Skin denervation was common in Ala97Ser, and degeneration of cutaneous nerve terminals was correlated with the severity of clinical phenotypes and the level of CSF protein.

ObjectiveAutonomic neuropathy is a major component of familial amyloid polyneuropathy (FAP) due to mutated transthyretin, with sudomotor failure as a common manifestation. This study aimed to investigate the pathology and clinical significance of sudomotor denervation.MethodsSkin biopsies were performed on the distal leg of FAP patients with a follow‐up duration of 3.8 ± 1.6 years. Sudomotor innervation was stained with 2 markers: protein gene product 9.5 (PGP 9.5), a general neuronal marker, and vasoactive intestinal peptide (VIP), a sudomotor nerve functional marker, followed by quantitation according to sweat gland innervation index (SGII) for PGP 9.5 (SGIIPGP 9.5) and VIP (SGIIVIP).ResultsThere were 28 patients (25 men) with Ala97Ser transthyretin and late onset (59.9 ± 6.0 years) disabling neuropathy. Autonomic symptoms were present in 22 patients (78.6%) at the time of skin biopsy. The SGIIPGP 9.5 and SGIIVIP of FAP patients were significantly lower than those of age‐ and gender‐matched controls. The reduction of SGIIVIP was more severe than that of SGIIPGP 9.5 (p = 0.002). Patients with orthostatic hypotension or absent sympathetic skin response at palms were associated with lower SGIIPGP 9.5 (p = 0.019 and 0.002, respectively). SGIIPGP 9.5 was negatively correlated with the disability grade at the time of skin biopsy (p = 0.004), and was positively correlated with the interval from the time of skin biopsy to the time of wheelchair usage (p = 0.029).InterpretationThis study documented the pathological evidence of sudomotor denervation in FAP. SGIIPGP 9.5 was functionally correlated with autonomic symptoms, autonomic tests, ambulation status, and progression of disability. Ann Neurol 2015;78:272℃283

Previous assessments of the sudomotor system have depended on functional tests, and only a few studies document the pathologic findings of postganglionic nerve degeneration quantitatively and at the ultrastructural level. We developed a quantitative system of sudomotor innervation in skin biopsies of the distal leg by immunostaining of nerve fibers with anti-protein gene product 9.5 (PGP9.5) and by counterstaining with Congo red. A computerized area-based morphometric analysis was used to quantify the sweat gland innervation index (SGII), defined as the area of nerve fibers normalized to the area of sweat glands. This approach reduced the variations in measurements of sweat gland areas compared to the commonly used method by ∼5.6-fold (2.47% ± 2.54% vs 13.97% ± 14.24%, p < 0.001); hence, variations in SGII were also reduced. We examined 35 Type 2 diabetic patients (24 men and 11 women; mean age, 56.5 ± 12.8 years), with symmetrical length-dependent neuropathy and reduced intraepidermal nerve fiber density (0.76 ± 0.95 fibers/mm). By light and electron microscopy, PGP9.5-positive nerve terminals surrounded Congo red-positive sweat gland secretory coils in controls; these periglandular nerve terminals were either absent or markedly reduced in diabetic patients. Diabetic patients had lower SGII values than age- and sex-matched controls (2.60% ± 1.96% vs 4.84% ± 1.51%, p < 0.0001). The SGII values were lower in patients with anhidrosis of the feet versus those with normal sweating of the feet (0.89% ± 0.71% vs 3.10% ± 1.94%, p < 0.01). Thus, skin biopsy offers combined assessment of sudomotor innervation.