Fabry disease has a varied clinical presentation due to the presence of classical and atypical manifestations and variable expressions in female heterozygotes.
Classical Fabry disease
Patients with classical Fabry disease are affected by multi-organ involvement giving rise to multiple characteristic signs and symptoms.1 Onset usually occurs in childhood between the ages of 3 and 10 years. Boys are typically affected earlier and more severely than girls.2 However, the age of onset, clinical features and clinical course of Fabry disease varies widely, even within families.2
Atypical variants are individuals in whom clinical manifestations are confined to one organ system. These phenotypes occur in male hemizygotes. Unlike classically affected male hemizygotes, they generally have residual α-galactosidase A activity. Atypical variants are usually identified serendipitously in the fourth to sixth decades of life during medical evaluations unrelated to Fabry.1 Atypical variants are sub-classified based on the organ system involved.
Cardiac variants are individuals in whom the heart is predominantly or exclusively affected.3,4 These patients are asymptomatic during most of their lives and develop late-onset cardiac or cardiopulmonary disease. Classical manifestations of Fabry disease such as acroparesthesias, angiokeratoma, corneal verticillata and hypohidrosis/anhidrosis are usually absent. These patients have been identified during evaluation of other unrelated medical problems or of their family members. Typical manifestations in cardiac variants are non-obstructive hypertrophic cardiomyopathy and myocardial infarctions.2
Individuals referred to as having renal variants are those in whom the kidneys are predominantly or exclusively affected. These patients have been detected among Japanese chronic dialysis patients found to have low α-galactosidase A activity and GLA gene mutations.5
Female heterozygotes may present with clinical phenotypes ranging from mild to severe disease comparable to that in classically affected hemizygous males.6 Clinically asymptomatic female heterozygotes are uncommon. In general, female heterozygotes show a more protracted disease course compared to classically affected males, but they suffer most of the same manifestations with comparable frequency.6-8