Review
I - Disease name and synonyms
-
Fabry's disease
-
Anderson-Fabry disease
-
Alpha-galactosidase A deficiency
-
Angiokeratoma corporis diffusum
-
Ceramide trihexosidosis
-
Ruiter-Pompen-Wyers syndrome
-
Sweeley-Klionsky disease
II - Definition
III - Epidemiology
Methods | Source | Ascertainment period | Total number of cases | No. per 100000 | Country and reference |
---|---|---|---|---|---|
Birth prevalence (number of postnatal plus prenatal enzymatic diagnoses divided by number of births) | Two centres holding all enzymatic analyses in Australia | 1980-1996 | 36 | 0.85 | Australia [34] |
Birth prevalence (number of cases born within a certain period divided by total number of live births in the same period) | All the laboratories making pre- and postnatal diagnoses of LSDs in The Netherlands | 1970-1996 | 27 | 0.21 | The Netherlands [33] |
Prevalence of obligate carriers | By family history, from the UK AFD register | 1980-1995 | 60 | 0.29 | UK (females only) [26] |
Prevalence | Records from regional genetic units and enzyme reference laboratories; records from individual doctors | 1980-1995 | 98 | 0.27 | UK (males only) [425] |
Birth prevalence (number of cases born within a certain time period divided by total number of live births in the same period) | Two main reference centres for diagnosis of sphingolipidoses by enzyme analysis of patients under 5 years suspected of LSD | 1997-2002 | 1 | 0.015 | Turkey [426] |
Birth prevalence (number of postnatal plus prenatal enzymatic diagnoses divided by number of live births) in north Portugal | One centre providing all pre- and postnatal diagnoses of LSDs in Portugal | 1982-2001 | 1 | 0.12 | North Portugal [427] |
Neonatal screening | Northern Italy | 2004-2006 | 12 | 30 | Italy [35] |
Neonatal screening | Taiwan | 2006-2008 | 73 | 80 | Taiwan [36] |
IV - Clinical description
A. Early signs and symptoms: Fabry disease at the pediatric age
Organ system | Sign/Symptom |
---|---|
Nervous system
| Acroparesthesias |
Nerve deafness | |
Heat intolerance | |
Hearing loss, tinnitus | |
Gastrointestinal tract
| Nausea, vomiting, diarrhoa |
Postprandial bloating and pain, early satiety | |
Difficulty gaining weight | |
Skin
| Angiokeratomas |
Hypohidrosis | |
Eyes
| Corneal and lenticular opacities |
Vasculopathy (retina, conjunctiva) | |
Kidneys
| Microalbuminuria, proteinuria |
Impaired concentration ability | |
Hyperfiltration | |
Increased urinary Gb3 excretion | |
Heart
| Impaired heart rate variability |
Arrhythmias | |
ECG abnormalities (shortened PR interval) | |
Mild valvular insufficiency |
B. Kidney involvement
C. Cardiac involvement
Left ventricular structural changes
Right ventricular structural changes
Electrocardiographic abnormalities
Valvular involvement
Coronary involvement
Exercise capacity
Autonomic dysfunction
Aortic root dilatation
D. Cerebrovascular lesions
E. Auditory and vestibular abnormalities
F. Ocular manifestations
G. Respiratory involvement
H. Skeletal involvement
I. Depression and quality of life
J. Miscellaneous
Anemia
Arterial remodeling and intima-media thickening
Azoospermia
Facial dysmorphism
Hypothyroidism
Lymphoedema
Parapelvic kidney cysts
Priapism
K. Heterozygous females
L. Atypical variants
Cardiac variant
Renal variant
Intermediate variant
V - Etiology
A. Genetics
B. Gene location
C. Molecular pathology
D. Structure of human α-Galactosidase A
VI - Diagnosis
A. Biochemical diagnosis
Enzymatic assay
Globotriaosylceramide measurement
B. Genotyping
C. Screening
D. Histology
Light microscopy
Electron microscopy
E. Ancillary markers
F. Biomarkers
VII - Differential diagnosis
VIII - Genetic counseling
IX - Prenatal diagnosis
X - Management
A. Conventional medical treatment and adjunctive therapies for Fabry disease related morbidities
Pain
Organ/system | Assessment | Guidelines |
