Sudomotor innervation in transthyretin amyloid neuropathy: Pathology and functional correlates

Abstract

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

Cutaneous nerve biomarkers in transthyretin familial amyloid polyneuropathy

“…This compares favorably with biopsies from other tissue sources including sural nerve, fat pad, and salivary gland biopsies. 11,34 In such studies, Congo red staining without birefringence was observed in the epidermis and diffusely throughout the sweat glands, which we not did observe in our disease controls. This strategy allowed us to assess larger portions of the sample with fewer sections, as well as to convincingly wtTTR protein stained prominently in healthy control epidermis (B, arrows), whereas there was little wtTTR staining in the epidermis from TTR-FAP subjects (D, arrow).…”

“…The striking presence of endoneurial and dermal collagen amyloid that often engulfs dermal nerve fibers suggests that axonal loss might result from amyloid-induced compression and that arteriole involvement accelerates the injury through a superimposed ischemia. 11 Additionally, we observed that proximal thigh IENFD and SGNFD were reduced in TTR-FAP patients compared to age-/gender-matched controls. 9,38,39 Cutaneous Nerve Fiber Densities in TTR-FAP and TTR-noPN We observed that unmyelinated nerve fiber densities, including IENFD, SGNFD, and PMNFD, were markedly reduced at the distal leg in TTR-FAP patients.…”

“…11,[31][32][33] We used 50 mm sections, in contrast to 8 mm sections that are typically used to assess fat pad biopsies. This compares favorably with biopsies from other tissue sources including sural nerve, fat pad, and salivary gland biopsies.…”

New technologies for the assessment of neuropathies

“…Studies have also shown that skin biopsy can not only provide structural and pathological evidence of nerve degeneration, but also provide surrogate markers of function, thereby widening the applications of skin biopsy in assessing the involvement of the peripheral autonomic system and as a potential outcome measure in clinical trials. For example, reductions in sudomotor innervation correlated with autonomic symptoms, progressive disability and reduced performance in autonomic functional tests in 28 patients with familial amyloid neuropathy 138 . In 97 patients with diabetic neuro pathy, innervation of sweat glands correlated with glycated haemoglobin and BMI 139 .…”

The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations

“…Patients with SFN followed for approximately 2.5 years showed progression of epidermal nerve fiber loss although healthy control subjects maintained stable nerve fiber densities [98]. Similarly, loss of epidermal nerve fibers can be seen in individuals with transthyretin familial amyloid polyneuropathy before large fiber involvement becomes evident [35, 116]. In patients followed longitudinally before, during, and after oxaliplatin chemotherapy, IENFD testing performed as well as a composite score of signs, symptoms, and nerve conduction results in assessing the progression of chemotherapy-induced peripheral neuropathy [29].…”