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Ocular signs correlate well with disease severity and genotype in Fabry disease.

Pitz S, Kalkum G, Arash L, Karabul N, Sodi A, Larroque S, Beck M, Gal A - PLoS ONE (2015)

Bottom Line: This finding could be confirmed by applying age adjusted severity scores.Moreover, the prevalence of cornea verticillata was significantly higher in patients with (male, 76.9%; female, 64.5%) and missense (male, 79.2%; female, 67.4%) mutations versus mild missense (male, 17.1%; female, 23.1%) and the p.N215S (male, 15.0%; female, 15.6%) mutations (P<0.01).Further confirmatory studies are needed.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, University Medical Centre, Johannes Gutenberg University, Mainz, Germany.

ABSTRACT
Ocular signs in Fabry disease have generally been regarded to be primarily of diagnostic value. We explored whether ocular findings, alone or in particular in combination with the α-galactosidase A gene mutation, have predictive value for disease severity. Data from the Fabry Outcome Survey (FOS), a large, global database sponsored by Shire, were selected for adult patients who had undergone ophthalmological examination. Three ocular signs were assessed: cornea verticillata, tortuous conjunctival and/or retinal vessels, and cataract. Fabry disease severity was measured using FOS Mainz Severity Score Index and modifications thereof. Ophthalmological data were available for 1203 (699 female, 504 male) adult patients with eye findings characteristic of Fabry disease in 55.1%. Cornea verticillata had a similar distribution in women (51.1%) and men (50.8%), whereas tortuous vessels and Fabry cataract were somewhat more frequent in men than in women. Patients with cornea verticillata, selected as the principal ocular sign for this study, had more severe disease (median score, 20.0) versus those without ocular signs (11.0; P<0.001). This finding could be confirmed by applying age adjusted severity scores. Moreover, the prevalence of cornea verticillata was significantly higher in patients with (male, 76.9%; female, 64.5%) and missense (male, 79.2%; female, 67.4%) mutations versus mild missense (male, 17.1%; female, 23.1%) and the p.N215S (male, 15.0%; female, 15.6%) mutations (P<0.01). Our analyses show a correlation between the prevalence of ocular changes in Fabry disease and disease severity. Consequently, information on ocular findings and α-galactosidase A gene mutation may help assess the risk for more severe Fabry disease. These observed findings are of notable clinical importance, as Fabry disease is characterized by high clinical course variability and only weak genotype-phenotype correlation at the individual patient level. Further confirmatory studies are needed.

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Disease severity score by type of mutation and presence of cornea verticillata.Median ariFOS-MSSI score by type of mutation and presence of cornea verticillata in adult (A) male and (B) female patients. ariFOS-MSSI = age-related individual Fabry Outcome Survey Mainz severity score index.
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pone.0120814.g005: Disease severity score by type of mutation and presence of cornea verticillata.Median ariFOS-MSSI score by type of mutation and presence of cornea verticillata in adult (A) male and (B) female patients. ariFOS-MSSI = age-related individual Fabry Outcome Survey Mainz severity score index.

Mentions: According to our classification, mutations and missense mutations result in enzyme protein with no or negligible activity, whereas alpha-galactosidase A produced by a mild missense allele or the p.N215S mutation has a low but still consequential residual activity. Under the assumption that the higher the residual enzyme activity, the less severe the phenotype, we would expect a gradual decrease of the ariFOS-MSSI scores from mutations towards p.N215S. Such a pattern was indeed found (S7 Table), indicating a positive correlation between the type of mutation and overall disease severity in patients presenting with eye findings versus those with no eye findings. In men and women with or missense mutations, ariFOS-MSSI scores were significantly higher (P<0.001 to P = 0.017) among patients with ocular signs (ie, cornea verticillata; S7 Table). Moreover, in male patients with cornea verticillata who had , missense, or mild missense mutations, ariFOS-MSSI scores were also higher than the corresponding average severity score predicted for age (the zero line in Fig. 5).


