How can the severity of the signs and symptoms of Fabry disease be evaluated?
In 2004, a clinical scoring system was developed to assess the severity of the signs and symptoms of Fabry disease and to monitor the disease course. The Mainz Severity Score Index (MSSI) assesses four components of Fabry disease signs and symptoms1:
Using the MSSI, signs and symptoms of Fabry disease are grouped into one of the four components and weighted according to their contribution to morbidity. Each sign and symptom is assigned a single rating and summed to produce a total score for each component. The general and renal components have a maximum score of 18, whereas the neurological and cardiovascular components have a maximum score of 20. Scores of individual components are then combined to produce a total MSSI score.1
To reflect the clinical spectrum of Fabry disease, total MSSI scores are then divided by severity: mild (<20), moderate (20‒40) and severe (>40). Assessment of the MSSI indicated that it was highly specific in differentiating Fabry disease from other disorders with a similar phenotype.1
However, the MSSI is confounded by the progressive natural history of Fabry disease with ageing, making comparisons between patient age groups invalid. For example, patients with Fabry disease aged 20‒30 years will typically have a lower MSSI score than patients aged 40‒50 years, despite younger patients potentially expressing a more severe disease phenotype. Consequently, using data from the ongoing Fabry Outcome Survey (FOS; sponsored by Shire, now part of Takeda), a modified version of the MSSI was developed (FOS-MSSI) and published in 2006. This validated scoring system is age- and gender-adjusted, enabling comparisons of disease severity between different patient subgroups, irrespective of age or gender.2 Total FOS-MSSI scores are also subdivided into mild (≤18), moderate (19‒38) and severe (>38) Fabry disease. One study of 655 patients enrolled in the FOS with clinical signs and symptoms of Fabry disease assessed Fabry disease severity using the FOS-MMSI. In total, 273 adult males (median age, 38 years), 277 adult females (median age, 44 years), 45 paediatric males (median age, 11 years) and 60 paediatric females (median age, 13 years) were included in the study. The findings indicated that a greater proportion of male patients were generally more severely affected than females, and disease progression was more rapid in males. Female patients with Fabry disease with the same disease severity as males were typically ≥6 years older, and also exhibited a greater disease progression with age; however, this pattern was delayed by 10‒20 years.3
An alternative disease severity scoring system for Fabry disease (Fabry DS3) was published in 2010. This disease severity index includes five domains4:
- Peripheral nervous system (3 items; maximum average score of 4)
- Renal (3 items; maximum average score of 8)
- Cardiac (3 items; maximum average score of 8)
- Central nervous system (2 items; maximum average score of 8)
- Patient-reported outcome (1 item; maximum average score of 4).
Each of the four clinical domain items are scored individually by the evaluating clinician. The domain score is then calculated by averaging the scores for all domain items. A total Fabry DS3 score is the sum of the five average domain scores, with a maximum possible score of 32. Total Fabry DS3 scores are then subdivided by severity to represent mild (<8), moderate (8‒12) or severe (>12) disease. The validity, reliability and feasibility of the Fabry DS3 suggest that it is a useful and reliable assessment to monitor disease severity and progression in a given patient.4
The Fabry-specific Pediatric Health and Pain Questionnaire (FPHPQ) assesses the following symptoms specific to Fabry disease in children5:
- Heat and cold intolerance
- Swollen eyelids
- Gastrointestinal symptoms
- Feeling thirsty
- Difficulty hearing
- Ringing or buzzing noise in the ears
- Ability and enjoyment to participate in sports.
The FPHPQ was validated in 2012 and was shown to be a reliable assessment of paediatric patient-reported symptoms of Fabry disease. The FPHPQ comprises 23 symptom-related items clustered into three subscales: pain associated with heat or exertion; pain associated with cold; and abdominal pain and fatigue symptoms. Equal weight is given to each item and they are scored as follows: 0=never, 1=seldom, 2=sometimes, 3=often and 4=always. An additional item of pain intensity is measured using a 0‒10 numeric rating scale, and two items require numeric responses: (1) number of times experiencing the onset of pain and (2) number of school days missed. Two additional items with a ‘yes’ or ‘no’ response regarding the difficulty in hearing and other problems not mentioned are included. The scores for each item are summed with higher subscale scores representing more severe symptoms or worse health. The FPHPQ is considered a useful tool for understanding the severity and progression of Fabry disease in paediatric patients.5
Three separate age-specific versions of the FPHPQ are available for children aged 4‒7 years, 8‒12 years and 13‒18 years. For children aged 4‒7 years, the FPHPQ is completed by their parents. Translations of the FPHPQ are available in Dutch, English, French, German, Italian, Norwegian, Spanish and Swedish.5
C-ANPROM/INT/FAB/0016; Date of preparation: March 2021
- Whybra C, Kampmann C, Krummenauer F, et al. The Mainz Severity Score Index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Clin Genet 2004; 65: 299-307.
- Hughes DA, Ramaswami U, Barba Romero M-Á, et al. Age adjusting severity scores for Anderson-Fabry disease. Mol Genet Metab 2010; 101: 219-227.
- Whybra C, Bahner F, Baron K. Measurement of disease severity and progression in Fabry disease. In: Mehta A, Beck M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford, UK: Oxford PharmaGenesis, 2006.
- Giannini EH, Mehta AB, Hilz MJ, et al. A validated disease severity scoring system for Fabry disease. Mol Genet Metab 2010; 99: 283-290.
- Ramaswami U, Stull DE, Parini R, et al. Measuring patient experiences in Fabry disease: validation of the Fabry-specific Pediatric Health and Pain Questionnaire (FPHPQ). Health Qual Life Outcomes 2012; 10: 116.