Aetiology

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

Genetics

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

Males (hemizygous): more severe, earlier onset (classic phenotype or later-onset cardiac variant); penetrance is near complete with classic variants but varies with later-onset variants^[7]

Females (heterozygous): variable severity due to X-inactivation (lyonization), from asymptomatic to a classic phenotype; in a registry of 1,077 women, 69.4% had symptoms or signs of Fabry disease, and most develop clinically significant disease^[6]^[7]

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
More than 1,000 GLA variants described; several once reported as pathogenic have been reclassified as uncertain or benign, so check the current classification before cascade testing or treatment^[6]^[7]

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); women need GLA sequencing, as enzyme activity is often normal^[6]

Prevalence

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

Later-onset variants are more common than the classic phenotype: newborn screening suggests up to 1 in 8,800, and pathogenic GLA variants are found in ~1% of patients with LVH or HCM^[1]^[6]

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)

Biomarkers: plasma lyso-Gb3 (globotriaosylsphingosine) supports the diagnosis and is used for monitoring; high-sensitivity troponin (often raised where there is LGE) and NT-proBNP.^[6]^[10]

ECG: a short PR interval without pre-excitation is an early finding; LVH voltages and repolarisation change follow; with progression, PR prolongation, AV block, bundle branch block and sinus node dysfunction with chronotropic incompetence develop.^[6]

Echocardiography: concentric LVH (asymmetric septal hypertrophy can occur), prominent papillary muscles, diastolic dysfunction, and reduced longitudinal strain in the basal inferolateral wall where scar develops.^[6]

Cardiac MRI: the key test for cardiac involvement and staging.^[6]^[8]^[9]^[10]

Low native T1: reflects myocardial sphingolipid storage; present in most patients with LVH and in a proportion before LVH develops, making it the earliest imaging marker of cardiac involvement^[8]^[9]
Discriminating value: low native T1 separates Fabry disease from other causes of LVH (sarcomeric HCM, amyloidosis, hypertensive heart disease), which have normal or raised T1^[8]
LGE: mid-wall LGE of the basal inferolateral wall is typical, and in women can occur without LVH^[9]
Pseudonormalisation: native T1 within areas of LGE is normal or raised because of fibrosis, so read T1 segment by segment rather than as a global value^[9]
Inflammation: raised T2 in the LGE region, with raised troponin, indicates chronic inflammation ("hot fibrosis") and is associated with progression^[10]
Staging: (1) accumulation, low T1 without LVH; (2) hypertrophy and inflammation, LVH with LGE and raised T2 or troponin; (3) fibrosis and impairment, extensive LGE with falling function^[6]^[9]

Ambulatory ECG monitoring: for bradyarrhythmia, AF and NSVT, repeated at follow-up; an implantable loop recorder for unexplained palpitations or syncope.^[6]

Multi-organ assessment: renal function and proteinuria, ophthalmology, audiology, neurology (including brain MRI for white-matter lesions)

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 long-term ERT in patients with confirmed Fabry disease (males and females); UK SmPC^[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
- Pegunigalsidase alfa (Elfabrio®):
  - PEGylated ERT with a longer half-life; 1 mg/kg IV infusion every 2 weeks
  - Non-inferior to agalsidase beta for eGFR decline over 2 years (BALANCE)^[11]
  - Confirm licensing and UK funding position locally
- 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 aged ≥12 years weighing ≥45 kg with an amenable variant; not recommended if eGFR <30
- 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 foundational medical therapy 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

No validated SCD risk model: the HCM Risk-SCD calculator is not validated in Fabry disease.^[1]

Features associated with adverse cardiac events: LVH, extent of LGE, older age, male sex, NSVT and raised troponin or NT-proBNP.^[6]^[7]

Bradyarrhythmia: conduction disease is progressive and a significant minority need pacing; PR prolongation, QRS widening, LVH and older age identify those at risk, so ambulatory monitoring is repeated during follow-up.^[6]

Atrial fibrillation: common with advancing disease; a low threshold for anticoagulation is advised given the associated stroke risk.^[6]

ICD: for secondary prevention; primary prevention is individualised (extensive LGE, NSVT, severe LVH), as no Fabry-specific trial evidence exists.^[1]^[6]

Treatment response: disease-specific therapy works best when started before LGE develops; established fibrosis predicts a limited cardiac response.^[6]^[9]

Pregnancy Management

mWHO class II–III or above: refer to a Pregnancy Heart Team before conception (see Pregnancy).

