Clinical features of familial amyloidotic polyneuropathy with transthyretin p.Ala117Ser mutation in South Mainland China

Clinical features of familial amyloidotic polyneuropathy with transthyretin p.Ala117Ser mutation in South Mainland China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical features of familial amyloidotic polyneuropathy with transthyretin p.Ala117Ser mutation in South Mainland China Yeli Zhu, Jingxian Fan, Xiying Zhu, Wei Li, Zhaoyong Zhang, Hui Zheng, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5950252/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Apr, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 5 You are reading this latest preprint version 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(p.Ala117Ser) 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(p.Ala117Ser) 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 (ATTRv) TTR gene mutation clinical feature scoring model Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction 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 [ 1 ] . 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 [ 2 ] . It was subsequently reported in Japan (1968) [ 3 ] and Sweden (1976) [ 4 ] . ATTRv-PN has been reported in 29 countries, including Korea [ 5 ] , the United States of America [ 6 ] , China [ 7 ] , Thailand [ 8 ] , and many European countries [ 9 ] . The TTR gene is located on chromosome 18 and comprises four exons [ 10 ] . More than 130 mutations have been identified associated with this gene [ 1 ] . The p.Val30Met 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 [ 11 ] . 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 [ 12 – 15 ] . 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 (p.Ala117Ser) in Southern Mainland China was reported in 2018 [ 16 ] . Through investigating several ATTRv-PN centers in China, we found a founder effect in patients with Ala97Ser (p.Ala117Ser) 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 (p.Ala117Ser) and summarize its characteristic clinical manifestations. ATTRv-PN appears relatively rare in China, while our research provides the largest cohort of Ala97Ser (p.Ala117Ser) mutation cases to date. Subjects and Methods Patients We identified 21 patients from 20 distinct families diagnosed with Ala97Ser (p.Ala117Ser) 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 (p.Ala117Ser) 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. Nerve biopsy and pathological assessment A sural nerve (or sensory branch of the superficial peroneal nerve) biopsy was performed under local skin and tissue anesthesia, excluding the nerve. Nerve specimens were processed for routine stains (hematoxylin-eosin for overview and nerve morphology; Staining with TTR antibody and Congo red for amyloid) on frozen and semi-thin sections (azure-methylene blue). Serial consecutive sections were assessed. Electron microscopy samples were fixed in a 2.5% glutaraldehyde buffer for 2h, then with osmium acid, dehydrated in acetone, and embedded with epoxy resin. The sections were observed and photographed under an electron microscope. Multisystem evaluation Subsequently, we facilitated the diagnostic process through a comprehensive assessment of pathological changes in multiple organ systems, including the peripheral nervous system, autonomic nervous system, cardiovascular system, renal system, and ocular system. Peripheral neuropathy is assessed through neurological examination, electromyography (EMG), and nerve biopsy to quantify axonal or demyelinating damage. Autonomic dysfunction is evaluated via symptom profiling (e.g., orthostatic intolerance, gastrointestinal dysmotility) combined with orthostatic blood pressure testing to identify hemodynamic instability. Cardiac involvement requires multimodal imaging and functional analyses, including electrocardiography (ECG) for arrhythmia detection, echocardiography (Echo) to assess chamber dimensions and ejection fraction, and myocardial Tc-99m Pyrophosphate (PYP) Scintigraphy to delineate amyloid deposition or perfusion defects. Renal function is systematically monitored through serial measurements of serum creatinine (Scr) and urinary protein quantification (e.g., 24-hour proteinuria or urine protein-to-creatinine ratio) to stage chronic kidney disease. Ocular pathology is investigated by correlating subjective visual complaints (e.g., scotomas, blurred vision) with objective findings on fundoscopy, such as vitreous opacities or retinal vascular abnormalities, to confirm visual pathway compromise. Statistical analyses We used IBM SPSS Version 25 and Microsoft Office Excel. Descriptive statistics are mainly used in this study. Numeric variables are here described as means ± SD, numbers (n) with percentages (%) or median values, etc. Results were considered significant at p<0.05. Results Clinical features The basic information of the probands (18 males and 3 females) in the 20 families with Ala97Ser (p.Ala117Ser) ATTRv-PN is summarised in Table 1. All probands were from South Mainland China (see Figure 1). The age of onset was 56.5 ± 7.2 years (range 40-66). The period from the onset to the final diagnosis was 4.9 ± 3.9 years (range 0–13), and neurological assessments were performed at the time of diagnosis. Initial symptoms were numbness of the lower or upper extremities (15 patients), weakness of the lower limbs (2 patients), diarrhea and constipation (1 patient), erectile dysfunction (1 patient), Decreased exercise tolerance (1 patient), and chest tightness (1 patient). No cranial nerve defects, such as dysphagia, dysarthria, or hypertrophy of the tongue, were observed in any of the patients. The clinical manifestations are shown in supplementary table 1. Fifteen patients suffered from muscular weakness and amyotrophy in the upper and lower limbs to varying degrees in a distally accentuated manner. Paraesthesia was noted in all patients. Almost half of the patients experienced pain in the upper or lower limbs, although sensory dissociation was not conspicuous. Decreased tendon reflexes and carpal tunnel syndrome were prominent in most patients. Eighteen patients complained of autonomic dysfunction during the duration of the disease. However, specific symptoms varied from patient to patient. Constipation was observed in 11 patients. Six of the 11 patients complained about alternating occurrences of diarrhea and constipation. Seventeen patients experienced weight loss. Orthostatic hypotension was seen in seven patients. Erectile dysfunction was observed in 9 /18 male patients. Only four patients had hyperhidrosis. Two patients complained of disturbances in urination (urine retention). Additionally, the involvement of other organs was seen in seventeen patients by means of the multisystemic assessment described in the methods section. Cardiac dysfunction was the most common (17 patients), specifically arrhythmia, cardiac hypertrophy, and symptomatic heart failure. Only 4 patients had renal dysfunction (manifested by abnormal 24-hour urine protein quantification). Four patients experienced ocular dysfunction: decreased vision (4 patients), vitreous opacity (1 patient), and cataract (1 patient). However, none of the patients had glaucoma. Other symptoms included edema (8 patients), dry cough (8 patients), and hemorrhagic rash (2 patients). The various system dysfunction scores of the probands are shown in Figure 2. Neurophysiological manifestations NCS showed axonal-type sensorimotor polyneuropathy (detailed in Table 2). Most patients had long distal latency of the upper or lower extremities, but it was much smaller than in demyelinating neuropathies. All patients had reductions in the amplitudes of compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) from mild to severe. It is worth noting that the decline in SNAP was more noticeable than that in CMAP. The nerve damage of the lower limbs was more severe than that of the upper limbs. The SNAP of most of the lower extremities was not observed. Additionally, a decrease in the F wave was observed in nearly all tested nerves. Histopathological findings Fifteen patients underwent a sural or peroneal nerve biopsy. The main pathological changes in peripheral nerves were moderate to severely decreased myelinated and unmyelinated nerve fibers, accompanied by degenerative or regenerative changes in the axons and myelin sheath of myelinated nerve fibers, which is following the pathological characteristics of chronic active mixed peripheral neuropathy. Nerve biopsy revealed positive Congo red staining in 11/15 patients (73.3%). Congo red staining showed multiple red-stained amyloid deposits and bright apple-green coloration under a polarising microscope. MGT staining found axonal degeneration of green substances in some large myelinated fibers. The histopathologic findings of patient no. 10 are shown in Figure 3. Tc-99m Pyrophosphate (PYP) Scintigraphy Four patients underwent Tc-99m Pyrophosphate (PYP) Scintigraphy. Three of them demonstrated positive imaging findings indicative of transthyretin cardiac amyloidosis (ATTR-CA), meeting the 2020 AHA diagnostic criteria for cardiac amyloidosis with Grade 2-3 radiotracer uptake on visual grading. One patient did not fulfill the criteria for ATTR-CA positivity (Grade 0 per 2020 AHA classification). Representative imaging of Patient 21 is illustrated in Figure 4. Discussion ATTRv-PN appears relatively rare in South Mainland China, while our study provides the largest cohort of Ala97Ser (p.Ala117Ser) mutation cases. In the 1990s, a family with ATTRv-PN was first diagnosed at the Peking Union Medical College Hospital [ 17 ] . It is estimated that there are approximately 1997 cases in China [ 18 ] . Over 40 case reports have been published recently, including reports of multiple ATTRv-PN families. Studies describe a mutation in the TTR gene, different from that observed in Europe [ 