---|---|---|
General
| General status, quality of life (SF36® Health survey, EuroQOL or PedsQL® measurement mode), school or work performance, depression, anxiety, drug use, somatic growth | Baseline (at first visit), every 12 months |
Complete physical examination | Baseline, every 12 months | |
Genetic counseling | Baseline, on request | |
Alpha-galactosidase A activity and genotype | If not previously performed or determined | |
Kidney
| Serum creatinine, ionogram, BUN; morning spot urine for urinary protein/creatinine ratio and albumin/creatinine ratio Urinary Gb3 (optional) | Baseline. Every 3 months if CKD stage 1 or 2 and >1 g/day of proteinuria or CKD stage 4 Every 6 months if CKD stage 3 Every 12 months if CKD stage 1 or 2 and <1 g/day of proteinuria |
Cardiac
| Palpitations, angina Blood pressure, rhythm | Baseline, every 6 months Every evaluation visit |
ECG, echocardiography 2-D with Doppler | Baseline, every 12 months | |
Holter monitoring | If an arrhythmia is suspected or palpitations are present | |
Cardiac MRI | Every other year | |
Coronary angiography | If clinical signs of angina | |
Neurologic
| Acroparesthesias, fatigue, fever, heat and cold tolerance, stroke-related symptoms, TIA | Baseline, every 12 months |
Neurologic examination, questionnaires (Brief Pain Inventory) | Baseline, every 12 months | |
Brain MRI without contrast | Baseline At time of a TIA or stroke event In females to document CNS involvement Every 3 years | |
Magnetic resonance angiography | If cerebral vasculopathy should be excluded | |
Comorbid stroke risk factors: Cholesterol (Total, LDL, HDL), triglycerides, Lpa, total plasma homocysteine | Baseline, every 12-24 months | |
ENT
| Tinnitus, hearing loss, vertigo, dizziness | Baseline, every 6 months |
Audiometry, tympanometry, otoacoustic emissions | Baseline, every 12 months thereafter | |
Ophthalmologic
| General ophthalmologic exam (slit-lamp, direct ophthalmoscopy, best corrected visual acuity, visual fields) | Baseline, every 12-24 months |
Pulmonology
| Cough, exertional dyspnea, wheezing, exercise intolerance | Baseline, every 12 months |
Spirometry | If clinical signs | |
Gastrointestinal
| Postprandial abdominal pain, bloating, diarrhea, nausea, vomiting, early satiety, difficulty gaining weight Endoscopic evaluations | Baseline, every 12 months If symptoms persist or worsen despite treatment |
Skeletal
| Bone mineral density, 25(OH) vitamin D levels | Baseline |
Gastrointestinal symptoms
Skin symptoms
Cochleo-vestibular symptoms
Renal function
Cerebrovascular involvement
Cardiac involvement
Respiratory involvement
Endocrine dysfunction
Bone involvement
B. Prophylactic measures
XI - Enzyme replacement therapy
Subpopulation | Guidelines for onset of ERT |
---|---|
Adult males (over 16 years) | At time of diagnosis of Fabry disease |
Boys | At time of development of significant symptoms or if asymptomatic, consider at 7-10 years |
Females (all ages) | Symptoms or evidence of progression of organ involvement |
A. Efficacy and safety data of agalsidase alfa treatment
Amelioration of early clinical symptoms
Renal function
Cardiac morphology and function
Cerebrovascular events
Severity score and causes of death
B. Efficacy and safety data of agalsidase beta treatment
Clearance of Gb3 from renal cells, urine and cardiac cells
Amelioration of early clinical symptoms
Renal function
Cardiac morphology and function
Progression to major renal, cardiac, or cerebrovascular events, or death
C. Comparison between agalsidase alfa and agalsidase beta treatments
Randomized controlled trials
Fabrazyme®, agalsidase beta - 1 mg/kg/14 days | Replagal®, agalsidase alfa - 0.2 mg/kg/14 days | |
---|---|---|
Efficacy data on renal histology
