Clinical features of hereditary transthyretin amyloidosis-polyneuropathy with transthyretin Ala97Ser(p.Ala117Ser) mutation in South Mainland China

Abstract

Objective: Our study aimed to report the clinical features and epidemiological characteristics of hereditary transthyretin amyloidosis-polyneuropathy(ATTRv-PN) with TTR Ala97Ser(p.Ala117Ser) mutation from South Mainland China.

Methods: We identified 21 patients from 20 families diagnosed with Ala97Ser ATTRv-PN based on strict clinical and electrophysiological criteria from three centers. Clinical and laboratory data were retrospectively retrieved for analysis.

Results: A gender imbalance was noted with a male-to-female ratio of 18:3. All patients showed late onset, with the age of onset at 56.5 ± 7.2 years. The predominant initial symptom, reported by 15 patients (71.4%), was numbness. Paraesthesia was present in all patients. Eighteen patients (85.7%) had autonomic dysfunction. Cardiac, renal, and ocular dysfunctions were noted in 17 (80.9%), 4(19.0%), and 4(19.0%) patients, respectively. Nerve conduction studies have shown axonal-type sensorimotor polyneuropathy. The decline in sensory nerve action potentials was more noticeable than in compound muscle action potentials. The nerve damage present in the lower limbs was more severe than that in the upper limbs. Nerve biopsy revealed positive Congo red staining in 11/15 patients (73.3%).

Conclusion: ATTRv-PN appears relatively rare in South Mainland China, with our study providing the largest cohort of Ala97Ser mutation cases to date. We found a significant founder effect by combining the clinical and demographic characteristics. That helps us understand the gene's transmission pathway and lays the foundation for carrier screening and tertiary prevention and control. We also propose a new scoring model and demonstrate that this model allows the profiling of different genotypes of ATTRv-PN, facilitating early clinical detection and diagnosis.

Keywords: TTR gene mutation; Clinical feature; Hereditary transthyretin amyloidosis (ATTRv); Scoring model.

Fig. 1

Geographical distribution of the probands with Ala97Ser (p.Ala117Ser) ATTRv-PN. The dark blue region: 10 patients from Hunan province, China. The middle dark blue region: 7 patients fromGuangdong province, China. The light blue region: 3 patients from Fujian province, China. The gray region: 1 patient from Shanghai, China

Fig. 2

Various systems dysfunction scores of the probands with Ala97Ser (p.Ala117Ser) ATTRv-PN. P1-21: No. 1–21 patient. Radar Map (a) and Line Chart (b) show the various system dysfunction scores of all patients based on supplementary Table 1. One point for each of the following symptoms: Paresthesia, Sensory dissociation, allodynia, weakness, amyotrophy, decreased reflexes, carpal tunnel syndrome, diarrhea, constipation, weight reduction, orthostatic hypotension, hyperhidrosis, erectile dysfunction, urine retention, arrhythmia, cardiac hypertrophy, symptomatic heart failure, Gastrointestinal symptoms, renal dysfunction, vision loss, vitreous opacity, cataract, glaucoma

Fig. 3

Histopathologic findings of No.10 Patient. HE (a) and Congo red staining (c) observed multiple red-stained amyloid deposits. MGT staining found axonal degeneration of green substances in some large myelinated fibers (b). Moderately to severely decreased unmyelinated nerve fibers in each nerve bundle were shown by NF staining (d)

Fig. 4

Tc-99 m Pyrophosphate (PYP) Scintigraphy of NO.21 Patient. The result showed tracer retention in the anterior wall (counts were 497 K both at 1 h and 3 h post-injection), and the local uptake ratio was elevated (D/E = 1.99, F/G = 1.81), which is consistent with the imaging features of ATTR amyloid cardiomyopathy