A wide range of signs and symptoms are observed in classical Fabry Disease due to the storage of GL3 in a variety of cell types, including endothelial cells, renal (podocytes, tubular cells, glomerular endothelial, mesangial and intersticial cells), cardiac (cardiomyocytes and fibroblasts) and nerve cells.1
Neuropathic pain, experienced by 84-100% of classically affected males and 32-90% of heterozygous females.2 The pain may be episodic, characterised by agonizing burning pain originating in the extremities and radiating inwards to the limbs and other parts of the body (“Fabry crises”), or it may be chronic pain characterised by burning and tingling paraesthesias.
Fabry crises may be precipitated by fever, exercise fatigue, stress, and rapid changes in temperature. They may decrease in frequency and severity with increasing age.1 Pain exacerbated by exercise, heat or both, in patients who additionally exhibit a decreased cold sensation on quantitative sensory testing (QST) and abnormal intraepidermal nerve fiber density (IENFD), should increase clinical suspicion of FD.3
Cochleo-vestibular disorders including tinnitus and hearing loss.1
Hypohidrosis/anhidrosis, which can cause heat and exercise intolerance.1 Hyperhidrosis has also been described in Fabry patients and appears in childhood or adolescence.4
Angiokeratomas, characteristic clusters of small, reddish-purple raised skin lesions. They are typically found on the hips, back, thighs, buttocks, penis, and scrotum, although there is a wide variation in the pattern of distribution and density of the lesions. It is common for angiokeratomas to occur in mucosal areas including oral mucosa and conjunctiva.5
Characteristic angiokeratomas in Fabry Disease
Image courtesy of Robert J Desnick. Characteristic dark red to blue-black angiectases are typically found between the thigh (left) and umbilicus (right) regions (“bathing suit distribution”). The range in size from a pinpoint to several millimetres.
Transient ischemic attacks or strokes, experienced by 4.3%-6.9% of individuals with Fabry disease.6 Premature stroke is usually experienced in adulthood, although it can occur in adolescence and may be the first obvious major sign of Fabry disease.
Up to 50% of individuals experience stroke before being diagnosed with Fabry disease.6 Fabry disease may be a cause of unexplained stroke in young patients as screening studies have detected a prevalence of Fabry disease of around 1% in unexplained young (18-55 years) stroke cohorts.7,8 Although this is not a consistent finding, consideration of Fabry disease in young patients with unexplained stroke remains appropriate.9
Impaired heart rate variability, arrhythmias, ECG abnormalities (shortened PR interval) and mild valvular insufficiency are early signs of cardiac abnormalities. They can be present in adolescence in both genders.1
Proteinuria and microalbuminuria. These are early signs of renal involvement and commonly develop in the second to third decade of life.1 It has been demonstrated that there is significant accumulation of GL3 and damage to the podocytes before proteinuria is present in Fabry Disease.10
Cornea verticillata are asymptomatic characteristic corneal opacities. They are visible by slit-lamp microscopy. Cornea verticillata are almost universal among classically affected male hemizygotes and are a hallmark of Fabry Disease.1,11 They are also common in female heterozygotes.11
Used with permission from RL Abbott, MD. Distinctive corneal opacity (corneal verticillata or vortex keratopathy) in Fabry Disease. Note the whorl-like corneal rays emanating from a single vertex like the spokes of a wheel.
Gastrointestinal symptoms include abdominal pain, diarrhoea, nausea, vomiting, early satiety and difficulty gaining weight.1