Ten-year-long enzyme replacement therapy shows a poor effect in alleviating giant leg ulcers in a male with Fabry disease

Abstract

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (α-gal A), leading to the progressive accumulation of glycosphingolipids. Classical hemizygous males usually present symptoms, including pain and paresthesia in the extremities, angiokeratoma, hypo- or anhidrosis, abdominal pain, cornea verticillata, early stroke, tinnitus, and/or hearing loss, during early childhood or adolescence. Moreover, proteinuria, renal impairment, and cardiac hypertrophy can appear with age. Enzyme replacement is the most common therapy for Fabry disease at present which has been approved in Japan since 2004. We report a case involving a 27-year-old male with extreme terminal pain, anhidrosis, abdominal pain, tinnitus, hearing impairment, cornea verticillata, and recurrent huge ulcers in the lower extremities. At the age of 16 years, he was diagnosed with Fabry disease with a positive family history and very low α-gal A activity. He then received enzyme replacement therapy (ERT) with recombinant human agalsidase beta at 1 mg/kg every 2 weeks for 10 years. Throughout the course of ERT, his leg ulcers recurred, and massive excretion of urinary globotriaosylceramide and plasma globotriaosylsphingosine was observed. Electron microscopy of the venous tissue in the regions of the ulcer showed massive typical zebra bodies in the vascular wall smooth muscle cells.

Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene

“…The level of α-gal A activity was measured as previously reported [28]. In short, lymphocytes and skin fibroblasts (SFs) were sonicated, and the whole cell lysates were incubated with a mixture containing 700 mM 4-methylumbelliferyl-α- d -galactopyranoside (4 MUGal; Sigma), 0.5 M N -acetyl- d -galactosamine (GalNAc; Sigma), and 50 mM citrate-phosphate (pH 4.5) buffer in a water bath at 37 °C for 3 h. The reactions were stopped with 150 mM ethylenediaminetetraacetic acid (pH 11.5) buffer.…”

“…Quantification of lyso-Gb3 was performed as described before [28]. In short, 60 μL fresh plasma was separated from whole blood and placed into a 1.5 mL tube containing 540 μL 2-propanol (HPLC-grade, Kanto, Japan) and 20 μL internal standard.…”

A Cross-Sectional Study of the Dermatological Manifestations of Patients with Fabry Disease and the Assessment of Angiokeratomas with Multimodal Imaging

“…To the best of our knowledge, only two case studies have mentioned varicose veins in Fabry disease. One of the cases presented bilateral leg ulcers at an early age where venography revealed venous reflux and varicose veins, and further exploration of the family history led to the diagnosis of Fabry disease [28]. The other case report merely noted the presence of lower extremity varicose veins [29].…”

An overlooked cutaneous manifestation of Fabry disease: Lower‐extremity ulcers

“…It is not clear which pathogenetic mechanisms play roles in the development of these ulcers. Okada et al reported a patient with multiple leg ulcers that were refractory to enzyme replacement therapy, and they were able to show venous reflux and varices on the leg venography of their patient. They identified lysosomal deposition of glycosphingolipid as a zebra body in vascular smooth muscle cells and a few accumulations in the vascular endothelium on electron micrograph of the venous biopsy.…”