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This study was performed to assess cutaneous nerve fibre loss in conjunction with temperature and sweating dysfunction in familial dysautonomia (FD). In ten FD patients, we determined warm and cold thresholds at the calf and shoulder, and sweating in response to acetylcholine iontophoresis over the calf and forearm. Punch skin biopsies from calf and back were immunostained and imaged to assess nerve fibre density and neuropeptide content. Mean temperature thresholds and baseline sweat rate were elevated in the patients, while total sweat volume and response time did not differ from controls. The average density of epidermal nerve fibres was greatly diminished in the calf and back. There was also severe nerve loss from the subepidermal neural plexus (SNP) and deep dermis. The few sweat glands present within the biopsies had had reduced innervation density. Substance P immunoreactive (-ir) and calcitonin gene related peptide-ir (CGRP-ir) were virtually absent, but vasoactive intestinal peptide-ir (VIP-ir) nerves were present in the SNP. Empty Schwann cell sheaths were observed. Temperature perception was more impaired than sweating. Epidermal nerve fibre density was found to be profoundly reduced in FD. Decreased SP and CGRP-ir nerves suggest that the FD gene mutation causes secondary neurotransmitter depletions. Empty Schwann cell sheaths and VIP-ir nerves suggest active denervation and regeneration.
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