7 , 19 – 21 ] . Shortly before, a unicentric retrospective study reported that TTR Val30Met (p.Val50Met) remains mainland China's most common mutation type [ 22 ] . However, TTR Ala97Ser (p.Ala117Ser) mutations are relatively rare. Based on previous studies, the TTR Ala97Ser (p.Ala117Ser) mutation was one of the most common variants in the Chinese population, especially in Chinese kindreds from the Taiwan area. This mutation has never been reported in Caucasian populations. Detailed haplotype analyses demonstrated a shared haplotype in most patients with the Ala97Ser (p.Ala117Ser) mutation in the Taiwan area, suggesting a founder effect [ 23 ] . This may be related to the late onset of ATTRv-PN and the early onset of symptoms, which are mild and do not interfere with fertility. Except for the first report of the ATTRv-PN family with a proven TTR Ala97Ser (p.Ala117Ser) mutation from mainland China [ 16 ] , our study reported another 20 pedigrees with the same mutation. Furthermore, all cases were from south China, especially Hunan and Guangdong provinces. Despite the lack of genetic verification, we speculate that the TTR Ala97Ser (p.Ala117Ser) mutation originated in South Mainland China. Our study demonstrated the characteristics of ATTRv-PN with the TTR Ala97Ser (p.Ala117Ser) mutation in mainland China. Similar to previous reports, significantly more men than women were diagnosed with this mutation. However, it is unclear whether there is a protective factor for women due to the small sample size and the possibility of selection bias. The Ala97Ser(p.Ala117Ser) patients showed late onset – almost all were over 50 years of age. It differed from Val30Met(p.Val50Met) patients, which showed early or late onset [ 24 ] . The course from the onset to final diagnosis ranged from 0 to 13 years, while there was no significant correlation between this and the severity of clinical manifestations. Numbness of the lower or upper extremities was among the most common initial symptoms. Due to its insidious onset, there is usually a delay in the diagnosis of this disease, which makes it difficult to treat. Apart from peripheral nerve dysfunction, autonomic dysfunction was also particularly prominent. Constipation was more common than orthostatic hypotension, and it (constipation) often manifested as alternating between diarrhea and constipation. Remarkably, almost all males had erectile dysfunction at an early stage, which is an important feature that differentiates them from female patients. Cardiac dysfunction was the most common involvement of other organs. One of the 21 patients died of a cardiac incident shortly after the diagnosis. A unique phenotype of ATTRv-PN has been reported in a case report describing a distinctive chronic dry cough [ 16 ] . In our study, eight patients had similar symptoms. It occurs at different stages of the disease. Further research is needed to confirm this mechanism. Although nerve biopsy helped diagnose the disease, not all patients in our study underwent a nerve biopsy. Only 11/15 (73.3%) patients showed positive Congo red staining. Patients with ATTRv-PN negative Congo red staining might get misdiagnosed. Interestingly, Neurophysiological examinations [ 25 ] , vagus nerve ultrasonography [ 26 ] , neurofilament light chain [ 27 ] , and skin biopsy [ 28 ] also helped with the diagnosis. The final diagnosis was based on genetic and pathological examinations. In the absence of definitive amyloid deposits, a definitive diagnosis needs to be made in the context of the previously described clinical manifestations of multisystem involvement, genetic evidence, and the exclusion of other diseases. In addition, many factors, such as the rarity of the disease in the general population, physicians’ lack of understanding of various clinical features, and limited diagnostic tools (i.e., histopathology and gene screening), lead to a high misdiagnosis rate and poor prognosis. ATTRv-PN is often misdiagnosed as chronic idiopathic axonal polyneuropathy, chronic inflammatory demyelinating polyneuropathy, and lumbar spinal stenosis. Diabetes or chronic alcoholism may cause polyneuropathies similar to ATTRv-PN. It may also be misdiagnosed as Charcot-Marie-Tooth or motor neuron disease. Delayed diagnosis is the main obstacle to the optimal management of ATTRv-PN in China. There is usually an interval of several years from the initial clinical symptoms of the disease to the final diagnosis. Because of the significant unmet medical needs for this rare and fatal disease, there is an urgent need to raise disease awareness to facilitate early diagnosis and timely treatment. Historically, mutations in the TTR gene have predominantly been associated with symptoms affecting the peripheral nerves and cardiac system. Consequently, existing literature has visually represented the proportion of peripheral nerve and cardiac impairments across various mutation sites, facilitating people's