Clinical Cues for the Early Diagnosis of Transthyretin-Related Polyneuropathy

Abstract

Background and purpose: The estimated prevalence of hereditary transthyretin-related familial amyloid polyneuropathy (TTR-FAP) and the small number of known patients in Germany indicate that many patients with TTR-FAP remain undiagnosed, and may instead be classified as "idiopathic." The aim of this study was to identify biomarkers for detecting TTR-FAP among a cohort of patients with idiopathic polyneuropathy (PNP).

Methods: Clinical evaluations (including the Neuropathy Impairment Score and Neuropathy Disability Score), nerve conduction studies (NCSs), quantitative sensory testing, and autonomic function tests were performed on 23 patients with TTR-FAP and 89 with idiopathic PNP. Discriminant analysis was then performed to identify variables useful for predicting TTR-FAP.

Results: Patients with TTR-FAP had paresis of the finger and thumb muscles, and reduced vibration perception and increased pressure pain in the upper and lower extremities. The NCSs showed that action potentials were smaller in the median, ulnar (both motor and sensory), and sural nerves in TTR-FAP. The sensory nerve conduction velocity was also reduced in the ulnar nerve. Autonomic neuropathy was confirmed by reduced sympathetic skin responses in the hands and feet in TTR-FAP. Multivariate discriminant analysis revealed that finger abduction strength, sensory ulnar nerve action potential amplitude, and vibration detection and pressure pain thresholds in the upper extremities were sufficient to correctly identify TTR-FAP in 81.3% of cases.

Conclusions: Detailed clinical and neurophysiological investigations of standard parameters in the upper limb may help to identify the otherwise-rare TTR-FAP.

Keywords: amyloidosis; neurophysiology; polyneuropathy; quantitative sensory testing; transthyretin.

Fig. 1. Results of the pain pressure (A) and vibration (B) tests in the upper limbs. Patients with TTR-FAP were more sensitive to pain pressure in the upper and lower limbs. Vibration perception at the wrist was impaired more in patients with TTR-FAP. ^*p<0.05; ^**p<0.01. Idiop, idiopathic; LL, lower limb; PPT, pressure pain threshold; TTR-FAP, transthyretin-related familial amyloid polyneuropathy; UL, upper limb.

Fig. 2. Differences in action potential amplitudes in nerve conductions studies. Patients with TTR-FAP presented with smaller motor nerve potentials in the median and ulnar nerves. Sensory nerve potentials were also smaller in the median, ulnar, and sural nerves, which is a sign of further axonal damage in this group. ^*p<0.05; ^**p<0.01; ^***p<0.001. Idiop.PNP, idiopathic polyneuropathy; m, motor nerve potential; NCS, nerve conduction study; s, sensory nerve potential; TTR-FAP, transthyretin-related familial amyloid polyneuropathy.

Fig. 3. SSR results in both the upper and lower limbs. Autonomic dysfunction in the TTR-FAP group was evident from lower SSR amplitudes in the upper and lower extremities. ^***p<0.001; ^****p<0.0001. Idiop, idiopathic; LL, lower limb; SSR, sympathetic skin response; TTR-FAP, transthyretin-related familial amyloid polyneuropathy; UL, upper limb.