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

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.

Hereditary transthyretin amyloidosis-polyneuropathy (ATTRv-PN) is an autosomal dominant genetic disorder caused by point mutations of the TTR gene. It is characterized by amyloid deposition in many systems including the peripheral and autonomic nervous system [1external link, opens in a new tab]. It is a systemic disease that involves various organs (such as the heart, eyes, and kidney) and usually presents as progressive peripheral neuropathy with adult-onset. In 1952, Andrade first described ATTRv-PN in northern Portugal [2external link, opens in a new tab]. It was subsequently reported in Japan (1968) [3external link, opens in a new tab] and Sweden (1976) [4external link, opens in a new tab]. ATTRv-PN has been reported in 29 countries, including Korea [5external link, opens in a new tab], the United States of America [6external link, opens in a new tab], China [7external link, opens in a new tab], Thailand [8external link, opens in a new tab], and many European countries [9external link, opens in a new tab].

The TTR gene is located on chromosome 18 and comprises four exons [10external link, opens in a new tab]. More than 130 mutations have been identified associated with this gene [1external link, opens in a new tab]. The Val30Met (p.Val50Met) variant of TTR is most commonly identified among patients living in small clusters and scattered families worldwide and was first described as the cause of ATTRv-PN in 1984 [11external link, opens in a new tab]. Moreover, certain specific mutations are associated with small clusters of families in particular areas. For example, the TTR Ala97Ser (p.Ala117Ser) mutation is common among Chinese kindreds from the Taiwan area [12external link, opens in a new tab,13external link, opens in a new tab,14external link, opens in a new tab,15external link, opens in a new tab]. However, this mutation seems to be mainly distributed in South Mainland China. Subsequently, the first ATTRv-PN family with a proven missense mutation c.349G > T Ala97Ser in Southern Mainland China was reported in 2018 [16external link, opens in a new tab]. Through investigating several ATTRv-PN centers in China, we found a founder effect in patients with Ala97Ser mutation in South China, and it may be related to patients in the Taiwan area. The study aimed to document the distribution features of ATTRv-PN with Ala97Ser mutation and summarize its characteristic clinical manifestations. ATTRv-PN appears relatively rare in China, while our research provides the largest cohort of Ala97Ser mutation cases to date.

Patients

We identified 21 patients from 20 distinct families diagnosed with Ala97Ser ATTRv-PN, based on strict clinical and electrophysiological criteria from the Department of Neurology of three centers: Southern Medical University Nanfang Hospital, Peking University First Hospital, Central South University Third Xiangya Hospital, September 2013 to September 2024. All patients signed an informed consent form prior to inclusion in the study. All patients conformed to the latest diagnostic criteria for ATTRv-PN, particularly the typical pathological features of the nerve biopsy, mutations in the TTR Ala97Ser gene, and the exclusion of other diseases. Furthermore, the clinical and laboratory data were retrieved for analysis. Procedures of the tests (nerve conduction study(NCS), ultrasonic cardiogram (UCG), cerebrospinal fluid (CSF) examination, routine blood and urine examinations, genetic analysis, nerve biopsies, etc.) followed established protocols.

TTR gene analysis

Peripheral venous blood samples were obtained for DNA analysis from the patients. Genomic DNA was isolated from the blood samples following a standard protocol. Briefly, the four exons of the entire human TTR gene (NCBI Reference Sequence: NG_009490.1, NM_000371.3) were amplified by polymerase chain reaction (PCR). The PCR products were purified and sequenced directly by Sanger sequencing.

Electrophysiologic assessment

Neuroelectrophysiological assessment was done in all patients following standard procedures with surface stimulating and recording electrodes, including nerve conduction studies (orthodromic recording) of motor and sensory nerves at the lower and upper limbs in combination with the test of F wave. Motor conduction was investigated in the median, ulnar, tibial, and common peroneal nerve. Sensory conduction was investigated in the median, ulnar, superficial fibular, and sural nerves.