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Inherited Cardiac Conditions reference

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Fabry Disease

Quick Summary

Definition: An X-linked lysosomal storage disorder caused by deficient α-galactosidase A activity, with multisystem globotriaosylceramide accumulation including a hypertrophic cardiac phenocopy.[1]

  • Prevalence: 1 in 40,000-117,000 (classic), ~1-3% of unexplained LVH (late-onset cardiac variant)[2]
  • Key gene: GLA (X-linked), severe in males (hemizygous), variable in females (heterozygous, X-inactivation)
  • Hallmark: LVH mimicking HCM + angiokeratomas + acroparesthesias + renal/CNS disease (classic), or isolated cardiac LVH (late-onset)
  • High-risk markers: Severe LVH, NSVT, stroke, renal failure, low enzyme activity
  • First-line Mx: Enzyme replacement therapy (agalsidase alfa/beta), chaperone therapy (migalastat if amenable mutations), manage cardiac/renal complications

Aetiology

Monogenic (Mendelian): 100%, GLA variant causing α-galactosidase A deficiency[2]

Genetics

Inheritance: X-linked (GLA gene on chromosome Xq22.1)

Males (hemizygous, ~1 abnormal X): Penetrance nearly 100%, more severe, earlier onset (classic phenotype or late-onset cardiac variant)

Females (heterozygous, 1 normal + 1 abnormal X): Penetrance 50-70%, variable severity due to X-inactivation (lyonization) - can range from asymptomatic to severe (30% asymptomatic, 40% mild-moderate, 30% severe)

Pathophysiology: α-galactosidase A deficiency → accumulation of globotriaosylceramide (Gb3) in lysosomes → cellular dysfunction, particularly in vascular endothelium, cardiomyocytes, renal podocytes, neurons → progressive multi-organ disease. Cardiac: Gb3 accumulation in cardiomyocytes → LV hypertrophy, fibrosis, conduction abnormalities, valvular disease.

Genotype-phenotype correlation:

  • Null mutations/severe mutations: Classic phenotype, early onset, multi-organ
  • Missense mutations with residual activity: Late-onset cardiac or renal variants, minimal extra-cardiac features
  • Over 1000 GLA mutations described; some variants of uncertain significance

Screening: All males with unexplained LVH should have α-Gal A enzyme testing (especially if low/normal voltage ECG, short PR, renal impairment, or young stroke)

Prevalence

1 in 40,000 to 1 in 117,000 (classic phenotype)[2]

Late-onset cardiac variant may be more common (~1-3% of unexplained LVH cohorts)

More severe in males (hemizygous); females variably affected (heterozygous)

Diagnosis

Confirming the diagnosis: in males a low plasma/leukocyte α-galactosidase A activity is diagnostic. In females enzyme activity is often normal, so GLA gene sequencing is mandatory for diagnosis and family cascade. Plasma lyso-Gb3 supports the diagnosis and aids monitoring.[6][7]

Classic phenotype (males, childhood onset):

  • Angiokeratomas (skin lesions)
  • Acroparesthesias (burning pain in extremities)
  • Hypohidrosis, corneal verticillata
  • Progressive renal, cardiac, cerebrovascular disease

Late-onset cardiac variant:

  • LVH (often mimics HCM)
  • Minimal or no extra-cardiac features
  • Usually males >40 years

Red flags suggesting Fabry vs HCM: Renal impairment, stroke at young age, absence of sarcomeric gene variant, low α-Gal A enzyme activity

Investigations

Enzyme assay: Low α-galactosidase A activity in males (diagnostic); unreliable in females

Genetic testing: GLA gene sequencing (essential in females)

Cardiac MRI: Concentric LVH, inferolateral mid-wall LGE, low T1 values

ECG: LVH, short PR interval common

Biomarkers: Elevated lyso-Gb3 (globotriaosylsphingosine)

Multi-organ assessment: Renal function, ophthalmology, audiology, neurology

Treatments

Disease-specific therapy:

