What additional treatment options are available for women with Fabry disease, taking into account genotype, organ involvement, infusion tolerance, and patient preference?

Treatment Options for Females with Fabry Disease

Females with Fabry disease should receive enzyme replacement therapy (ERT) when they have significant symptoms or progressive organ involvement, combined with aggressive adjunctive therapies targeting specific organ manifestations. 1

Primary Disease-Modifying Therapies

Enzyme Replacement Therapy (ERT)

• ERT should be offered to symptomatic females or those with evidence of progressive end-organ damage, including chronic acroparesthesias resistant to conventional therapy, persistent proteinuria (>300 mg/24 hours), GFR below 80 mL/minute/1.73 m², clinically significant cardiac involvement, previous cerebrovascular accident or transient ischemic attacks, or ischemic changes on brain MRI. 1
• Agalsidase beta at 1 mg/kg every other week is the standard dosing regimen. 2
• Agalsidase alpha has demonstrated significant reduction in left ventricular mass specifically in female patients. 1
• ERT reduces the composite risk of renal, cardiac, cerebrovascular events, or death by 61% when started at earlier stages of disease. 2
• Female carriers require the same aggressive treatment approach as males when symptomatic, as disease presentation can be as severe as in males. 1, 2

Migalastat (Oral Pharmacological Chaperone)

• Migalastat 123 mg orally once every other day is indicated for adults with confirmed Fabry disease who have an amenable GLA variant based on in vitro assay data. 3
• Take on an empty stomach with no food or caffeine at least 2 hours before and 2 hours after dosing (minimum 4-hour fast). 3
• Swallow capsule whole; do not cut, crush, or chew. 3
• This option is particularly valuable for patients with infusion intolerance or preference for oral therapy. 3

Adjunctive Organ-Specific Therapies

Renal Protection

• ACE inhibitors or angiotensin receptor blockers (ARBs) for proteinuria (>300 mg/24 hours) to slow progression of kidney disease. 1, 2
• Dialysis or kidney transplantation for end-stage renal failure. 1
• Strict blood pressure control is essential to minimize ongoing cerebrovascular and renal disease. 2

Cardiovascular Management

• Antiplatelet therapy with aspirin and clopidogrel for patients with history of TIA or stroke. 2
• Anticoagulation therapy as indicated for thromboembolic risk. 2
• Statins for dyslipidemia management. 2
• Echocardiography and electrocardiography monitoring at least every 2 years. 2, 4

Neuropathic Pain Management

• Carbamazepine, gabapentin, or phenytoin for chronic acroparesthesias and neuropathic pain. 2, 4
• Avoid NSAIDs due to potential adverse effects on renal function. 2
• Minimize narcotic analgesics to prevent dependency given the chronic nature of disease. 2

Gastrointestinal Symptoms

• Consider ERT for chronic, disabling gastrointestinal dysfunction unresponsive to other medical management. 1
• Symptomatic management of gastrointestinal manifestations as needed. 1

Critical Monitoring Protocol

Surveillance Schedule

• Asymptomatic women should be evaluated annually, while symptomatic women require monitoring every six months. 1
• Annual evaluations must include cardiac and renal monitoring with urinary protein, creatinine clearance, and creatinine-to-albumin ratio. 2, 4
• Comprehensive brain MRI with T1, T2, and FLAIR-weighted sequences at baseline for cerebrovascular assessment. 2
• Magnetic resonance angiography (MRA) to evaluate for cerebral vasculopathy and dolichoectasia of vertebral/basilar arteries. 2

Baseline Assessment Requirements

• DNA-based diagnosis rather than enzyme activity testing is required in females, as they can have normal to very low α-Gal A activity. 1
• Organ biopsy (kidney or heart) may be required before starting ERT to document extent of GL-3 storage and exclude other etiologies. 1

Important Clinical Caveats

Treatment Limitations

• Strokes continue to occur despite ERT, though at reduced rates, emphasizing the need for aggressive adjunctive antiplatelet/anticoagulation therapy. 2
• Lost renal function is not recovered with ERT; proteinuria may be reversible only if treatment is started early. 1
• Initial infusion-associated reactions occur in approximately 57-59% of patients receiving ERT. 2

Management of Infusion Reactions

• Manage infusion-associated reactions with slow infusion rates and premedication with acetaminophen and antihistamines. 2

Medications to Avoid

• Avoid medications that inhibit α-galactosidase A activity: chloroquine, amiodarone, benoquin, or gentamicin. 2

Risk Factors for Poor Outcomes

• Advanced renal pathology (interstitial fibrosis, tubular atrophy, glomerulosclerosis), impaired GFR, and severity of baseline proteinuria predict worse therapeutic outcomes. 1
• Frequency of hypertrophic cardiomyopathy and cerebrovascular accidents increases in females over age 40. 1

Smoking Cessation

• Smoking cessation is mandatory to reduce cardiovascular and cerebrovascular risk. 2