Anderson–Fabry Disease Management: Role of the Cardiologist

Authors, Journal, Affiliations, Type, DOI

• Authors: Maurizio Pieroni, Mehdi Namdar, Iacopo Olivotto, Robert J. Desnick
• Journal: European Heart Journal (2024), 45(14):1395–1409
• Affiliations: San Donato Hospital (Arezzo, Italy); Hôpitaux Universitaires de Genève (Switzerland); Careggi Hospital & Meyer Children's Hospital (Florence, Italy); Icahn School of Medicine at Mount Sinai (New York, USA)
• Type: State of the Art Review
• DOI: https://doi.org/10.1093/eurheartj/ehae148

Overview

Anderson–Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by GLA gene mutations leading to α-galactosidase A deficiency and progressive Gb3 glycolipid accumulation, resulting in a distinctive HCM genocopy with cardiac involvement as the principal cause of morbidity and mortality. This review reframes AFD as a cardiologist-led condition, detailing the role of the cardiologist across diagnosis, staging, treatment timing, complication management, and emerging therapies including gene therapy and AI-driven diagnostics. The average diagnostic delay remains 14 years, and late initiation of disease-specific therapy results in irreversible cardiac fibrosis. Optimal management requires a dedicated multidisciplinary team with the cardiologist at its centre.

Keywords

Anderson–Fabry disease, Hypertrophic cardiomyopathy, Artificial intelligence, Gene therapy, Lysosomal storage disorder, Enzyme replacement therapy, GLA, Gb3, Migalastat

Key Takeaways

Clinical Phenotypes

• Classic AFD (males): α-Gal A activity <3% of normal; very high Lyso-Gb3; paediatric onset with neuropathic pain, angiokeratomas, cornea verticillata, GI symptoms, anhidrosis. Progressive cardiac/renal/cerebral damage from 2nd–4th decade.
• Late-onset AFD (non-classic): Residual enzyme activity; predominantly single-organ (cardiac) involvement in adulthood; ECG and CMR changes may be the only early findings. Prevalent in specific populations (N215S in Europe/North America; IVS4+919G>A in China/Taiwan; F113L in Portugal).
• Females (heterozygous): Phenotype ranges from asymptomatic to as severe as males; determined by random X-chromosome inactivation skewness and epigenetic factors. Generally milder with later onset.
• Prevalence: Classic phenotype ~1:40,000 males historically; late-onset ~1:3,000–1:1,200 in newborn screenings. UK Biobank (n=200,643): pathogenic variants for classic/late-onset found in 1:200,643 and 1:5,732, respectively.
• AFD accounts for 0.5–1% of all HCM diagnoses.

Pathophysiology of Cardiac Involvement

• Primary mechanism: Gb3 accumulation in cardiomyocytes, intramyocardial vessels, endocardium, valvular fibroblasts, and conduction tissue.
• Secondary mechanisms: lysosomal dysfunction → mitochondrial impairment → energetic deficit → hypertrophic signalling; inflammation (innate NK-T cells, TLR-4 activation); reactive oxygen species; defective autophagy → interstitial and replacement fibrosis.
• Electrophysiological effects: enhanced Na⁺/Ca²⁺ channel function in AFD cardiomyocytes → higher, shorter action potentials → ECG abnormalities, atrial and ventricular arrhythmia substrate.
• Sequence of damage (CMR-histology correlation): Gb3 tissue storage → reduced native CMR T1 → myocyte hypertrophy → wall thickening → interstitial fibrosis → LGE → systolic dysfunction. Storage precedes imaging detection.

Cardiac Clinical Profiles

• Morphology: Concentric biventricular hypertrophy (most common), disproportionate papillary muscle hypertrophy, preserved systolic function early.
• Heart failure: HFpEF predominates — 40% of AFD patients meet ESC HF criteria; 91% of these have HFpEF. Subclinical diastolic dysfunction may precede LVH.
• Coronary involvement: Microvascular dysfunction common; MINOCA (myocardial infarction with normal coronary arteries) is an early presentation, especially in females — often leads to unnecessary repeated coronary angiography.
• Arrhythmias: Palpitations in ~30%; substrate for VT (syncope, SCD risk in advanced disease); AF (atrial Gb3 + remodelling); sinus bradycardia and chronotropic incompetence; AV conduction disturbances in advanced cases.
• LVOTO: Uncommon; present in a minority; septal reduction therapy may be needed.