1. Enzyme Replacement Therapy (ERT)

  • Agalsidase alfa (Replagal®)[2]:
    • 0.2 mg/kg IV infusion every 2 weeks over 40 minutes
    • Licensed for all patients with confirmed Fabry disease (males and females); NICE HST6[5]
    • Infusion reactions common, pre-medicate with antihistamine ± paracetamol
  • Agalsidase beta (Fabrazyme®):
    • 1 mg/kg IV infusion every 2 weeks (higher dose than alfa)
    • Infuse slowly initially at 0.25 mg/min; titrate up as tolerated
    • Same infusion reaction precautions as alfa
  • Start early, before irreversible end-organ damage (fibrosis limits ERT response)
  • Stabilises or slows progression; cannot reverse established fibrosis
  • CONTINUE during pregnancy (see pregnancy section)

2. Chaperone therapy, migalastat (Galafold®)

  • For patients with amenable GLA variants only (check Galafold amenability table, not all variants respond)
  • Dose: 123 mg orally every other day (not daily); take on empty stomach or >2 hours after/before food
  • Oral; avoids IV infusions; non-inferior to agalsidase alfa (ATTRACT trial[3])
  • NICE HST4[4]; licensed in UK for adults and adolescents ≥16 years with amenable variants
  • Monitor renal function, LV mass, and Lyso-Gb3 every 6 months

3. Supportive cardiac and organ therapy

  • ACEi/ARB for proteinuria and LV dysfunction, ramipril 2.5–10 mg od; candesartan 4–32 mg od
  • SGLT2 inhibitor (dapagliflozin/empagliflozin 10 mg od) if CKD and/or LV dysfunction (renoprotective)
  • Antiarrhythmics/pacemaker/ICD as per standard guidelines for underlying arrhythmia/conduction disease
  • Standard GDMT if DCM develops (see DCM section)
  • Antiplatelet/anticoagulation if stroke history (cryptogenic stroke in young = investigate for Fabry)
Related Resources

Complications

  • LVH and HCM-phenocopy: progressing to diastolic then systolic heart failure once fibrosis (LGE) is established[1]
  • Arrhythmia and conduction disease: atrial fibrillation, bradyarrhythmia or AV block needing pacing, and ventricular arrhythmia
  • Systemic disease: early stroke or TIA, progressive renal failure, neuropathic pain and GI symptoms, so cardiac care sits within multisystem management

Risk Stratification

Cardiac complications: Progressive LVH, heart failure, arrhythmias, conduction disease

Prognosis improved with early ERT - but cannot reverse established fibrosis

Pregnancy Management

Pregnancy in Fabry Disease (mWHO Class II-III)

PRECONCEPTION COUNSELLING:

  • Risk stratification:
    • Good cardiac/renal function, on ERT, stable disease: mWHO II (low-moderate risk)
    • Moderate LVH, proteinuria, GFR >60: mWHO II-III (moderate risk)
    • Severe LVH (>15mm), LVEF <50%, GFR <60: mWHO III-IV (high risk, pregnancy discouraged)
    • Advanced renal failure (GFR <30), severe cardiac dysfunction: mWHO IV (contraindicated)
  • X-linked inheritance pattern:
    • Female carriers (heterozygous):
      • 50% of daughters will be carriers (variable expression, can develop disease)
      • 50% of sons will be affected (classic severe phenotype)
    • Affected males: All daughters will be carriers, all sons unaffected (male cannot pass X-linked to son)
    • Prenatal testing available (CVS, amniocentesis)
    • Preimplantation genetic diagnosis (PGD) option
  • Baseline assessment:
    • Echo (LVH severity, LVEF, valves)
    • Cardiac MRI (LGE pattern, mass quantification)
    • Renal function (GFR, urinary protein:creatinine ratio)
    • Blood pressure (baseline hypertension common)
    • ECG (conduction disease, arrhythmia)
  • Enzyme Replacement Therapy (ERT):
    • Agalsidase alfa (Replagal) 0.2mg/kg IV every 2 weeks OR
    • Agalsidase beta (Fabrazyme) 1mg/kg IV every 2 weeks
    • CRITICAL: Continue ERT throughout pregnancy - benefits outweigh theoretical risks
    • Stopping ERT → disease progression, organ damage, worse outcomes
    • Registry data: No increased congenital anomalies with ERT exposure
    • ERT does NOT cross placenta (large protein molecule)
  • Alternative therapies:
    • Migalastat (oral chaperone therapy) - limited pregnancy data, discuss with specialist
    • Lucerastat (substrate reduction) - insufficient data, avoid in pregnancy