understanding of the clinical manifestations associated with different TTR gene mutation locations. However, it is important to note that TTR gene mutations can also impact other organs and systems, including the kidneys, eyes, and autonomic nervous system. Our study introduces a more comprehensive radar chart for multidimensional assessment, enhancing the graphical representation of clinical symptoms associated with different TTR gene mutation sites. Nonetheless, our study's sample size remained insufficient for robust statistical analysis, and all cases were sourced exclusively from southern China. Consequently, these findings may not be representative of the rest of China or the world, thereby constraining the generalizability and precision of the results. Moreover, this study was conducted retrospectively, which introduced challenges such as incomplete data and selection bias. Notably, there was a disproportionate male-to-female ratio among the participants, and a significant delay was observed between the onset of symptoms and the final diagnosis. The retrospective design further precluded the possibility of patient follow-up, resulting in a deficiency of information regarding patient treatment and prognosis. These limitations may have impeded the precise assessment and comprehensive understanding of the disease under investigation. Although the TTR gene was examined in all participants of this study, other potential genetic variants and gene-environment interactions were not analyzed or discussed. These aspects need further investigation in more comprehensive and detailed studies. Conclusion Our findings elucidate the clinical spectrum of ATTRv-PN associated with the TTR Ala97Ser (p.Ala117Ser) mutation in Southern China, underscoring the need for more extensive, multi-centric studies to fully delineate the disease's impact. Declarations Funding Supported by grants from Horizontal projects funded by Pfizer（74310325）and the Nanfang Hospital Baiyun Branch Dean’s Fund (BYYZ24007). Availability of data and materials The data sets generated and analyzed during the current study are available from the corresponding author upon reasonable request. All data generated and analyzed during this study are included in this article. Acknowledgements We thank the patients who participated in this study. We thank the professors of Peking University First Hospital, Third Xiangya Hospital of Central South University, for providing valuable cases. We thank the technicians in the Neuromuscular Pathologic Team, Electron Microscope Room, and Neurophysiology Room of Nanfang Hospital of Southern Medical University, Department of Neurology, for their assistance. Author Information Affiliations Department of Neurology, Southern Medical University Nanfang Hospital, Southern Medical University, Guangzhou, China Yeli Zhu, Jingxian Fan,Wei Li, Zhaoyong Zhang, Hui Zheng, Haishan Jiang Department of Neurology, Central South University Third Xiangya Hospital, Central South University, Hunan, China Xiying Zhu, Ruxu Zhang Department of Neurology, Peking University First Hospital, Peking University, Beijing, China Lingchao Meng Department of Neurology, The First affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China Zhihua Zhou Contributions YZ, JF and XZ wrote and edited the manuscript. WL contributed pathological assessment. ZZ and HZ designed the figures and tables. ZZ, LM, RZ and HJ provided clinical samples and information. Corresponding Author Correspondence to Lingchao Meng, Ruxu Zhang& Haishan Jiang Conflicts of interest The authors declare that there is no conflict of interest. Ethics declarations Ethics approval and consent to participate Approved by Medical Ethics Committee of Southern Medical University Southern Hospital. Consent for publication Not applicable. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References ADAMS D, KOIKE H, SLAMA M, et al. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease [J]. Nat reviews Neurol. 2019;15(7):387–404. ANDRADE C. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves [J]. Brain. 1952;75(3):408–27. ARAKI S, MAWATARI S, OHTA M, et al. Polyneuritic amyloidosis in a Japanese family [J]. Arch Neurol. 1968;18(6):593–602. ANDERSSON R. Familial amyloidosis with polyneuropathy. A clinical study based on patients living in northern Sweden [J]. Acta Med Scand Suppl. 1976;590:1–64. RYU JK, BAIK H W BAEJS, et al. Familial amyloid polyneuropathy in Korea: the first case report with a proven ATTR Lys35Asn gene [J]. Amyloid: Int J experimental Clin Invest : official J Int Soc Amyloidosis. 2005;12(1):62–4. ZHEN D B, SWIECICKI P L, ZELDENRUST S R, et al. Frequencies and geographic distributions of genetic mutations in transthyretin- and non-transthyretin-related familial amyloidosis [J]. Clin Genet. 