter two patient groups as well.

Special attention was paid to the quantitative relationship between the parameters based on the III-4 target (FFS and FVS, precisely as recommended by the American Medical Association (2001) and the corresponding newly defined parameters (FFS* and FVS*, respectively) based on the V-4 target.

In total, 17 USH1b and 24 USH2a patients underwent V-4 Goldmann perimetry examinations and thus were included in the present analyses.

Statistical analysis

Regression analysis was used to analyse cross-sectional functional visual score data (FAS, FFS* or FVS*) for the Finnish USH3 patients in relation to patient age. Deterioration was concluded to be significant if the correlation coefficient was negative at a probability level of <0.025.

The regression data obtained for the functional visual scores (FAS, FFS* and FVS*) for the Finnish USH3 patients were compared to the corresponding scores for the Dutch USH1b and USH2a patients (Pennings et al. 2004). The regression lines were compared using a procedure (Prism, Version 4; GraphPad, San Diego, California, USA) fairly similar to covariance analysis. Regression lines were concluded to differ significantly if either the F-test pertaining to the comparison between the slopes of these lines produced a significant value (p < 0.05), or – when the slopes were not significantly different – if the F-test pertaining to the comparison between the elevations of the lines (i.e. a measure for dispersion comprising grand means of both x and y values for each subset of regression data) produced a significant value. Regression lines were also compared using an optimum age window for the comparison in question. Non-linear regression analysis was used to find the age at which the FVS* was 50% and a 95% confidence interval (CI) was also obtained for this estimate.

Results

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Functional visual scores in USH3 patients compared to those in USH1b and USH2a patients (cross-sectional analysis)

Figure 1 shows the FAS, FFS* and FVS* data for USH3 plotted together with those for the Dutch USH1b and USH2a patients as previously published (Pennings et al. 2004). All scores deteriorated significantly for the USH3 patients. Although many of the FAS data for USH3 patients tended to be lower at more advanced ages than those measured for USH1b or USH2a patients, there was no significant difference found between the regression lines. Comparison of the FFS* or FVS* data between the patient groups showed a significant difference between the elevations of the regression lines: at a given age, the highest scores belonged to the USH2a patients, whilst the lowest scores belonged to the USH3 patients. The significant difference could be attributed to the USH3 and USH2a groups. Corresponding differences were found between the ages at which the FVS* equalled 50%. These ages were estimated to be 28 years for USH3 and 39 years for USH2a; the estimated 95% CIs did not overlap (Table 1).

image

Figure 1. FAS, FFS* and FVS* for USH3. Finmajor homozygotes (solid triangles) plotted together with the corresponding data for the Dutch USH1b (dots) and USH2a (open circles) patients. Regression lines (dotted line = USH3, solid line = USH1b, dashed line = USH2a) are included. The bold regression line indicates significant deterioration. Small symbols represent outlying values, which were excluded from regression analyses. Vertical hairlines show age windows (22–48 years). Finmajor/Finminor compound heterozygotes are also plotted (solid squares) but these data were excluded from regression and subsequent analyses.

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Table 1.  Slopes (score ‘% change per year’) for the cross-sectional regression lines relating to the FAS, FFS* and FVS* for USH3, USH1b and USH2a. Pooled slopes are included. The slopes relating to the FFS or FVS (based on test target III-4 and previously published by Pennings et al. (2004) for USH1b and USH2a are shown in parentheses for comparison.
 FASFFS* (FFS)FVS* (FVS)Age at FVS* 50%
    Years(95% CI)
USH3−1.3−1.4−1.8 28(24–32)
USH1b−0.6−1.6 (−1.3)−1.6 (−1.5)33(28–38)
USH2a−0.8−0.9 (−1.0)−1.6 (−1.4)39(35–44)
Pooled−0.9−1.3 −1.7  

There was no significant difference in slope detected between the three patient groups. Applying the age window (Fig. 1) did not introduce essential changes.

Table 1 lists the slopes for the cross-sectional regression lines relating to the FAS, FFS* and FVS* for the separate groups USH3, USH1b and USH2a; pooled slopes are included. The slopes relating to the FFS for USH1b and USH2a, previously published by Pennings et al. (2004), are also included for comparison. The pooled slopes indicate that the FAS deteriorated by a value of close to − 1% per year, the FFS* by a value slightly below − 1.5% per year and the combined score FVS* by a value slightly over − 1.5% per year. The parameter changes − from FFS to FFS* and from FVS to FVS* depending on the target used − did not entail substantial changes in slope for the reference groups USH1b and USH2a.

Data for the three heterozygous Finmajor/Finminor patients are shown in Fig. 1, but were excluded from further analysis because of the small numbers of observations. Nevertheless, it can be seen that these patients tended to show relatively poor scores for their age.