PREGNANCY MANAGEMENT:

  • Monitoring frequency:
    • Cardiology + nephrology review each trimester (monthly if complications)
    • Echo each trimester (assess LVH, LVEF, valvular function)
    • Renal function + proteinuria each trimester
    • BP monitoring (home BP if hypertensive)
  • Enzyme Replacement Therapy:
    • CONTINUE ERT every 2 weeks throughout pregnancy
    • Same dose as pre-pregnancy (weight-based)
    • Administer in hospital/infusion centre (monitor for infusion reactions)
    • Adjust dose if significant weight gain (recalculate based on current weight)
  • Cardiac management:
    • Generally well tolerated if LVEF preserved
    • Heart failure symptoms rare unless advanced disease
    • Arrhythmia risk (monitor if history of AF/VT)
    • Beta-blockers safe if needed for arrhythmia/BP control
  • Renal management:
    • Proteinuria: If present, low-dose aspirin 75-150mg from 12 weeks (pre-eclampsia prophylaxis)
    • GFR monitoring: Stable GFR expected with continued ERT
    • If GFR declining: Increase monitoring, optimize BP control
    • ACE-I/ARBs: STOP pre-conception (teratogenic); restart postpartum if proteinuria/hypertension
  • Hypertension:
    • Common in Fabry (renal + vascular involvement)
    • Target BP <140/90 mmHg (or <135/85 if end-organ damage)
    • Labetalol, nifedipine, or methyldopa safe in pregnancy
    • Avoid atenolol (IUGR risk)
  • Pre-eclampsia risk:
    • Increased risk if proteinuria or hypertension
    • Low-dose aspirin from 12 weeks (prophylaxis)
    • Monitor BP, proteinuria, symptoms closely
  • Pain management:
    • Fabry-associated neuropathic pain common (acroparesthesias)
    • Paracetamol safe
    • Gabapentin/pregabalin: Limited data, avoid if possible (use if pain severe and refractory)
    • Carbamazepine: Teratogenic, avoid

LABOUR & DELIVERY:

  • Delivery planning:
    • Tertiary centre if cardiac dysfunction or renal impairment
    • Standard obstetric unit acceptable if stable disease
    • MDT planning at 32-34 weeks
  • Mode of delivery:
    • Vaginal delivery preferred if stable cardiac function
    • Caesarean section for obstetric indications or if LVEF <40%, severe LVH, decompensated
    • Assisted second stage if moderate-severe LVH (reduce maternal effort)
  • Anaesthesia:
    • Epidural safe and preferred (good pain control, reduces sympathetic surge)
    • General anaesthesia if caesarean: Standard precautions for LVH (avoid tachycardia, maintain preload)
  • Intrapartum monitoring:
    • Continuous ECG if arrhythmia history or severe LVH
    • Standard obstetric monitoring otherwise
  • ERT timing:
    • Continue regular ERT schedule (do NOT delay infusion for delivery)
    • If delivery falls on infusion day: Give ERT post-delivery when stable

POSTPARTUM:

  • Immediate postpartum:
    • Standard monitoring unless complications
    • Resume/continue ERT on regular schedule
  • Restart medications:
    • ACE-I/ARB if proteinuria or hypertension (enalapril safe with breastfeeding)
    • Continue beta-blockers if on during pregnancy
  • Follow-up:
    • Echo at 6 weeks (ensure return to baseline)
    • Renal function at 6 weeks
    • Resume standard Fabry monitoring protocols (6-12 monthly specialist review)
  • Breastfeeding:
    • Safe and encouraged
    • ERT (agalsidase) does NOT enter breast milk (large protein molecule)
    • Medications: Beta-blockers, ACE-I (enalapril, captopril) compatible
  • Contraception:
    • All methods safe
    • COCP: Check no contraindications (age >35 + hypertension would contraindicate)
    • Progesterone-only or LARC if cardiovascular risk factors
  • Newborn screening:
    • Male infants: Enzyme assay (α-galactosidase A) to confirm affected status
    • Female infants: Genetic testing (enzyme levels unreliable in heterozygotes)
    • Early diagnosis allows early ERT initiation (better long-term outcomes)

