Small fibers in Fabry disease: baseline and follow-up data under enzyme replacement therapy

Abstract

Fabry disease (FD) is an X-linked lysosomal storage disorder which may lead to impaired peripheral nerve function, mostly affecting small nerve fibers, and to neuropathic pain. Characteristics of the neuropathy associated with FD and the covariates for its development and temporal course have not been described in a large cohort. We studied small fiber function and morphology in 120 Fabry patients at baseline and in subgroups of these until 4-year follow-up. Baseline neurological (89/120) and electrophysiological (106/120) examination was mostly normal. Quantitative sensory testing revealed impaired cold detection thresholds in 84% of men and 39% of women. Lower leg intraepidermal nerve fiber density (IENFD) was reduced to 46% in Fabry patients compared to controls and to 12.5% in men with impaired renal function. Patients with abnormal IENFD more often had pain. Group means for IENFD did not improve under enzyme replacement therapy (ERT), but IENFD in the back increased under ERT in 4/15 patients with good renal function and clinical improvement. Cutaneous cytokine gene expression did not differ from controls. We conclude that ERT may improve proximal skin innervation in patients with good renal function, but does not protect small fiber function in men with impaired renal function.

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

“…However, the data here suggest that the small molecule, perhaps given its greater exposure in the peripheral and CNS was more effective. Moreover, improvements in small fiber neuropathy and neuropathic pain have been reported in patients treated with agalsidase β (11) and agalsidase α (14). Intervening early may be an important consideration, because the small fiber peripheral neuropathy is likely due to nerve fiber loss.…”

“…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.…”

Uncertain Diagnosis of Fabry Disease in Patients with Neuropathic Pain, Angiokeratoma or Cornea Verticillata: Consensus on the Approach to Diagnosis and Follow-Up

“…The neuropathic pain that is caused by FD has a characteristic presentation and is related to the presence of SFN. In 95% of male and 75% of female FD patients, an abnormal heat detection threshold for cold and/or diminished intraepidermal nerve fibre density is found (Biegstraaten et al 2011(Biegstraaten et al , 2012Uceyler et al 2011). In case of a variant in the GLA gene and the presence of neuropathic pain in hands and feet starting at childhood and increasing with heat/fever (Biegstraaten et al 2012;Uceyler et al 2013), there is no known alternative diagnosis.…”

The neurological manifestations of Fabry disease. A review

“…Лечение эффективно при гипертрофии левого желудочка, [105,106]. Заместительная терапия эффектив-на при легком и умеренном поражении почек, но неэф-фективна в тяжелых случаях (при протеинурии >1 г/сутки и грубом снижении уровня клубочковой фильтрации) [107][108][109]. При раннем начале лечения отмечается улуч-шение функционирования ЖКТ [110][111][112].…”