Diagnosis and Staging

• ECG red flags (early): Short P-wave duration, short PQ interval, prolonged R-wave peak time, lower 4/8 QRS spatial velocity — precede LVH.
• ECG red flags (advanced): High voltages, ST-T depression, T-wave inversions in precordial ± inferolateral leads; bundle branch block if diffuse damage.
• Echocardiographic features: Concentric biventricular hypertrophy, papillary muscle hypertrophy, hyperechogenic myocardium, impaired GLS — none pathognomonic. Strain analysis detects subclinical dysfunction even without LVH.
• CMR: Gold standard for differential. Reduced native T1 values = earliest CMR marker of Gb3 storage (precedes LVH, but note: >45% myocytes already vacuolated when T1 falls). T2 elevation = inflammation (basal inferolateral). LGE = fibrosis (midwall/epicardial inferolateral pattern); pseudo-normalization of T1 in LGE regions. Extracellular volume remains largely normal (unlike amyloidosis).
• CMR staging (4 stages): Stage 1 (pre-LVH, reduced T1 only) → Stage 2 (LVH + T2 elevation ± early LGE) → Stage 3 (extensive LGE + inferolateral thinning) → Stage 4 (systolic dysfunction).
• Enzymatic testing: α-Gal A activity in leucocytes or dry blood spot — reliable in males (classic and late-onset have low but detectable activity). In females, enzymatic activity may be normal → genetic testing mandatory.
• Lyso-Gb3 (plasma): Elevated in pathogenic variants; useful to distinguish pathogenic from benign VUS; monitored on treatment (drop expected on starting ERT/migalastat).
• Endomyocardial biopsy: Reserved for strong clinical suspicion with uncertain GVUS; electron microscopy shows Gb3-laden myocyte inclusions.
• Screening: HCM/unexplained LVH populations — AFD prevalence 0.5–4% depending on selection criteria.

Emerging Diagnostic Approaches

• AI-ECG: Deep learning detects LV dysfunction, HCM, dilated CM, amyloidosis from 12-lead ECG signatures.
• AI-echocardiography: Automated chamber quantification, strain measurement, HCM/amyloidosis differential (AUC 0.83/0.98 in LVH populations).
• AI-CMR: Accelerated image analysis; virtual LGE from non-contrast sequences.
• AI-phenotypic pattern recognition: Tool calibrated on ~5,000 AFD patients — AUC 0.82 for AFD identification.
• AI-variant pathogenicity: Protein language model deep learning for GLA GVUS prediction.
• Newborn screening: Identifies classic and (mostly) late-onset variants early; raises ethical dilemmas re: when to treat and how to follow patients who may not develop disease for decades.

Disease-Specific Therapies

Enzyme Replacement Therapy (ERT)

• Agalsidase alfa (0.2 mg/kg IV q2w) and agalsidase beta (1.0 mg/kg IV q2w): both EU-approved since 2001; agalsidase beta FDA-approved from age 2.
• Biochemically similar; agalsidase beta has more mannose-6-phosphate residues (greater lysosomal uptake) and higher sialylation (less hepatic uptake).
• Pegunigalsidase alfa (PEGylated, cross-linked): FDA/EMA approved 2023 at 1.0 mg/kg q2w; non-inferior to agalsidase beta; reduced immunogenicity and prolonged half-life; real-world data still needed.
• Biosimilars of agalsidase beta approved in South Korea and Japan.
• Early ERT initiation critical — long-term data show slowing/halting of progression when started early. In classic AFD males, ERT recommended at any age, irrespective of symptoms.
• Cost: ~€300,000/year for both ERT and chaperone; cost-effectiveness considerations arise in advanced irreversible organ damage.
• Anti-drug antibodies (ADAs): Neutralising ADAs can limit ERT efficacy; mitigation strategies (dose escalation, oral tolerance, immunosuppression) under investigation.

Pharmacologic Chaperone Therapy (Migalastat)

• Small molecule stabilises misfolded α-Gal A produced by amenable GLA missense variants.
• Amenability: Defined by ≥1.2-fold increase in enzyme activity in standardised in vitro assay (~60% of missense variants qualify).
• Approved: EMA 2016, FDA 2018; oral, q48h; for patients ≥12 years, eGFR >30 mL/min/1.73m².
• Caution: In vitro amenability ≠ in vivo treatability in some cases; discrepancies between assays; certain 'amenable' variants require further clinical evidence.
• Real-world efficacy promising in late-onset patients; most evidence derived from heterogeneous populations.

