Fabry Disease (Anderson-Fabry Disease) - Management

Background

Typical angiokeratomas of Fabry disease: dark, punctate lesions clustered over the lower trunk and buttocks (Bradley & Daroff's Neurology)

Disease-Specific Therapies

1. Enzyme Replacement Therapy (ERT)

• ERT should be initiated before irreversible end-organ damage for maximum benefit - early treatment in men with classic phenotype yields the best renal and cardiac outcomes.
• Predicators of poorer renal response: high baseline proteinuria, worse baseline eGFR, delayed treatment initiation, history of cardiac or cerebrovascular events.
• ERT can be administered during dialysis sessions.
• Infusion reactions (flushing, chest discomfort, rash, pruritus, nasal congestion) are common; pre-medication and slowing infusion rate are standard management.
• Approximately 50-60% of male patients develop IgG antibodies to agalsidase beta; their long-term clinical significance is debated.

• Classic males: treat at first symptoms or signs of organ involvement
• Females: treat when symptomatic (cardiac, renal, or neurological involvement)
• May be considered with eGFR <45 mL/min/1.73m², on dialysis, or with cognitive impairment

• Advanced end-organ damage with no further expected benefit
• Patient preference after informed discussion
• Severe infusion reactions not manageable with pre-medication

2. Oral Pharmacological Chaperone Therapy - Migalastat (Galafold)

• Only for amenable GLA variants (specific missense mutations causing misfolding, confirmed via an in vitro cell-based assay - not all GLA variants are amenable)
• Dose: 123 mg orally every other day (to avoid competitive inhibition of the enzyme substrate)
• Age: Approved for adults ≥16 years
• Advantages: Oral, no infusion reactions, convenient, available in ambulatory settings
• The ATTRACT trial showed non-inferiority to ERT in stabilizing renal function in amenable-variant patients; also reduces LV mass index and GI symptoms
• Migalastat is not effective in patients with null mutations (frameshift, nonsense) or non-amenable missense variants

Supportive (Organ-Specific) Management

Renal

• ACE inhibitors or ARBs for proteinuria reduction (standard CKD management); note that recombinant α-Gal A may interact with endogenous ACE, causing transient BP drops during infusions
• Target BP <130/80 mmHg
• Kidney transplantation is preferred over dialysis for ESKD - Fabry nephropathy does not recur in the allograft, and transplant outcomes are better than dialysis. Kidney transplant is a first-choice therapy for Fabry-related kidney failure.
• Dialysis if transplant is not feasible

Cardiac

• LV hypertrophy monitoring: serial echocardiography and cardiac MRI (late gadolinium enhancement pattern in basal inferolateral wall is characteristic)
• Arrhythmia management: antiarrhythmics as indicated; pacemaker/ICD for heart block or malignant arrhythmia
• Hypertension: treat per standard guidelines; avoid beta-blockers in patients with existing sinus bradycardia
• Angina: manage small-vessel disease; epicardial coronary disease is uncommon
• ERT may stabilize or modestly regress LV hypertrophy when started early

Neurological - Neuropathic Pain

• Acute pain crises: NSAIDs, avoiding temperature extremes and triggering stressors
• Chronic neuropathic pain: gabapentin, carbamazepine, phenytoin, amitriptyline
• Stroke prevention: antiplatelet agents; aggressive vascular risk factor management (hypertension, dyslipidemia, smoking cessation, diabetes)
• TIAs and stroke most commonly involve the posterior circulation (vertebrobasilar)

Gastrointestinal

• Pain relief, H2-blockers or PPIs, prokinetic agents, pancreatic enzyme supplementation
• Dietary adjustments for postprandial bloating and early satiety

Skin (Angiokeratomas)

• Cosmetic removal with argon laser therapy (does not address underlying disease)

Hypohidrosis/Anhidrosis

• Avoidance of heat and exertion; cool environments; appropriate clothing

Psychiatric

• Depression is common: SSRIs or SNRIs are first-line

Dyslipidemia

• Routine surveillance and statin therapy per standard guidelines

Monitoring Parameters

Emerging and Investigational Therapies (as of 2025-2026)

• Substrate reduction therapy (SRT): inhibitors of glucosylceramide synthase (upstream precursor of Gb3) - reduce substrate synthesis rather than replacing or stabilizing enzyme
• mRNA therapy: periodic administration of mRNA encoding human α-Gal A (preclinical / early trials)
• AAV-based gene therapy: several trials actively recruiting; aims for durable α-Gal A expression
• Moss-derived α-galactosidase (moss-αGAL): plant-derived ERT with mannose-terminated glycans; shows strong kidney tissue affinity; early trials ongoing
• Second-generation enzyme formulations in development

Phenotypes and Treatment Timing

Diagnosis Triggers

1. Acroparesthesias/neuropathic pain since childhood
2. Unexplained persistent proteinuria
3. Hypertrophic cardiomyopathy with prominent diastolic dysfunction
4. Progressive CKD of unknown cause
5. Cryptogenic stroke or TIA
6. X-linked family history of ESKD, stroke, or HCM
7. Recurrent GI symptoms (nausea, diarrhea, abdominal pain)

Recent evidence note (2025): A 2025 Orphanet J Rare Dis study (Lenders et al.) examined ERT vs. migalastat outcomes in female patients specifically, highlighting that female patients with amenable variants may achieve equivalent organ stabilization with oral migalastat. The 2025 BIMDG guidelines (June 2025) now include pegunigalsidase alfa (Elfabrio) as a first-line ERT option alongside agalsidase alfa and beta.