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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 required to confirm the diagnosis and enable family cascade (genotype is also needed in males for cascade testing and treatment decisions). 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

1. General measures:

  • Genetic counselling and family cascade testing (X-linked inheritance), see the Genetic Testing page

2. Medical therapy:

  • 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
    • In patients already established on ERT, continuation during pregnancy is often considered where maternal benefit is expected, decided with Fabry/metabolic, cardiology and obstetric input (see pregnancy section)
  • 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
  • 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)
    • Standard GDMT if DCM develops (see DCM section)
    • Antiplatelet/anticoagulation if stroke history (cryptogenic stroke in young = investigate for Fabry)

3. Device therapy:

  • Antiarrhythmics/pacemaker/ICD as per standard guidelines for underlying arrhythmia/conduction disease

4. Advanced heart failure and/or transplant referral:

  • Standard advanced-heart-failure/transplant pathways apply if cardiomyopathy progresses to end-stage disease, as for any cardiomyopathy; renal transplantation may be relevant for Fabry nephropathy, managed jointly with nephrology

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: high risk, warranting detailed counselling by a Pregnancy Heart Team
    • Advanced renal failure (GFR <30) with severe cardiac dysfunction: very high risk, generally corresponding to mWHO IV, where pregnancy is usually advised against following specialist counselling
  • 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
    • Continuation of agalsidase during pregnancy may be considered in women with significant disease after a specialist risk-benefit discussion
    • Published case-series and registry data are reassuring but limited; avoid universal claims that benefits always outweigh risks
    • Registry data: No increased congenital anomalies with ERT exposure
    • Avoid definitive placental-transfer claims unless formulation-specific specialist advice is documented
  • 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:
    • Where continuation was agreed pre-conception, ERT is generally continued on the same 2-weekly schedule 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 generally considered compatible 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 generally considered compatible 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 generally considered compatible
    • 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 ahead of expected delivery, timing individualized rather than fixed
  • 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 generally 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 is considered compatible 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:
    • Generally encouraged
    • Agalsidase is a large protein, so transfer into breast milk and absorption by the infant are both expected to be low; confirm with specialist pharmacy or metabolic advice and product-specific guidance
    • Medications: Beta-blockers, ACE-I (enalapril, captopril) compatible
  • Contraception:
    • No specific method is excluded
    • 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:

  • In patients already established on ERT, continuation through pregnancy is usually favoured where maternal benefit is expected; decide with Fabry/metabolic, cardiology and obstetric input
  • Monitor cardiac + renal function each trimester
  • Low-dose aspirin if proteinuria (pre-eclampsia prophylaxis)
  • Pregnancy is usually well tolerated if baseline cardiac and renal function are good
  • 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

  • Consider Fabry disease in any patient with unexplained LVH, especially with renal, neurological, pain, corneal or family-history red flags; in males use alpha-galactosidase A activity with genetic confirmation, in females use GLA sequencing because enzyme activity may be normal[1]
  • Fabry can mimic HCM - consider if no sarcomeric gene variant found[1]
  • Multi-organ disease - nephrology, neurology, ophthalmology involvement
  • Treatment available (ERT/chaperone) - early diagnosis critical[1]
  • Pregnancy is usually well tolerated if stable on ERT with good cardiac/renal function (mWHO II-III)
  • Do not stop ERT reflexively in pregnancy; continuation is usually favoured in those already established on it, decided with specialist input
  • Monitor cardiac + renal function each trimester; low-dose aspirin from 12 weeks if proteinuria

References & Review Date

Last reviewed: July 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.2018.02.014
  3. Hughes DA, et al. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J Med Genet. 2017;54(4):288–296. doi:10.1136/jmedgenet-2016-104178
  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