2015;88(4):396–400. LIU G, NI W, WANG H, et al. Clinical features of familial amyloid polyneuropathy carrying transthyretin mutations in four Chinese kindreds [J]. J peripheral Nerv system: JPNS. 2017;22(1):19–26. PASUTHARNCHAT N, TAYCHARGUMPOO C, VORASETTAKARNKIJ Y, et al. Ala97Ser transthyretin amyloidosis-associated polyneuropathy, clinical and neurophysiological profiles in a Thai cohort [J]. BMC Neurol. 2021;21(1):206. PARMAN Y, ADAMS D. Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP [J]. Curr Opin Neurol. 2016;29(Suppl 1):S3–13. BENSON M D, KINCAID JC. The molecular biology and clinical features of amyloid neuropathy [J]. Muscle Nerve. 2007;36(4):411–23. SARAIVA M J, COSTA P P BIRKENS, et al. Family studies of the genetic abnormality in transthyretin (prealbumin) in Portuguese patients with familial amyloidotic polyneuropathy [J]. Volume 435. Annals of the New York Academy of Sciences; 1984. pp. 86–100. LIU Y T, LEE Y C, YANG C C et al. Transthyretin Ala97Ser in Chinese-Taiwanese patients with familial amyloid polyneuropathy: genetic studies and phenotype expression [J]. J Neurol Sci, 2008, 267(1–2): 91 – 9. YANG N C, LEE M J, CHAO C C, et al. Clinical presentations and skin denervation in amyloid neuropathy due to transthyretin Ala97Ser [J]. Neurology. 2010;75(6):532–8. CHAO C C, HUANG C M, CHIANG H H, et al. Sudomotor innervation in transthyretin amyloid neuropathy: Pathology and functional correlates [J]. Ann Neurol. 2015;78(2):272–83. HSU H C, LIAO M F HSUJL, et al. Phenotypic expressions of hereditary Transthyretin Ala97Ser related Amyloidosis (ATTR) in Taiwanese [J]. BMC Neurol. 2017;17(1):178. YUAN Z, GUO L, LIU X, et al. Familial amyloid polyneuropathy with chronic paroxysmal dry cough in Mainland China: A Chinese family with a proven heterozygous missense mutation c.349G > T in the transthyretin gene [J]. J Clin neuroscience: official J Neurosurgical Soc Australasia. 2019;60:164–6. Guan HZ, Liu Q, Chen L, Qian M, Liu Z, Guan YZ, Ren HT, Zhao YH, Chen M, Tian Z, Zou X, Cui LY. The clinical, pathological and genetic studies of transthyretin familial amyloid polyneuropathy. Chin J Neurol. 2015;48(1):7–12. SCHMIDT H H, WADDINGTON-CRUZ M, BOTTEMAN M F, et al. Estimating the global prevalence of transthyretin familial amyloid polyneuropathy [J]. Muscle Nerve. 2018;57(5):829–37. LIU J Y, GUO Y J, ZHOU C K et al. Clinical and histopathological features of familial amyloidotic polyneuropathy with transthyretin Val30Ala in a Chinese family [J]. J Neurol Sci, 2011, 304(1–2): 83 – 6. LYU MENGLC, ZHANG H. Hereditary Transthyretin Amyloidosis in Eight Chinese Families [J]. Chin Med J. 2015;128(21):2902–5. CHEN H, ZHOU X, WANG J et al. Exome Sequencing and Gene Prioritization Correct Misdiagnosis in a Chinese Kindred with Familial Amyloid Polyneuropathy [J]. Scientific reports, 2016, 6(26362. DU K, LI F, WANG H, et al. Hereditary transthyretin amyloidosis in mainland China: a unicentric retrospective study [J]. Ann Clin Transl Neurol. 2021;8(4):831–41. CHAO H C, LIAO Y C, LIU Y T, et al. Clinical and genetic profiles of hereditary transthyretin amyloidosis in Taiwan [J]. Ann Clin Transl Neurol. 2019;6(5):913–22. MISU K, HATTORI N, NAGAMATSU M et al. Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan. Clinicopathological and genetic features [J]. Brain, 1999, 122 (Pt 10)(1951-62. CASTRO J, MIRANDA B, DE CASTRO I, et al. Changes in nerve conduction studies predate clinical symptoms onset in early onset Val30Met hereditary ATTR amyloidosis [J]. Eur J Neurol. 2022;29(3):826–32. DU K, XU K, CHU X, et al. Vagus nerve ultrasound in transthyretin familial amyloid polyneuropathy: A pilot study [J]. J neuroimaging: official J Am Soc Neuroimaging. 2022;32(2):285–91. LUIGETTI M, DI PAOLANTONIO A, GUGLIELMINO V, et al. Neurol sciences: official J Italian Neurol Soc Italian Soc Clin Neurophysiol. 2022;43(4):2845–8. Neurofilament light chain as a disease severity biomarker in ATTRv: data from a single-centre experience [J]. LEONARDI L, ADAM C, BEAUDONNET G, et al. Skin amyloid deposits and nerve fiber loss as markers of neuropathy onset and progression in hereditary transthyretin amyloidosis [J]. Eur J Neurol. 2022;29(5):1477–87. Tables Table 1 The clinical features of the p roband s with p.Ala117Ser TTR-FAP Patient No. Gender Nationality Birthplace Age (years) Interval (years) Initial complaints Muscle power (MRC)， upper/lower limbs Tissue proof Diagnosis Onset Distal Proximal 1 M Han Changsha, Hunan 66 59 7 Numbness of upper extremities 3- / 2 4- / 4 None 2 M Han Zhuzhou, Huan 61 58 3 Numbness of limbs 5 / 4+ 4+/ 3 None 3 M Han Loudi, Hunan 50 47 3 Diarrhea and constipation 5 / 5 5 / 5 Sural N 4 M Han Chenzhou, Hunan 66 64 2 Chest tightness 5 / 5 5 / 5 None 5 M Han Shanghai 62 58 4 Numbness of upper extremities 1 / 2 3+/3+ Sural N 6 M Han Chaozhou, Guangdong 62 56 6 Weakness of lower extremities 1 / 2 4 / 4 Sural N 7 M Han Hengyang, Hunan 61 54 7 Erectile dysfunction 4- /4- 4 / 5 Sural N 8 M Han Hengyang, Hunan 67 64 3 Numbness of lower extremities NK/0 4 / 4 Sural N 9 M Han Shenzhen, Guangdong 60 52 12 Numbness