Early cerebral manifestations in a young female with Fabry disease with skewed X-inactivation

To the Editor : Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A (αGal A). Accumulation of globotriaosylceramide (Gb3) in different cell types eventually leads to renal insufficiency, cardiomyopathy and central nervous system (CNS) involvement (1). CNS involvement is mainly characterized by white matter lesions (WMLs) and strokes (2, 3). Several cohort studies revealed that females with FD often do develop clinical manifestations, although the disease generally follows a milder course (4–7). WMLs and strokes have been reported in young males with FD (8–10), but not in young females. In this letter, we report the enzymatic, biochemical and molecular characteristics of a young female patient with FD who had signs of CNS involvement from the very early age of 13 years. The proband was the patient’s grandmother, diagnosed with FD after the evaluation of unexplained renal insufficiency. Patient’s aunt, mother and sister were subsequently also diagnosed with FD. The patient had several early signs and symptoms of FD: minor acroparesthesia during exercise, a few angiokeratoma on the trunk, cornea verticillata and bilateral high-frequency hearing loss. Renal and cardiac assessments were normal. Brain magnetic resonance imaging (MRI) at the age of 15 years showed a 4-mm periventricular WML on T2 and fluid-attenuated inversion recovery (FLAIR) images near the right posterior horn (Fig. 1a). In retrospect, this lesion was already present on the MRI performed at the age of 13 years. Intravenous enzyme replacement and antiplatelet therapy was started. One year later, a hemorrhagic infarction was present in the left globus pallidus (Fig. 1b) without any symptoms. Risk factors for cardiovascular disease only revealed a history of cigarette smoking. Fibrinogen, clotting factor VIII, antithrombin deficiency, lupus anticoagulant, factor II mutation, factor V Leiden mutation, protein (a) (b)