| At 6 months (n = 58): - Total clearance of Gb3 in renal intersticial capillary endothelial cells [323] - Total clearance of Gb3 in glomerular, mesangial and interstitial cells [323] - Partial clearance of Gb3 in arterial smooth muscular cells [357] At 54 months: - Significant clearance maintained in several renal cells types (n = 8) [309] | At 6 months (n = 26), glomeruli with mesangial widening decreased by a mean of 12.5% for patients receiving agalsidase alfa versus a 16.5% increase for placebo (p = 0.01) [324] |
Efficacy data on renal function
| Significant risk reduction (-61%) of renal, cardiac, cerebrovascular complications and death in per protocol analysis that adjusted on an imbalance in baseline proteinuria (n = 74; p = 0.034) [325] At 54 months (n = 44) [309]: Stabilization of eGFR for 90% of patients (- 0,4 ml/min/1,73 m2/year) (n = 42) | At 6 months (n = 26) [324]: - Significant increase of creatinine clearance in treated group versus placebo - No significant difference of inuline clearance between the 2 groups At 54 months (n = 25) [327]: - Patients with stage 1 CKD: average eGFR loss of - 1,6 ml/min/1,73 m2/year - Patients with stage 2 CKD: average eGFR loss of - 2,6 ml/min/1,73 m2/year - Patients with stage 3 CKD: average eGFR loss of - 4,9 ml/min/1,73 m2/year [327] At 5 years (FOS® data): - Male patients with stage 1 CKD: mean yearly fall in eGFR = -2.83 ml/min/1,73 m2/year - Male patients with stage 2 CKD: mean yearly fall in eGFR = -2.17 ml/min/1,73 m2/year - Male patients with stage 3 CKD: mean yearly fall in eGFR = -3.0 ml/min/1,73 m2/year [333] |
Efficacy data on cardiac histology
| Significant Gb3 clearance in cardiac endothelial cells at 6 months [323] maintained at 54 months [309, 359] No clearance of Gb3 in cardiomyocytes [359] | A mean 20% reduction in myocardial Gb3 content was demonstrated over the 6 months of ERT compared to a mean 10% increase in patients receiving placebo (p = 0.42) [326] |
Efficacy data on cardiac function and geometry (clinical trials)
| Significant risk reduction (-61%) of renal, cardiac, cerebrovascular complications and death in the per protocol analysis that adjusted on an imbalance in baseline proteinuria (n = 74; p = 0.034) [325] | Left ventricular mass, as measured by MRI, was significantly reduced following 6 months of treatment with agalsidase alfa compared with placebo (p = 0.041) [326] |
Efficacy data on peripheral nervous system based on clinical trials
| Significant improvement in pain scores at 54 months (p = 0.016) [309] Significant improvement in quality of life at 54 months (p = 0,007) (n = 52) [309] | Significant decrease of average pain scores at 6 months (n = 26) [324] |
Efficacy data on pediatric population based on clinical trials
| At 12 months (n = 16): - Significant clearance of plasma Gb3 (normalization) - Significant clearance of Gb3 in skin specimens - Patient diaries documented significant reductions in school absences due to sickness. - Reduction in gastro-intestinal symptoms [362] | |
Immunogenicity
| IgG reported for 90% of patients [323] | IgG reported for 56% of the patients No report of IgE |
Infusion time
| 90 (once safety established) - 180 minutes | 40 - 60 minutes |
Home based treatment availability after hospital initiation
| Yes | Yes |
Treatment costs (in France)
| - Vial cost (35 mg): 3,370 euros - Annual cost of therapy for a 70 kg adult patient: 161,781 € (year 2010) | - Vial cost (3.5 mg): 1,685 euros - Annual cost of therapy for a 70 kg adult patient: 161,781 € (year 2010) |
Market authorization approval
| - European market authorization approval: August 2001 - European Medicines Agency (EMA) exceptional circumstances lifted (February 2008) - American market authorization approval: April 2003 | - European market authorization approval: August 2001 - European Medicines Agency (EMA) exceptional circumstances maintained - American market authorization approval: none |