Objective: To investigate the small fibers pathology in Friedreich´s Ataxia (FRDA).

Background: FRDA is an inherited movement disorder caused by homozygous GAA expansions in the FXN gene. FRDA manifests with progressive gait instability, sensory loss and non-neurological features such as pes cavus, scoliosis and cardiomyopathy. Typically, FRDA affects dorsal root ganglia and large myelinated fibers in dorsal spinal roots and peripheral nerves. Sparse findings from sural nerve and skin biopsies suggest that also unmyelinated small fibers may be affected.

Methods: Genetically confirmed FRDA patients and healthy controls were enrolled at the Department of Neurology of Innsbruck Medical University. Impaired glucose tolerance, vitamin B12 and folate deficiency were set as exclusion criteria. Study-related examinations included: intraepidermal nerve fibers (IENF) quantification in the distal leg, quantitative sensory testing (QST), skin sympathetic reflex (SSR) and cardiovascular autonomic testing. Autonomic symptoms were investigated by means of the SCOPA-aut questionnaire. Disease severity was quantified with the SARA scale.

Results: Twenty-three patients were recruited (Age= 40±13 years, SARA=21±8). IENF density (14 patients) was significantly reduced compared to controls (IENF_log10 FRDA=0,48±0,11, Controls=0,95±0,2; p=0,000001). IENF density values were extremely variable within the patient group and showed a strong inverse correlation with the shorter GAA expansion (R2=0.861, p=0,000002). Temperature and pain perception at QST (14 FRDA) did not differ between patients and controls, although a tendence towards a higher mechanical pain threshold was noticed in the firsts (FRDA=512(256;512), Controls=256 (171;512), p=n.s.). Findings at autonomic testing (13 FRDA) were comparable to that of controls, except for higher heart rate during rest and at head-up tilt in FRDA. Two patients had orthostatic hypotension and 3 had absent SSR (Age: 52, 60 and 37). Symptoms referred to multiple autonomic domains, particularly bladder function, thermoregulation and sweating, were reported. SCOPA-aut scores (FRDA=5,5(4,8;15,5)) showed a weak correlation with IENF density (R2=0.376, p=0,026).

Conclusions: FRDA patients show marked small fibers abnormalities. The severity of epidermal denervation strongly correlates with the underlying genetic defect. Clinically, only mild signs of small fibers dysfunction are detected.

References: 1. Nolano M, Provitera V, Crisci C, Saltalamacchia AM, Wendelschafer-Crabb G, Kennedy WR, et al. Small fibers involvement in Friedreich’s ataxia. Ann Neurol. 2001;50(1):17-25. 2. Koeppen AH, Mazurkiewicz JE. Friedreich ataxia: neuropathology revised. J Neuropathol Exp Neurol. 2013;72(2):78-90.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-clinical-and-pathological-study-of-small-fibers-in-friedreichs-ataxia/