of upper extremities 5 / 5 5 / 5 Sural N 10 M Han Hengyang, Hunan 65 52 13 Numbness of upper extremities 4 / 3 4- / 4- Sural N 11 M Han Shenzhen, Guangdong 59 57 2 Numbness of lower extremities 2 / 0 4- / 4- Peroneal N 12 F Han Jieyang, Guangdong 68 65 3 Numbness of upper extremities 2 / 2 4- / 4- Peroneal N 13 F Han Loudi, Hunan 67 66 1 Numbness of lower extremities 5 / 5 5 / 5 Peroneal N 14 M Han Jiangmen, Guangdong 59 57 2 Numbness of lower extremities 4+/4 5/5 Peroneal N 15 M Han Chenzhou, Hunan 41 41 0 Numbness of limbs 5/5 5/5 None 16 M Han Nanping, Fujian 67 57 10 Numbness of upper extremities 3/2 4/4 Peroneal N 17 M Han Nanping, Fujian 40 40 0 Decreased exercise tolerance 5/5 5/5 None 18 F Han Fuzhou, Fujian 72 66 6 Weakness of lower extremities 4/3 4/3 None 19 M Han Heyuan, Guangdong 65 55 10 Numbness of limbs 5/4 5/4 Peroneal N 20 M Han Chaozhou, Guangdong 68 60 8 Numbness of limbs 5-/4+ 5-/4+ Sural N 21 M Han Xiangtan,Hunan 60 59 1 Numbness of lower extremities 5-/4 5/5 Peroneal N Average 61.2± 8.3 56.5 ± 7.2 4.9 ± 3.9 M: male. F: female. N: nerve. NK: unknown.None: without biopsy. Sural N: sural nerve. SP N: superficial peroneal nerve. C-: Congo red staining negative. C+: Congo red staining positive. Table 2 Clinical presentations of the probands with p.Ala117Ser ATTR-PN in various report s References Lai et al. Yang et al. Liu et al. Chao et al. Tachibana et al. Klein et al. Chen et al. Yuan et al. Our study Origin the Taiwan area, China the Taiwan area, China the Taiwan area, China the Taiwan area, China the Taiwan area, China USA Mainland China Mainland China Mainland China Gender (M/F) 14/4 16/3 3/2 25/3 1/0 1/0 1/0 1/0 18/3 Age of onset (years) 65.2 ± 5.4 59.5 ± 5.7 51.2 59.9 ± 6.0 68 64 68 55 56.5±7.2 Weakness NA 19 (19) 5 (5) 28 (28) + NA + + 15 (21) Paresthesia NA 19 (19) 5 (5) 28 (28) + NA − + 21 (21) Allodynia NA 11 (19) NA 15 (28) − NA − − 10 (21) Autonomic dysfunction NA 19 (19) 5 (5) 22 (28) + NA + + 18(21) Cardiac dysfunction NA NA 3 (5) NA + NA + NA 17 (21) Gastrointestinal symptoms NA 18 (19) 5 (5) NA + NA + + 13 (21) Renal dysfunction NA NA 1 (5) NA NA NA NA − 4(21) Ocular dysfunction NA NA NA NA NA NA NA − 4(21) “+”with the symptom, “−” without the symptom, NA: not applicabl Supplementary Files Supplementarytable1.docx Supplementarytable2.docx Cite Share Download PDF Status: Published Journal Publication published 28 Apr, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Reviewers agreed at journal 01 Apr, 2025 Reviewers invited by journal 01 Apr, 2025 Editor assigned by journal 01 Apr, 2025 First submitted to journal 29 Mar, 2025 Editorial decision: Minor revision 28 Feb, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5950252","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":436795378,"identity":"433e50ae-1104-4e74-98c2-f6ea06aff5f3","order_by":0,"name":"Yeli Zhu","email":"","orcid":"","institution":"Southern Medical University Nanfang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yeli","middleName":"","lastName":"Zhu","suffix":""},{"id":436795379,"identity":"bbf5d8f2-22b4-4839-9be9-d6bd8f502322","order_by":1,"name":"Jingxian Fan","email":"","orcid":"","institution":"Southern Medical University Nanfang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jingxian","middleName":"","lastName":"Fan","suffix":""},{"id":436795380,"identity":"49bc25d3-1bab-4652-8302-c62f1e95afe0","order_by":2,"name":"Xiying Zhu","email":"","orcid":"","institution":"Central South University Third Xiangya Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiying","middleName":"","lastName":"Zhu","suffix":""},{"id":436795381,"identity":"e2f44b37-06ea-423a-afcf-03f225bbebda","order_by":3,"name":"Wei Li","email":"","orcid":"","institution":"Southern Medical University Nanfang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Li","suffix":""},{"id":436795382,"identity":"027bd26b-309d-4a50-aa38-925b6622fcf9","order_by":4,"name":"Zhaoyong Zhang","email":"","orcid":"","institution":"Southern Medical University Nanfang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhaoyong","middleName":"","lastName":"Zhang","suffix":""},{"id":436795383,"identity":"08ffbeea-880d-48e2-b38e-c7969a6da09f","order_by":5,"name":"Hui Zheng","email":"","orcid":"","institution":"Southern Medical University Nanfang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Zheng","suffix":""},{"id":436795384,"identity":"77783b36-c615-4bbc-a60f-2725ebd75598","order_by":6,"name":"Zhihua Zhou","email":"","orcid":"","institution":"The First Affiliated Hospital of Guangdong Pharmaceutical University","correspondingAuthor":false,"prefix":"","firstName":"Zhihua","middleName":"","lastName":"Zhou","suffix":""},{"id":436795385,"identity":"4936f1c7-8013-4509-bf65-7a1aeae40706","order_by":7,"name":"Lingchao Meng","email":"","orcid":"","institution":"Peking University First Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lingchao","middleName":"","lastName":"Meng","suffix":""},{"id":436795386,"identity":"3a3f9e8c-5a7c-433e-8b6c-603f15676a0b","order_by":8,"name":"Ruxu