What is the management and treatment for Fabry disease?

Fabry Disease Management and Treatment

Primary Treatment: Enzyme Replacement Therapy

Enzyme replacement therapy (ERT) with agalsidase beta at 1 mg/kg intravenously every 2 weeks is the cornerstone of treatment for Fabry disease, addressing the underlying α-galactosidase A deficiency and preventing irreversible organ damage. 1, 2

Indications for ERT Initiation

• All males with classical Fabry disease should begin ERT, ideally before irreversible organ damage occurs 1
• Symptomatic heterozygous females require the same aggressive ERT approach as males, as disease severity can be equivalent 1, 3
• Initiate treatment in pediatric patients aged 2 years and older with confirmed Fabry disease to prevent disease progression 2
• Patients with stroke or TIA should receive ERT regardless of age, gender, or other organ involvement 4

ERT Efficacy and Outcomes

• ERT reduces the composite risk of renal, cardiac, cerebrovascular events, or death by 61% when initiated at earlier disease stages 4, 3
• Treatment stabilizes renal function if started when urinary protein excretion is <1 g/24 hours 3
• ERT slows the decline in eGFR from -3.2 mL/min/1.73 m²/year (untreated) to -1.5 mL/min/1.73 m²/year (treated) 2
• Left ventricular hypertrophy is reduced with continued therapy 3, 5
• Neuropathic pain typically resolves within 6 months of treatment initiation 1, 5
• Gastrointestinal symptoms improve after 6-8 months of therapy 5

Dosing Considerations

• Standard dosing is agalsidase beta 1 mg/kg every 2 weeks 1, 4
• Higher doses or longer treatment duration may be required to clear massive glycosphingolipid accumulation in podocytes and cardiomyocytes 1
• The 1 mg/kg dose demonstrates clearance of globotriaosylceramide in vascular endothelium of kidney, heart, and skin after 6-12 months 1

Managing Infusion Reactions

• Infusion-associated reactions occur in 57-59% of patients 4, 3
• Premedicate with acetaminophen and antihistamines before each infusion 4
• Use slow infusion rates to minimize reactions 4
• Life-threatening anaphylaxis can occur during early treatment or after extended therapy 2

Alternative Therapies

Chaperone Therapy (Migalastat)

• Migalastat is an oral alternative for patients with specific "amenable" GLA variants 6, 7
• Advantages include oral administration and non-immunogenicity, but genetic testing is required to confirm variant amenability 6

Emerging Therapies

• Pegunigalsidase alfa (pegylated α-galactosidase A) shows reduced immune response and prolonged half-life 6, 7
• Substrate reduction therapy (venglustat, lucerastat) is under investigation and may cross the blood-brain barrier 6, 7
• Gene therapy approaches are in clinical trials with promising early results 6, 7

Essential Adjunctive Management

Cardiovascular Protection

• Strict blood pressure control is mandatory to minimize cerebrovascular disease progression 4
• ACE inhibitors or ARBs are required for patients with proteinuria >300 mg/24 hours 4, 3
• Statin therapy for dyslipidemia should be initiated 4
• Antiplatelet therapy (aspirin and/or clopidogrel) is essential for patients with prior TIA or stroke 4

Pain Management

• First-line agents for neuropathic pain are carbamazepine, gabapentin, or phenytoin 4, 3
• Avoid NSAIDs due to adverse effects on renal function 4
• Minimize narcotic analgesics to prevent dependency given the chronic disease course 4

Medications to Avoid

• Do not use chloroquine, amiodarone, benoquin, or gentamicin, as these inhibit α-galactosidase A activity 4

Lifestyle Modifications

• Smoking cessation is mandatory 4

Comprehensive Monitoring Strategy

Baseline Evaluation

• Brain MRI with T1, T2, and FLAIR sequences to assess cerebrovascular involvement 4
• Magnetic resonance angiography (MRA) to evaluate for dolichoectasia of vertebral/basilar arteries 4
• Echocardiography and electrocardiography to assess cardiac involvement 4
• Renal function assessment including serum creatinine, eGFR, and 24-hour urine protein or spot protein-to-creatinine ratio 3

Ongoing Surveillance

• Annual evaluations must include cardiac and renal monitoring 4
• Echocardiography and electrocardiography at least every 2 years 4
• Annual urinary protein, creatinine clearance, and creatinine-to-albumin ratio 4
• Plasma GL-3 or lyso-Gb3 levels may serve as markers of disease burden and treatment efficacy 1, 3

Critical Clinical Caveats

• Strokes continue to occur despite ERT, emphasizing the absolute necessity of aggressive antiplatelet/anticoagulation therapy 4
• Treatment benefits are more pronounced when therapy begins at less advanced stages of organ dysfunction 3
• Stopping ERT in symptomatic patients risks irreversible organ damage, particularly renal fibrosis and cardiac complications 3
• Higher anti-agalsidase beta antibody titers are associated with less robust GL-3 clearance 3
• Female carriers can be as severely affected as males and require identical treatment intensity when symptomatic 1, 4
• Enrollment in Fabry disease registries is encouraged to advance understanding of natural history and treatment outcomes 1, 2