Ocular signs correlate well with disease severity and genotype in Fabry disease.

Pitz S, Kalkum G, Arash L, Karabul N, Sodi A, Larroque S, Beck M, Gal A - PLoS ONE (2015)

Disease severity score by type of mutation and presence of cornea verticillata.Median ariFOS-MSSI score by type of mutation and presence of cornea verticillata in adult (A) male and (B) female patients. ariFOS-MSSI = age-related individual Fabry Outcome Survey Mainz severity score index.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4363518&req=5

pone.0120814.g005: Disease severity score by type of mutation and presence of cornea verticillata.Median ariFOS-MSSI score by type of mutation and presence of cornea verticillata in adult (A) male and (B) female patients. ariFOS-MSSI = age-related individual Fabry Outcome Survey Mainz severity score index.
Mentions: According to our classification, mutations and missense mutations result in enzyme protein with no or negligible activity, whereas alpha-galactosidase A produced by a mild missense allele or the p.N215S mutation has a low but still consequential residual activity. Under the assumption that the higher the residual enzyme activity, the less severe the phenotype, we would expect a gradual decrease of the ariFOS-MSSI scores from mutations towards p.N215S. Such a pattern was indeed found (S7 Table), indicating a positive correlation between the type of mutation and overall disease severity in patients presenting with eye findings versus those with no eye findings. In men and women with or missense mutations, ariFOS-MSSI scores were significantly higher (P<0.001 to P = 0.017) among patients with ocular signs (ie, cornea verticillata; S7 Table). Moreover, in male patients with cornea verticillata who had , missense, or mild missense mutations, ariFOS-MSSI scores were also higher than the corresponding average severity score predicted for age (the zero line in Fig. 5).

Bottom Line: This finding could be confirmed by applying age adjusted severity scores.Moreover, the prevalence of cornea verticillata was significantly higher in patients with (male, 76.9%; female, 64.5%) and missense (male, 79.2%; female, 67.4%) mutations versus mild missense (male, 17.1%; female, 23.1%) and the p.N215S (male, 15.0%; female, 15.6%) mutations (P<0.01).Further confirmatory studies are needed.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, University Medical Centre, Johannes Gutenberg University, Mainz, Germany.

ABSTRACT
Ocular signs in Fabry disease have generally been regarded to be primarily of diagnostic value. We explored whether ocular findings, alone or in particular in combination with the α-galactosidase A gene mutation, have predictive value for disease severity. Data from the Fabry Outcome Survey (FOS), a large, global database sponsored by Shire, were selected for adult patients who had undergone ophthalmological examination. Three ocular signs were assessed: cornea verticillata, tortuous conjunctival and/or retinal vessels, and cataract. Fabry disease severity was measured using FOS Mainz Severity Score Index and modifications thereof. Ophthalmological data were available for 1203 (699 female, 504 male) adult patients with eye findings characteristic of Fabry disease in 55.1%. Cornea verticillata had a similar distribution in women (51.1%) and men (50.8%), whereas tortuous vessels and Fabry cataract were somewhat more frequent in men than in women. Patients with cornea verticillata, selected as the principal ocular sign for this study, had more severe disease (median score, 20.0) versus those without ocular signs (11.0; P<0.001). This finding could be confirmed by applying age adjusted severity scores. Moreover, the prevalence of cornea verticillata was significantly higher in patients with (male, 76.9%; female, 64.5%) and missense (male, 79.2%; female, 67.4%) mutations versus mild missense (male, 17.1%; female, 23.1%) and the p.N215S (male, 15.0%; female, 15.6%) mutations (P<0.01). Our analyses show a correlation between the prevalence of ocular changes in Fabry disease and disease severity. Consequently, information on ocular findings and α-galactosidase A gene mutation may help assess the risk for more severe Fabry disease. These observed findings are of notable clinical importance, as Fabry disease is characterized by high clinical course variability and only weak genotype-phenotype correlation at the individual patient level. Further confirmatory studies are needed.

Show MeSH
Related in: MedlinePlus