Pregnancy in Fabry Disease (risk depends on cardiac and renal phenotype)

PRECONCEPTION COUNSELLING:

Risk stratification:
- Normal LV function, no significant LVH or arrhythmia, preserved renal function: generally lower risk
- There are no validated Fabry-specific risk classes: judge cardiac risk as for the corresponding cardiomyopathy phenotype (LV function, LVH and outflow obstruction, arrhythmia) and add renal risk (serum creatinine, proteinuria, hypertension), with counselling by a Pregnancy Heart Team
X-linked inheritance pattern:
- Heterozygous females (not merely carriers; expression is variable and many develop disease):
  - 50% of daughters will be heterozygous (variable expression; many develop clinically significant disease)
  - 50% of sons will be hemizygous and affected (classic or later-onset phenotype, depending on the familial variant)
- Affected (hemizygous) males: All daughters will be heterozygous (variable expression), all sons unaffected (an X-linked variant cannot pass from father 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 (serum creatinine, 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
- Human data are very limited^[5]: a 2019 review found 8 published pregnancies treated with ERT, all with a successful outcome, but case reports are too few and too selective to exclude a fetal risk^[12]
Alternative therapies:
- Migalastat (oral chaperone therapy): not recommended in pregnancy; plan a switch to ERT with the specialist if treatment is needed. Breastfeeding is a separate decision^[13]
- 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)
- Renal monitoring: serum creatinine and proteinuria through pregnancy (calculated eGFR is not valid in pregnancy^[14]); data on renal outcomes in pregnancy, with or without ERT, are limited
- If creatinine or proteinuria rising: increase monitoring, optimise 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; otherwise as for other heart disease (severe heart failure, uncontrolled arrhythmia), decided by the Pregnancy Heart Team
- 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:

Evidence is limited to small cohorts: PROFABIA (Haninger-Vacariu et al, Orphanet J Rare Dis 2024; 44 women, 70 pregnancies) and a 41-woman survey (Holmes & Laney, JIMD Rep 2015)
No life-threatening maternal complications were reported in these cohorts, but only 2 PROFABIA pregnancies involved ERT, so outcomes on ERT are largely unstudied
Cardiac event risk in pregnancy has not been quantified; assess by phenotype (LVH, LVEF, arrhythmia, renal function) with a Pregnancy Heart Team
Higher rates of hypertension and pre-eclampsia (11.5% vs 3.8% population rate in PROFABIA), especially with baseline proteinuria/hypertension
Fetal outcomes: more preterm birth (20% vs 7%), low birth weight and small-for-gestational-age infants in PROFABIA; data on ERT exposure are too sparse for firm conclusions
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 each child of a heterozygous mother (sons hemizygous and affected; daughters heterozygous with variable expression)
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 / Stable	Advanced / Complicated
Frequency	Every 1–2 yrs (surveillance for onset)	Annual	Every 6 months
Clinical review	Multisystem symptom review	Symptoms, multisystem assessment	As above + device check
ECG	Periodic (PR interval, early LVH)	Annual (PR interval, LVH, conduction)	Each visit
Echocardiography	Every 1–2 years (early LVH)	Annual (LV mass, function)	6-monthly
Holter / ambulatory	As indicated	Annual (bradyarrhythmia, AF, VT)	6-monthly
CMR	Consider (T1 mapping detects early involvement)	Every 2–3 years (T1 mapping, LGE)	As clinically indicated
Bloods	Renal function, lyso-Gb3	Annual (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 with good cardiac and renal function, although pre-eclampsia and preterm birth are more frequent
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: October 2026

Key studies in Fabry disease · the landmark studies, drawn to scale with the other inherited cardiac conditions.

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
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
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
NICE Highly Specialised Technology HST4 (2017). Migalastat for treating Fabry disease. nice.org.uk/guidance/hst4
Takeda UK Ltd. Replagal 1 mg/ml concentrate for solution for infusion (agalsidase alfa): Summary of Product Characteristics. electronic medicines compendium. medicines.org.uk/emc/product/9186/smpc
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
Dougherty S, Germain DP, Oudit GY, et al. Cardiac manifestations of Fabry disease. npj Cardiovasc Health. 2025;2:40. doi:10.1038/s44325-025-00058-6
Sado DM, White SK, Piechnik SK, et al. Identification and assessment of Anderson-Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping. Circ Cardiovasc Imaging. 2013;6(3):392–398. doi:10.1161/CIRCIMAGING.112.000070
Nordin S, Kozor R, Medina-Menacho K, et al. Proposed stages of myocardial phenotype development in Fabry disease. JACC Cardiovasc Imaging. 2019;12(8):1673–1683. doi:10.1016/j.jcmg.2018.03.020
Nordin S, Kozor R, Bulluck H, et al. Cardiac Fabry disease with late gadolinium enhancement is a chronic inflammatory cardiomyopathy. J Am Coll Cardiol. 2016;68(15):1707–1708. doi:10.1016/j.jacc.2016.07.741
Wallace EL, Goker-Alpan O, Wilcox WR, et al. Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study. J Med Genet. 2024;61(6):520–530. doi:10.1136/jmg-2023-109445
Madsen CV, Christensen EI, Nielsen R, et al. Enzyme replacement therapy during pregnancy in Fabry patients: review of published cases of live births and a new case of a severely affected female with Fabry disease and pre-eclampsia complicating pregnancy. JIMD Rep. 2019;44:93–101. doi:10.1007/8904_2018_129
Amicus Therapeutics UK Ltd. Galafold 123 mg hard capsules (migalastat): Summary of Product Characteristics. electronic medicines compendium. medicines.org.uk/emc/product/10934/smpc
Wiles K, Bramham K, Chappell L, et al. UK Kidney Association clinical practice guideline: pregnancy and renal disease. 2019. ukkidney.org

Fabry Disease (Anderson-Fabry)