Emerging Therapies

• Substrate reduction therapy (SRT): Oral glucosylceramide synthase inhibition (lucerastat, venglustat) — both failed to show efficacy in trials to date; trials ongoing. Nanoparticle-delivered siRNA SRT in preclinical stages.
• mRNA therapy: Systemic GLA mRNA delivery (preclinical).
• Gene therapy: AAV2/6 carrying GLA cDNA (isaralgagene civaparvovec) — Phase 1/2 in 13 patients: supraphysiologic α-Gal A levels; 5 patients ceased ERT with maintained enzyme activity; renal biopsy evidence of substrate reduction. Phase 3 pending. A separate AAV trial placed on FDA clinical hold (atypical HUS, renal vessel thrombosis). Lentiviral and iPSC strategies also in development.

Management of Cardiac Complications

• Heart failure (HFpEF): Follow current guideline-based HFpEF management. SGLT2 inhibitors should be considered — approved for HFpEF; may also benefit AFD nephropathy.
• LVOTO: Septal reduction therapy (surgical myectomy or alcohol ablation) for persistent symptoms. Cardiac myosin inhibitors (mavacamten) should NOT be used in AFD (approved for sarcomeric HCM only).
• Atrial fibrillation: Follow existing AF guidelines; ablation experience in AFD is sparse and outcomes may be suboptimal due to atrial remodelling. Prefer DOACs over warfarin to reduce cerebral microbleed risk and warfarin nephropathy.
• Revascularisation / pacing: Follow standard guidelines.
• SCD prevention:
  • HCM Risk-SCD calculator must not be used in AFD — not validated in this population.
  • ICD in primary prevention should be considered in patients with massive LVH + extensive CMR scarring, particularly when accompanied by: arrhythmic/unexplained syncope, NSVT on Holter, or pacing indication.
  • Antiarrhythmic drugs: limited by coexisting LVH, HF, and renal dysfunction.
  • Amiodarone should be AVOIDED — interferes with lysosomal function, may worsen enzymatic deficiency and impair ERT/migalastat efficacy.
• Anticoagulation: Prefer DOACs over VKAs for thromboembolic prevention.

Monitoring

• Clinical assessment + ECG + echocardiography + Holter: at least annually.
• CMR: every 2–3 years (or more frequently if rapid progression suspected).
• Biomarkers: hs-troponin and NT-proBNP — useful for disease evolution monitoring.
• Lyso-Gb3: monitor for treatment response; failure to drop on ERT/migalastat suggests unresponsiveness.
• Cardiological follow-up in late-onset newborn-screen-identified patients: Dedicated paediatric → adult transition programmes urgently needed.

Limitations of the Document

• State-of-the-art review — no primary data generated; evidence quality for non-classic phenotype and females is weaker (heterogeneous populations, registry data, small trials).
• Treatment efficacy data in late-onset AFD less robust than classic; recommendations largely extrapolated from mixed-phenotype studies.
• Gene therapy trials are early-phase; safety data limited.
• Real-world data for pegunigalsidase alfa lacking.
• Conflicts of interest: all authors have received speaker/advisory fees and/or research grants from AFD therapeutic companies.

Key Concepts Mentioned

• concepts/Fabry-Cardiomyopathy — central subject; pathophysiology, staging, cardiac management
• concepts/HFpEF — 40% of AFD patients have HFpEF by ESC criteria; SGLT2i applicable
• concepts/Phenotypic-Approach-to-Cardiomyopathy — AFD is a key HCM genocopy requiring phenotype-based aetiological diagnosis
• concepts/Late-Gadolinium-Enhancement — inferolateral midwall LGE pattern in AFD
• concepts/LVOTO — uncommon in AFD; myosin inhibitors contraindicated
• concepts/AAV-Gene-Delivery — AAV2/6 gene therapy for AFD in Phase 1/2 trial
• concepts/HCM-Risk-SCD — explicitly contraindicated for SCD risk stratification in AFD

Key Entities Mentioned

• entities/Anderson-Fabry-Disease — the primary entity; genetics, phenotypes, systemic management
• entities/Amiodarone — contraindicated in AFD; interferes with lysosomal function
• entities/Heart-Failure — cardiac manifestations, HFpEF predominance

Wiki Pages Updated

• wiki/sources/fabry-ehj-2024.md — created (this file)
• wiki/entities/Anderson-Fabry-Disease.md — updated (comprehensive content from this source merged with esc-cmp-2023)
• wiki/concepts/Fabry-Cardiomyopathy.md — created
• wiki/concepts/HFpEF.md — updated (AFD as genetic HFpEF cause)
• wiki/entities/Amiodarone.md — updated (AFD-specific contraindication)
• wiki/wikiindex.md — updated
• wiki/sourceindex.md — updated
• log.md — appended