Paediatric Fabry disease: prognostic significance of ocular changes for disease severity

FOS is an ongoing, prospective, observational registry designed to collect clinical outcomes in patients with Fabry disease who are treatment naïve, currently treated with agalsidase alfa, or were previously treated with any ERT. For this retrospective cross-sectional analysis, data in FOS were collected from patients examined from 2001 through August 2014, with the approval of the ethical review board at each participating centre (see list in Additional file 1: Table S1). Upon enrolment into FOS, written informed consent was obtained from each patient (or parent/legal guardian for minor patients) and a physician documented each patient’s medical history, the year of diagnosis, signs and symptoms of the disease, and treatment. Depersonalised data were selected for boys (hemizygotes) and girls (heterozygotes) who underwent a detailed ocular examination, including slit-lamp examination of the anterior segment, as well as fundoscopy. The prevalence of Fabry-specific eye abnormalities was analysed in the overall FOS population, as previously described [30]. Ocular vessel tortuosity was assessed semi-quantitatively (as none, mild, moderate, or severe) by the examining eye care practitioner and was not separated between retinal and conjunctival vessels in the FOS database. FOS collects real-world data on routine clinical evaluation parameters. Therefore, no specific training was provided to practitioners to assure constancy and reliability of data collection in this multicentre study. The presence or absence of corneal haze and subepithelial corneal lines was not reported as a sign and/or symptom of Fabry disease in FOS.

Descriptive summary statistics are presented. For categorical parameters, numbers and percentages of affected patients are reported; for continuous parameters, medians and ranges are shown. The Wilcoxon nonparametric statistic was used to compare groups. Statistical analyses were conducted using SAS V.9.2 (SAS Institute Inc., Cary, NC, USA), and data collection and analysis were supported by Shire.

Associations between eye abnormalities and severity of systemic involvement were evaluated using the disease-specific FOS Mainz severity score index (FOS-MSSI) [31, 32], which consists of four sections that cover general, neurological, cardiovascular, and renal signs and symptoms of Fabry disease [32]. Each section is weighted according to its contribution to disease morbidity, and individual organ-related scores are added to calculate the total FOS-MSSI score, which is categorised as mild (≤18), moderate (19–38), or severe (>38) [32]. Because the FOS-MSSI scoring system was not developed for and has not been validated in children, an age adjustment of the FOS-MSSI score was calculated, using an equation based on age [33, 34]. The age-adjusted FOS-MSSI disease severity scores represent the observed FOS-MSSI score minus the expected FOS-MSSI score for that patient’s age; thus, a positive age-adjusted score indicates the patient has more severe manifestations than average, and a negative age-adjusted score indicates the patient has less severe disease than average [33]. The CV subscore was removed from the total FOS-MSSI score to avoid skewing comparisons between patients with and without CV. Ocular signs were correlated with age-adjusted FOS-MSSI values.

Among 2379 patients with data available at the August 3, 2014 extraction date, 255 were children at FOS entry; 232 underwent their first ocular examination before the age of 18 years (Table 1). At least one of the eye findings described was found in 117/232 (50.4%) children. Observed eye findings included CV (Fig. 1a) in 108/232 (46.6%), retinal and/or conjunctival vessel tortuosity (Fig. 1b, c) in 49/229 (21.4%), and posterior spoke-like lens opacity (Fig. 1d) in 5/227 (2.2%) patients. More than half (137/232; 59.1%) of the children received agalsidase alfa treatment at any time.

Ocular signs of Fabry disease were noted in 55/101 (54.5%) girls and 62/131 (47.3%) boys who had undergone ocular examination (Table 1). CV was more common and tended to be seen at younger ages in girls than boys (seen in 52.5% of girls and 42.0% of boys; median age at first presentation, 8.9 years and 10.7 years, respectively). This is consistent with previously published reports [2, 3]. However, tortuous ocular vessels were more common and tended to be seen at younger ages in boys than girls (seen in 24.4% of boys and 17.3% of girls; median age at first finding, 10.1 years in boys and 12.0 years in girls) and reflect more severe disease; this was also seen in a previously published single-centre study [35]. Posterior spoke-like lens opacities were uncommon, being reported in only three girls and two boys.

Of the 232 children with ocular examinations, 108 patients had a first diagnosis of CV during the study period. The distribution of first onset of CV by age category is shown in Fig. 2.

Among the 19 children who had their last FOS-MSSI assessments before 6 years of age, four (two females) had eye findings; CV was seen in all four, tortuous vessels in two girls, and none had lens opacities. Three of the four children <6 years of age with eye findings were symptomatic with neurological signs (including hypohidrosis and/or anhidrosis). Of the 15/19 children <6 years of age with no eye findings, two were treated and six (four girls and two boys) had neurological symptoms of Fabry disease documented in FOS.

Eighty one (59.1%) of the 137 treated paediatric patients in this study had at least one eye finding, whereas 36 (37.9%) of the 95 untreated children had any eye findings. Among the 41 treated girls, 27 (65.9%) had any eye findings versus 14 (34.1%) without eye findings (Table 1).

Of the 117 children who had eye findings, 36 (30.8%) had not received ERT during the study period, 61 (52.1%) had their first eye finding before starting therapy, and 20 (17.1%) had their first eye finding after starting therapy.

Summary statistics for any ocular sign (including CV, tortuous retinal and/or conjunctival vessels, and posterior spoke-like lens opacity) generally showed more severe disease as measured by age-adjusted FOS-MSSI total scores in children with eye findings versus those without eye findings (median, 0.5 versus −2.3; p < 0.001; Table 2). These differences were statistically significant for the presence of any eye finding as well as for presence of CV and tortuous vessels (Table 2) and remained consistent when boys and girls were grouped separately. The relationship between disease severity and age at assessment by the presence (or absence) of any eye lesion is illustrated in a scatter plot (Additional file 2: Figure S1). Children with eye findings (in red) had more severe disease across all ages than children without any eye findings (in black). Disease severity increased with age in children with and without eye findings. As expected, disease severity increased with age in each group (“any eye finding” and “no eye finding”), and the differences between the two groups remained quite constant over time; the “any eye finding” group showed greater disease severity over all ages.

As a large international registry, FOS encompasses data from 118 clinics in 22 countries worldwide and this includes retrospective findings from a large number of eye care practitioners who likely have varying assessment strategies. FOS is a registry for patient data collected in real-world clinical settings; thus, this was not a controlled trial specifically designed to assess all parameters reported here and there were no planned scheduled assessments with all data evaluated, so only part of the information might be collected at each patient visit. Information regarding specific concurrent medications that might induce similar eye findings was not available. Furthermore, it lacks stringent inclusion and exclusion criteria seen in clinical trial settings, and thus has the potential for selection bias. In addition, the current analyses were cross-sectional in nature and, ideally, a controlled longitudinal study would be conducted to confirm these results.