Fabry disease is a treatable disease, and management is now focused on enzyme replacement therapy, although oral pharmacological chaperone therapy seems a promising alternative treatment for patients with specific mutations
Fabry disease is a treatable disease, and management is now focused on enzyme replacement therapy, although oral pharmacological chaperone therapy seems a promising alternative treatment for patients with specific mutations
- Medical history and family pedigree
- Clinical examination
- Vital signs
- Pain score (BPI)
- Age appropriate Quality of Life score (SF-36 or EQ5D)
- Severity Score Index – Mainz Severity Score Index.
- MRI brain examination
- QSART assessment of sweating (where available)
- EMG and quantitative/qualitative sensory testing.
- ECG
- 24 hour ECG
- Echocardiogram
- Exercise testing
- Blood pressure.
- Glomerular filtration rate/creatinine clearance
- 24 hour urine total protein/microalbumin (or morning sample mg/g creatinine)
- Renal biopsy (at the discretion of the renal physician).
- Slit-lamp examination (cornea verticillata)
- Retro-illumination (cataract)
- Fundoscopy (vascular abnormalities)
- Pure tone audiogram
- Brainstem-evoked potentials – at the discretion of the neurologist
- Vestibular examinations
- DEXA scan
- Full blood count
- Urea and electrolytes
- Liver function tests
- Fasting lipid profile
- Plasma Gb3/lyso-Gb3
- Urine Gb3/lyso-Gb3
- The presence of another life-threatening illness with a life expectancy of < one year
- End-stage FD patients who are deemed too severely affected to benefit from ERT (for example, severely incapacitated following cerebrovascular disease).
- Non-compliance
- Persistent life threatening or severe infusion reactions that do not respond to prophylaxis
- End-stage renal disease, without an option for renal transplantation, in combination with advanced heart failure
- Lack of response on neuropathic pain.
- 011FACETS: a randomised, placebo-controlled, study of treatment naïve patients with FD and kidney involvement. The primary endpoint, namely the clearance of interstitial capillary GL-3 inclusions, was not reached due to inclusion of 17 patients with a non-amenable mutation in the study.33 However the clinical efficacy of migalastat on the kidney was clearly demonstrated: annualised eGFRCK-D-EPI remained stable over an average of 36 months (Study 011+ extension, n=40). The annualised rate of change over this period was: –0.81 ml/min/1.73 m2/year (95% CI: –2,00–0.37). This long-term effect of migalastat on eGFR is comparable to the decline over time in healthy adults (approximately –1 ml/min/1.73m2) and the decline over time in FD patients treated with agalsidase beta.25
- 012 ATTRACT: a randomised (1.5:1) open-label, active-controlled, study of ERT-treated patients with amenable (responsive) mutations switched to migalastat compared to the control group who remained on ERT of 18 months’ duration. The primary objective of the study was to determine the comparability of migalastat to ERT in their effects on renal function: this primary endpoint was reached. Left ventricular mass index (LVMi) decreased significantly with migalastat treatment while there was no significant change with ERT (secondary endpoint). The composite outcome included cardiac, renal, and cerebrovascular events associated with morbidity and mortality in FD: the proportion of patients who had an event was 29% (10/34) in patients switching from ERT to migalastat and 44% (8/18) in those remaining on ERT.34
- Chronic pain: anticonvulsants (for example, carbamazepine, gabapentin, topimarate)
- ‘Fabry crises’: non-steroidal anti-inflammatory drugs, opiates, minimisation of activities that trigger painful crisis (for example, temperature changes, physical activity, stress).
- If desired by the patient: removal with argon laser therapy.
- Low-fat diet
- Small and frequent meals
- Motility agents.
- Rigorous control of arterial hypertension, preferably by an ACE inhibitor (avoid β-blockers if sinus bradycardia is present)
- Correct hyperlipidaemia: diet,
- statins
- Antithrombotic drugs: aspirin, aspirin + dipyridamole or clopidogrel
- Smoking cessation
- Correct obesity
- Treatment of cardiac arrhythmia: antiarrhythmics, anticoagulants, ICD, pacemaker
- Screening and treatment of coronary and/or carotid insufficiency
- Heart transplantation.
- Proteinuria: ACE inhibitor and ‘sartans’
- Renal failure: dialysis and renal transplantation.
- Neuropsychiatric medication/psychotherapy.
- Patient subgroup ≥90 and ≤ 135ml/min/1.73m2: GFR decline ≤ 1ml/min/1.73 m2/year
- Patient subgroup <90ml/min/1.73m2: GFR decline ≤2ml/min/1.73m2/year for men and ≤1ml/min/1.73m2/year for women
- Subgroup proteinuria >0.3g/day: no increase in proteinuria
- Subgroup proteinuria ≥1g/day: reduction of proteinuria to <1g/day.
- Cardiomyopathy (LVMi >51g/m2.7 in men and >48 g/m2.7 in women (LVM indexed to height): reduction of LVM into the normal range
- Improve heart failure
- Reduction in frequency and severity of rhythm disturbances.
- Improve age-appropriate quality of life measurement
- Reduced pain scores
- Reduce incidence of ischaemic stroke
- Normalise growth and development in children.
- Fabry disease (FD) is an X-linked inherited multi-systemic lysosomal storage disease.
- Early diagnosis is essential in order to provide appropriate and timely treatment.
- Awareness of the possibility of this disease must be increased among paediatricians, internal medicine physicians, neurologists, ophthalmologists and ENT specialists.
- FD is a treatable disease, and management is now focused on enzyme replacement therapy, although oral pharmacological chaperone therapy seems a promising alternative treatment for patients with specific mutations. Adjunctive therapies, including antithrombotic agents to prevent stroke and ACE/’sartans’ in case of proteinuria, are also very important in the management of these patients.
- There is a need of collect further outcome survey data (registries) and for comprehensive guidelines for optimising and standardising the diagnosis and treatment of FD patients.
- Brady RO et al. Enzymatic defect in Fabry’s disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967;276:1163–7.
- Mehta A et al; on behalf of the FOS investigators. Fabry disease defined: baseline clinical manifestations of 366 patients in FOS – the Fabry Outcome Survey. Eur J Clin Invest 2004;34:236–42.
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- Desnick RJ, Ioannou YA, Eng CM. α-Galactosidase A deficiency: Fabry disease. In: Scriver CR et al (eds) The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, Vol. 3; McGraw Hill, New York 2001:3733–74.
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- Mehta A et al. Fabry disease: a review of current management strategies. QJM 2010;103(9):641–59.
- Mehta A et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004;34:236–42.
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