Longitudinal data

Longitudinal data for USH3 are shown in Fig. 2. Only one of the nine patients for whom longitudinal regression lines could be calculated showed significant deterioration of the FAS. Significant proportions of the patients (according to binomial statistics) showed significant deterioration of the FFS* (six of nine patients) or the FVS* (four of six). The slope of each individual longitudinal regression line was compared to the slope of the corresponding overall cross-sectional regression line (Fig. 2, dotted line). Individual deterioration rates varied fairly symmetrically around the slope for the corresponding cross-sectional regression line and ranged from − 2 to 0.6 for the FAS, − 3.4 to 0.3 for the FFS* and − 2 to − 1.2 for the FVS*.

image

Figure 2. FAS, FFS* and FVS* for USH3 (solid triangles) Finmajor homozygotes. Individual longitudinal measurements connected by hairlines. Individual regression lines are included; these are bold for significant deterioration. The bold dotted line is the regression line for the cross-sectional USH3 data (Fig. 1). Incidental longitudinal data of one Finmajor/Finminor compound heterozygote are also plotted (solid squares) without a regression line.

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Discussion

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The cross-sectional analysis in this study revealed a significant deterioration of the FAS (1.3% per year), FFS* (1.4% per year) and FVS* (1.8% per year) with advancing age for USH3 patients. This rate of deterioration in visual function was fairly similar to that of USH1b or USH2a patients. The FVS* in USH3 patients was significantly poorer than in USH2a patients; the 50% score was attained about a decade earlier in the former. Inspection of the longitudinal data showed a rate of deterioration in visual function similar to the results from the cross-sectional analysis.

The heterozygous Finmajor/Finminor patients tended to show relatively poor functional vision scores compared to the homozygous Finmajor/Finmajor patients. Because of the small number (n = 3) they were excluded from further analysis. However, this is an interesting finding because Finmajor/Finminor patients tend to have better auditory function than homozygotes (Plantinga et al. 2005).

Earlier studies on VA and visual field deterioration in Usher syndrome compared USH1 and USH2 patients (Fishman et al. 1983, 1995; Piazza et al. 1986; van Aarem et al. 1995; Edwards et al. 1998; Seeliger et al. 1999; Tsilou et al. 2002; Pennings et al. 2004). In general, USH2 patients showed (significantly) more favourable results than USH1 patients. Fishman et al. (1983) suggested that visual fields in USH1 deteriorate more rapidly than in USH2. Our data confirms that at a given age USH2a patients score better than USH1b patients; however, a more rapid deterioration was not observed.

The study on Dutch Usher syndrome patients found no significant difference in field scores between patients with and without cataract (Pennings et al. 2004). For this reason we did not consider the issue of cataract in the analyses in our present study, although we realize that cataract could cause a difference in functional vision scores.

The previously published report on visual function loss in USH3 patients describes the course of visual handicap and typical refractive errors in USH3. Deterioration occurred below the age of 40 years, VA dropped below 0.05 (severely impaired) at the age of 37 years and the visual fields were of tubular shape without any peripheral islands at the average age of 30 years (Pakarinen et al. 1996). The report also suggested that hypermetropia with astigmatism is pathognomonic in USH3.

As described under Methods, the standard visual field scores could not be used in the analysis of the USH3 patient data. In order to check whether we could use the V-4 target instead of the III-4 target, we used linear regression analysis (data not shown) to compare between the FFS* and FFS data, as well as between the FVS* and the FVS data, for the Dutch Usher patients. It appeared that FFS* = FFS + 14 and FVS* = FVS + 14 over the whole range of scores involved. This finding implies that the changes in evaluation parameters applied did not introduce any apparent change in deterioration rate. The difference by a score of 14 should be kept in mind when comparing the present altered scores (FFS* or FVS*) to scores according to the original definitions (FFS or FVS). Thus, the FVS approximates the 50% score when FVS* = 64%.

Non-linear regression analysis focussing on FVS* = 64% showed that, on average, for USH3 patients the FVS attains values of <50% at ages >20 years, whereas this can be expected to be the case at ages >31 years for USH2a patients and ages >24 years for USH1b patients. This is a clinically important score because these patients (FVS <50%) may no longer sufficiently benefit from vision enhancement techniques (American Medical Association 2001).

It should be emphasized that most of the visual function deterioration in USH3 patients occurs after the deterioration in auditory function. Hearing deterioration is most severe during the first decades of life (Plantinga et al. 2005).

In conclusion, the rate of deterioration in visual function in Finnish USH3 patients was fairly similar to that in Dutch USH1b or USH2a patients. At a given age, visual field impairment in USH3 patients was fairly similar to that in USH1b patients but significantly poorer than in USH2a patients.

References

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
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