What is classical Fabry disease?

Fabry disease is caused by variants in the GLA gene encoding the enzyme alpha-galactosidase A (α-Gal A).1 Variants in the GLA gene culminating in no or little (<1%) α-Gal A enzyme activity are associated with classical Fabry disease.1,2

The initial signs of classical Fabry disease typically manifest in childhood. The earliest clinical symptoms of this disease phenotype include acroparaesthesia (tingling, numbness, or pins and needles in the hands or fingers), angiokeratomas (small, non-blanching, dark red or bluish benign skin lesions), heat intolerance, cornea verticillata in the eyes and gastrointestinal symptoms.3-6 In adulthood, later complications occur as the disease progresses, and may include renal failure, hypertrophic cardiomyopathy, cerebrovascular disease and reduced life expectancy (Figure 1) (see signs and symptoms of Fabry disease).6

Acroparaesthesia; atypical chronic or episodic pain; dizziness; hearing loss; heat and/or cold intolerance; hypohidrosis (impaired sweat function); pain crises; tinnitus; vertigo

Angiokeratomas

Abdominal pain and/or bloating; constipation; difficulty gaining weight in childhood; intermittent diarrhoea; nausea and vomiting

Cornea verticillata; cataract; central retinal artery occlusion (rare); conjunctival and retinal vasculopathy; reduced tear secretion

Pathological albuminuria or proteinuria; decreased glomerular filtration rate progressing to kidney failure

Atrial fibrillation; bradycardia; cardiac fibrosis; cardiomyopathy (particularly hypertrophic cardiomyopathy with concentric hypertrophy and minimal or absent outflow obstruction); chronotropic incompetence; heart failure (mostly with preserved ejection fraction); reduced exercise tolerance; sudden cardiac death; syncope; ventricular tachycardia

Aortic stiffness

Cerebral venous thrombosis; cervical carotid dissection; haemorrhagic stroke; ischaemic stroke; transient ischaemic attack

Common: anxiety, depression, panic attacks, social adaptive function difficulties

Rare: cognitive decline and dementia

Dry cough; dyspnoea; sleep-disordered breathing; wheezing

Lymphoedema in all or part of a limb (also below eyes), pitting oedema

Osteopaenia, osteoporosis 

Mild facial dysmorphism

Figure 1.
Clinical manifestations of classical Fabry disease. Reproduced and adapted with permission from Ortiz A et al. Mol Genet Metab 2018; 123: 416-427.7

 

C-ANPROM/INT/FAB/0015; Date of preparation: March 2021