Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease

Abstract

Fabry disease is an X-linked disorder caused by a deficiency of lysosomal alpha-galactosidase A resulting in accumulation of alpha-D-galatosyl conjugated glycosphingolipids. Clinical manifestations include a small-fiber neuropathy associated with debilitating pain and hypohidrosis. We report the effect of a 3-year open-label extension of a previously reported 6-month placebo-controlled enzyme replacement therapy (ERT) trial in which 26 hemizygous patients with Fabry disease received 0.2 mg/kg of alpha-galactosidase A every 2 weeks. The effect of ERT on neuropathic pain scores while off pain medications, quantitative sensory testing, quantitative sudomotor axon reflex test (QSART), and thermoregulatory sweat test (TST) is reported. In the patients who crossed-over from placebo to ERT (n = 10), mean pain-at-its-worst scores on a 0-10 scale decreased (from 6.9 to 4.5). There was a significant reduction in the threshold for cold and warm sensation in the foot. At the 3-year time-point, pre-ERT sweat excretion in 17 Fabry patients was 0.24 +/- 0.33 microl/mm(2) vs. 1.05 +/- 0.81 in concurrent controls (n = 38). Sweat function improved 24-72 h post-enzyme infusion (0.57 +/- 0.71 microl/mm(2)) and normalized in four anhidrotic patients. TST confirmed the QSART results. We conclude that prolonged ERT in Fabry disease leads to a modest but significant improvement in the clinical manifestations of the small-fiber neuropathy associated with this disorder. QSART may be useful to further optimize the dose and frequency of ERT.

Immune‐Mediated Myocarditis in Fabry Disease Cardiomyopathy

“…The heart is a major target of FD, and its involvement strongly influences life expectancy that was reduced, before ERT introduction, to 58.2 years for men and to 75.4 years for women 21. The impact of ERT on FDCM is still controversial because some studies show benefits from ERT administration in terms of relief,8, 9, 10 and others deny benefits, reporting an unaffected progressive trend 11, 12. Most experts agree on evidence showing that early ERT administration, particularly in prehypertrophic FDCM (MWT <11 mm), prevents disease progression, whereas the advanced form (MWT >15 mm) appears to be irreversible 12.…”

“…Indeed, the impact of enzyme replacement therapy (ERT) on FDCM is still controversial,8, 9, 10, 11, 12 and although there is agreement that early ERT administration, particularly in prehypertrophic FDCM, prevents progression of the disease, the advanced form is believed to be irreversible.…”

Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease

“…Although the pivotal clinical trials with ERT intimated a reduction in pain, longer-term studies in adults on ERT have been met with mixed results because treatment initiation typically began in the fourth to fifth decades of life (7,(11)(12)(13)(14). On the basis of the clinical experience with ERT, it is evident that Fabry patients may benefit from earlier ERT as well as from new adjunctive therapies that can more effectively reduce systemic substrate accumulation.…”

Cellular and tissue distribution of intravenously administered agalsidase alfa

“…Increased sweating and probably slowing of the progression of renal disease in adult male Fabry patients. [7][8][9]. While noncontrolled studies suggest reduction in left ventricular mass, the clinical impression thus far is that there has been no reduction in the incidence of stroke [10,11].…”