Cardiac Fabry Disease

Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of alpha galactosidase A, leading to accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Cardiac involvement causes left ventricular hypertrophy, conduction disease, arrhythmia, microvascular ischaemia and heart failure, and is the leading cause of death.

Prevalence of classic disease is about 1 in 40,000 to 1 in 117,000 live births, and is higher with late onset variants. Fabry disease accounts for about 0.5 to 1% of unexplained left ventricular hypertrophy in adults and more in screened series.

Classic disease (GLA variants with under 1% enzyme activity) presents in males in childhood with pain, angiokeratomas and hypohidrosis, and with cardiac disease in the 30s to 40s. Later onset (cardiac) variants, such as p.Asn215Ser, present with isolated left ventricular hypertrophy in the 50s and 60s. Females are heterozygous with variable, often significant, disease due to X-inactivation.

Pathophysiology.

Glycosphingolipid accumulates in cardiomyocytes, conduction tissue, valve and vascular endothelium. Storage alone accounts for a minority of wall thickness; myocyte hypertrophy driven by signalling and inflammation, and later fibrosis, make up the rest.

Early disease shows a short PR interval and low native T1 on MRI (storage), then rising T1, and inferolateral mid-wall late gadolinium enhancement with troponin leak and T-wave inversion (scar and inflammation).

Fibrosis leads to ventricular tachycardia, atrioventricular block, sinus node dysfunction and heart failure with preserved, then reduced, ejection fraction.

Cardiac symptoms: exertional dyspnoea, angina with normal coronary arteries, palpitations, presyncope and syncope. Extracardiac features: neuropathic pain in the hands and feet, angiokeratomas, hypohidrosis, corneal verticillata, tinnitus and hearing loss, proteinuria and chronic kidney disease, early stroke.

• ECG: short PR interval with delta-wave-free pre-excitation-like pattern early, LVH with strain, later bundle branch block, atrioventricular block, bradycardia and atrial fibrillation.
• Echocardiography: concentric LVH (often with prominent papillary muscles), reduced basal inferolateral strain, and a binary endocardial border sign in some.
• Cardiac MRI: low native T1 (early) and basal inferolateral mid-wall late gadolinium enhancement, with T2 elevation indicating active injury.
• Enzyme and genetics: males have leucocyte alpha galactosidase A activity under 5% (classic) or low, confirmed by GLA sequencing. Females need GLA sequencing because enzyme levels may be normal.
• Plasma lyso-Gb3 (raised in classic males, often in females), urine albumin to creatinine ratio, eGFR, troponin and NT-proBNP.
• Variants of uncertain significance need correlation with biomarkers, biopsy showing zebra bodies where needed, and family segregation.

Differential diagnosis.

• Hypertrophic cardiomyopathy (sarcomeric) and cardiac amyloidosis.
• Hypertensive heart disease and aortic stenosis.
• Danon disease, Noonan syndrome, and mitochondrial disease.
• Drug induced phospholipidosis (amiodarone, chloroquine, hydroxychloroquine).

Disease specific therapy (start in classic males at diagnosis and in females and later onset patients with organ involvement or progression):

• Agalsidase beta 1.0 mg/kg intravenously every 2 weeks, long term; initial infusion rate of 0.25 mg/min, home infusion after tolerance; monitor eGFR, proteinuria, lyso-Gb3, echocardiography and antibodies.
• Agalsidase alfa 0.2 mg/kg intravenously over 40 minutes every 2 weeks, long term; monitor eGFR, proteinuria, lyso-Gb3, echocardiography and antibodies.
• Pegunigalsidase alfa 1 mg/kg intravenously every 2 weeks, long term; infusion reactions are common in the first months; hypersensitivity and antibody monitoring.
• Premedicate infusion reactions with an antihistamine, paracetamol and, if needed, oral corticosteroid; slow the rate and stay with the patient.
• Migalastat 123 mg orally every other day at the same time, on an empty stomach (no food 2 hours before and 2 hours after); only for amenable GLA variants confirmed by cell based assay; avoid when eGFR is under 30 mL/min/1.73 m2.
• Avoid chloroquine, amiodarone and gentamicin, which inhibit intracellular alpha galactosidase A and can reduce enzyme replacement effect.

Cardiac therapy.

• Beta blockers and verapamil are used cautiously for angina and tachyarrhythmia because bradycardia and chronotropic incompetence are common; check for sinus node dysfunction and conduction disease first.
• Heart failure: loop diuretic (furosemide 20 to 80 mg orally daily, titrated to weight), spironolactone 25 to 50 mg daily (potassium under 5.0 mmol/L, eGFR over 30), SGLT2 inhibitor (dapagliflozin 10 mg daily at eGFR 25 or over, or empagliflozin 10 mg daily at eGFR 20 or over). ACE inhibitor or ARB (for example ramipril 2.5 to 10 mg daily) is used for proteinuria and heart failure, with monitoring of blood pressure, potassium and creatinine at 1 to 2 weeks.
• Atrial fibrillation: anticoagulate regardless of CHA2DS2-VASc score (apixaban 5 mg twice daily, 2.5 mg if two of age 80 or over, weight 60 kg or under, creatinine 133 micromol/L or over).
• Pacemaker for symptomatic bradycardia or atrioventricular block. ICD for secondary prevention, and primary prevention for non-sustained ventricular tachycardia with late gadolinium enhancement, or ejection fraction of 35% or under.
• Stroke prevention: antiplatelet therapy after ischaemic stroke, with ambulatory ECG for atrial fibrillation.
• Angina: low dose beta blocker or ranolazine 375 to 750 mg twice daily (maximum 750 mg twice daily; avoid in severe renal or hepatic impairment) with caution.
• Chronic kidney disease and neuropathic pain are managed in parallel.

Monitoring. Clinical review every 6 to 12 months, ECG and echocardiography annually, ambulatory ECG yearly, cardiac MRI every 2 to 3 years, eGFR, urine albumin to creatinine ratio and lyso-Gb3 every 6 to 12 months.

Referral and escalation. Refer all patients to a metabolic or Fabry specialist centre. Urgent review for syncope, high grade atrioventricular block or conduction disease, sustained ventricular tachycardia, stroke or transient ischaemic attack under age 55, a rapid fall in eGFR, or rising proteinuria.

Special groups.

• Pregnancy: enzyme replacement can generally continue after specialist review; migalastat is avoided.
• Relatives: X-linked cascade screening of all relatives, including daughters of affected males.
• Kidney impairment: migalastat is avoided at eGFR under 30; enzyme replacement continues; manage proteinuria.