PREGNANCY OUTCOMES DATA:

  • Fabry Registry data: >200 pregnancies analyzed
  • Maternal outcomes generally good if stable disease and continued ERT
  • No increased risk of cardiac events compared to non-pregnant Fabry patients
  • Slightly increased pre-eclampsia risk (especially if baseline proteinuria/hypertension)
  • Fetal outcomes: No increased congenital anomalies with ERT exposure
  • IUGR risk if maternal renal impairment or uncontrolled hypertension

KEY POINTS:

  • CONTINUE ERT throughout pregnancy - this is the most important intervention
  • Monitor cardiac + renal function each trimester
  • Low-dose aspirin if proteinuria (pre-eclampsia prophylaxis)
  • Pregnancy generally safe if good baseline cardiac/renal function
  • 50% risk to offspring (daughters carriers, sons affected if mother is carrier)
  • Newborn screening essential for early ERT initiation

Follow-up

Based on Fabry disease expert consensus recommendations[2][6][7].

Advanced / complicated = established LVH or fibrosis, arrhythmia or conduction disease, renal impairment, or significant extra-cardiac organ involvement / on disease-specific therapy.

Genotype-positive / phenotype-negative (G+/P−) = a confirmed pathogenic-variant carrier with no overt disease expression yet.

Genotype+ / Phenotype−Uncomplicated / StableAdvanced / Complicated
FrequencyEvery 1–2 yrs (surveillance for onset)AnnualEvery 6 months
Clinical reviewMultisystem symptom reviewSymptoms, multisystem assessmentAs above + device check
ECGPeriodic (PR interval, early LVH)Annual (PR interval, LVH, conduction)Each visit
EchocardiographyEvery 1–2 years (early LVH)Annual (LV mass, function)6-monthly
Holter / ambulatoryAs indicatedAnnual (bradyarrhythmia, AF, VT)6-monthly
CMRConsider (T1 mapping detects early involvement)Every 2–3 years (T1 mapping, LGE)As clinically indicated
BloodsRenal function, lyso-Gb3Annual (renal function, lyso-Gb3)As indicated

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

Key Points

  • Screen all men with unexplained LVH for Fabry disease (enzyme assay)[1]
  • Fabry can mimic HCM - consider if no sarcomeric gene variant found[1]
  • Treatment available (ERT/chaperone) - early diagnosis critical[1]
  • Multi-organ disease - nephrology, neurology, ophthalmology involvement
  • Pregnancy generally safe if stable on ERT with good cardiac/renal function (mWHO II-III)
  • CONTINUE ERT throughout pregnancy - do not stop
  • Monitor cardiac + renal function each trimester; low-dose aspirin from 12 weeks if proteinuria

References & Review Date

Last reviewed: June 2026

  1. Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. doi:10.1093/eurheartj/ehad194
  2. Ortiz A, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123(4):416–427. doi:10.1016/j.ymgme.2018.02.004
  3. Hughes DA, et al. Migalastat is non-inferior to enzyme replacement therapy in Fabry disease (ATTRACT trial). Ann Intern Med. 2017;166(7):485–493. doi:10.7326/M16-1499
  4. NICE Highly Specialised Technology HST4 (2017). Migalastat for treating Fabry disease. nice.org.uk/guidance/hst4
  5. NICE Highly Specialised Technology HST6 (2017). Agalsidase alfa and agalsidase beta for treating Fabry disease. nice.org.uk/guidance/hst6
  6. Pieroni M, Moon JC, Arbustini E, et al. Cardiac involvement in Fabry disease: JACC review topic of the week. J Am Coll Cardiol. 2021;77(7):922–936. doi:10.1016/j.jacc.2020.12.024
  7. Dougherty S, Germain DP, Oudit GY, et al. Cardiac manifestations of Fabry disease. npj Cardiovasc Health. 2025. doi:10.1038/s44325-025-00058-6