Zhang","email":"","orcid":"","institution":"Central South University Third Xiangya Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ruxu","middleName":"","lastName":"Zhang","suffix":""},{"id":436795387,"identity":"3cfc6645-bf9d-47d9-86fb-4fd60122c083","order_by":9,"name":"Haishan Jiang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAz0lEQVRIiWNgGAWjYBACxmYQ0cAgB+GykaDFmHgtEH0NDIkNRGthbmd+9vDrjrr0+dPOGDB8KDvMwD+7gZDD2MyNZc8czt1wO8eAcca5wwwSdw4Q0sJgJi3ZdiB3g3SOATNv22EGA4kEQlrYvwG11KXLzwZq+UucFh4zyY9tzAkMQIcxMxKppUwaqNJww+20goM959J5JG4Q0GLYf3yb5M+2Onn52ckbH/wos5bjn0FISwMwoHmgnANAzINbLRTIgxz3g6CyUTAKRsEoGNEAAAv2QE6LDwzoAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-7388-8659","institution":"Southern Medical University Nanfang Hospital","correspondingAuthor":true,"prefix":"","firstName":"Haishan","middleName":"","lastName":"Jiang","suffix":""}],"badges":[],"createdAt":"2025-02-03 10:25:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5950252/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5950252/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13023-025-03733-0","type":"published","date":"2025-04-28T15:57:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79818095,"identity":"67ac351c-eba7-48ea-9e40-e0e84dfcf900","added_by":"auto","created_at":"2025-04-03 08:16:29","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47842,"visible":true,"origin":"","legend":"\u003cp\u003eGeographical distribution of the probands with p.Ala117Ser ATTR-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.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5950252/v1/92c7720d4ad89702771ff990.jpg"},{"id":79819580,"identity":"a09466c3-dbda-4149-bdfd-db3bb3ddc4bb","added_by":"auto","created_at":"2025-04-03 08:32:29","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":161777,"visible":true,"origin":"","legend":"\u003cp\u003eVarious systems dysfunction scores of the probands with p.Ala117Ser ATTR-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 Table 2. 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.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5950252/v1/540fbba9ca45f8f5fc7c2198.jpg"},{"id":79819275,"identity":"5d7a5677-bea5-4b71-b208-e76dc3283a83","added_by":"auto","created_at":"2025-04-03 08:24:29","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":143634,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathologic 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).\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5950252/v1/7b71ecbf9a485318f8e615f9.jpg"},{"id":79818097,"identity":"1e40ed80-9327-4c56-a4b5-6b77618c3579","added_by":"auto","created_at":"2025-04-03 08:16:29","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":80878,"visible":true,"origin":"","legend":"\u003cp\u003eTc-99m Pyrophosphate (PYP) Scintigraphy of NO.21 Patient. The result showed tracer retention in the anterior wall (counts were 497K both at 1 hour and 3 hours 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.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5950252/v1/e20e3be6ef38b4a04e7b2f10.jpg"},{"id":81987708,"identity":"edbb742b-273c-4bcb-963d-5ac73b8064c0","added_by":"auto","created_at":"2025-05-05 16:05:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1509216,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5950252/v1/ac7d32aa-a528-4c4f-ae72-71ce94c00102.pdf"},{"id":79818111,"identity":"db987971-6cab-4ad2-a8ac-d3d0ce8dbed3","added_by":"auto","created_at":"2025-04-03 08:16:30","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32631,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5950252/v1/e954272c7baeec593a6bfd81.docx"},{"id":79819273,"identity":"7940f0c7-e0b7-40f9-b162-bc7ac45707a1","added_by":"auto","created_at":"2025-04-03 08:24:29","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":20696,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-5950252/v1/b0e97477007de6dfe5823f94.docx"}],"financialInterests":"","formattedTitle":"Clinical features of familial amyloidotic polyneuropathy with transthyretin p.Ala117Ser mutation in South Mainland China","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHereditary transthyretin amyloidosis-polyneuropathy (ATTRv-PN) is an autosomal dominant genetic disorder caused by point mutations of the \u003cem\u003eTTR\u003c/em\u003e gene. It is characterized by amyloid deposition in many systems including the peripheral and autonomic nervous system\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. 