Fabry Disease

Genetics

• X-linked recessive (with phenotype in heterozygous women)
• GLA gene on Xq22
• Over 1000 mutations described
• Classical (no enzyme activity) and later-onset (residual activity) phenotypes
• Prevalence ~1 in 40,000-60,000 (probably underdiagnosed)

Pathophysiology

• Alpha-galactosidase A deficiency
• Globotriaosylceramide (Gb3) accumulates in lysosomes
• Affects: podocytes, mesangial cells, vascular endothelium, cardiomyocytes, autonomic ganglia, sweat glands, cornea
• Lyso-Gb3 (deacylated form) is circulating biomarker

Organ Involvement

• Kidneys: podocyte injury → proteinuria → FSGS-like CKD → ESKD
• Heart: LVH, conduction disease, arrhythmias, heart failure
• CNS: stroke, white matter lesions, vertigo, hearing loss, depression
• PNS: small fibre neuropathy, autonomic dysfunction
• Skin: angiokeratomas (umbilical, bathing-trunk distribution)
• Eyes: cornea verticillata (whorl-like deposits, asymptomatic)
• GI: cramping, diarrhoea

CHILDHOOD (often delayed diagnosis):

• Acroparaesthesia — burning hand/foot pain (especially in heat, fever, exercise)
• Heat/cold intolerance, hypohidrosis
• GI symptoms (abdominal cramping after meals)
• Angiokeratomas appear in adolescence
• Corneal whorls (on slit lamp)

Young Adulthood

• Microalbuminuria → overt proteinuria
• Mild LVH on echo
• First TIA/stroke (often before 40)

Adulthood

• CKD, often reaching dialysis in 4th-5th decade in untreated men
• Severe LVH, heart failure, AF
• Recurrent strokes
• Hearing loss
• Depression, fatigue

WOMEN (heterozygotes):

• Spectrum from asymptomatic to fully affected (X-inactivation)
• Average symptoms 10 years later than men
• Cardiac involvement now recognised as common
• Need careful monitoring

When To Suspect

• Unexplained proteinuria/CKD in young adult
• Unexplained LVH (especially if 'HCM phenocopy')
• Young stroke (<55 years)
• Family history of any of the above
• Burning hand/foot pain since childhood

First-line (Men)

• Dried blood spot (DBS) for alpha-Gal A enzyme activity
• Low/absent activity → confirm with GLA gene sequencing

First-line (Women)

• GLA gene sequencing — enzyme test unreliable

Adjuncts

• Plasma lyso-Gb3 (raised in active disease, useful for monitoring)
• Urine Gb3
• Kidney biopsy (if uncertain): foot process effacement, lamellar 'zebra body' inclusions in podocytes on EM
• Echocardiogram (LVH, late gadolinium enhancement on cardiac MR)
• MRI brain (white matter lesions, pulvinar sign)
• Audiometry
• Slit lamp (corneal verticillata)

Family Screening

• Mandatory — index case has on average 5 affected relatives
• Genetic counselling at UK specialist centre
• Children of affected mother: 50% risk per pregnancy

Disease-modifying

1. Enzyme Replacement Therapy (Ert)

• Agalsidase alfa (Replagal) 0.2 mg/kg IV every 2 weeks
• Agalsidase beta (Fabrazyme) 1.0 mg/kg IV every 2 weeks
• Start before significant organ damage if possible
• Slows but does not reverse CKD progression
• Cardiac fibrosis is irreversible — start early
• Home infusion programmes available in UK

2. Oral Chaperone Therapy

• Migalastat (Galafold) 123 mg every other day
• Only for 'amenable' GLA mutations (~30-50% of patients)
• Stabilises mutant enzyme, increases activity

Adjunctive

• RAS blockade (ACE/ARB) for proteinuria — first-line
• SGLT2 inhibitor — increasingly used
• Statin (high CV risk)
• Antiplatelet for stroke prevention
• Pain: pregabalin, gabapentin, carbamazepine; avoid opioids long-term
• Cardiac: ICD if indicated, anticoagulation for AF
• Renal replacement (dialysis, transplant) when needed — Fabry does not recur in transplant

UK Network

• Tertiary centres: Royal Free Hospital (London), Salford Royal, Birmingham, Addenbrooke's, Manchester (children)
• National Specialised Commissioning funds ERT and migalastat through these centres
• Annual multidisciplinary review (renal, cardiac, neuro, ENT, genetics, pain)