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\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. It was subsequently reported in Japan (1968)\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e and Sweden (1976)\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. ATTRv-PN has been reported in 29 countries, including Korea\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, the United States of America\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, China\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e, Thailand\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, and many European countries \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe \u003cem\u003eTTR\u003c/em\u003e gene is located on chromosome 18 and comprises four exons\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. More than 130 mutations have been identified associated with this gene \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. The p.Val30Met 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\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Moreover, certain specific mutations are associated with small clusters of families in particular areas. For example, the \u003cem\u003eTTR\u003c/em\u003e Ala97Ser (p.Ala117Ser) mutation is common among Chinese kindreds from the Taiwan area\u003csup\u003e[\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. 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\u0026thinsp;\u0026gt;\u0026thinsp;T Ala97Ser (p.Ala117Ser) in Southern Mainland China was reported in 2018\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Through investigating several ATTRv-PN centers in China, we found a founder effect in patients with Ala97Ser (p.Ala117Ser) 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 (p.Ala117Ser) and summarize its characteristic clinical manifestations. ATTRv-PN appears relatively rare in China, while our research provides the largest cohort of Ala97Ser (p.Ala117Ser) mutation cases to date.\u003c/p\u003e"},{"header":"Subjects and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eWe identified 21 patients from 20 distinct families diagnosed with Ala97Ser (p.Ala117Ser) 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 \u003cem\u003eTTR\u003c/em\u003e Ala97Ser (p.Ala117Ser) 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.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTTR gene analysis\u003c/h3\u003e\n\u003cp\u003ePeripheral 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 \u003cem\u003eTTR\u003c/em\u003e 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.\u003c/p\u003e\n\u003ch3\u003eElectrophysiologic assessment\u003c/h3\u003e\n\u003cp\u003eNeuroelectrophysiological 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.\u003c/p\u003e\n\u003ch3\u003eNerve biopsy and pathological assessment\u003c/h3\u003e\n\u003cp\u003eA sural nerve (or sensory branch of the superficial peroneal nerve) biopsy was performed under local skin and tissue anesthesia, excluding the nerve. Nerve specimens were processed for routine stains (hematoxylin-eosin for overview and nerve morphology; Staining with TTR antibody and Congo red for amyloid) on frozen and semi-thin sections (azure-methylene blue). Serial consecutive sections were assessed. Electron microscopy samples were fixed in a 2.5% glutaraldehyde buffer for 2h, then with osmium acid, dehydrated in acetone, and embedded with epoxy resin. The sections were observed and photographed under an electron microscope.\u003c/p\u003e\n\u003ch3\u003eMultisystem evaluation\u003c/h3\u003e\n\u003cp\u003eSubsequently, we facilitated the diagnostic process through a comprehensive assessment of pathological changes in multiple organ systems, including the peripheral nervous system, autonomic nervous system, cardiovascular system, renal system, and ocular system. Peripheral neuropathy is assessed through neurological examination, electromyography (EMG), and nerve biopsy to quantify axonal or demyelinating damage. Autonomic dysfunction is evaluated via symptom profiling (e.g., orthostatic intolerance, gastrointestinal dysmotility) combined with orthostatic blood pressure testing to identify hemodynamic instability. Cardiac involvement requires multimodal imaging and functional analyses, including electrocardiography (ECG) for arrhythmia detection, echocardiography (Echo) to assess chamber dimensions and ejection fraction, and myocardial Tc-99m Pyrophosphate (PYP) Scintigraphy to delineate amyloid deposition or perfusion defects. Renal function is systematically monitored through serial measurements of serum creatinine (Scr) and urinary protein quantification (e.g., 24-hour proteinuria or urine protein-to-creatinine ratio) to stage chronic kidney disease. Ocular pathology is investigated by correlating subjective visual complaints (e.g., scotomas, blurred vision) with objective findings on fundoscopy, such as vitreous opacities or retinal vascular abnormalities, to confirm visual pathway compromise.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eWe used IBM SPSS Version 25 and Microsoft Office Excel. Descriptive statistics are mainly used in this study. Numeric variables are here described as means\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, numbers (n) with percentages (%) or median values, etc. Results were considered significant at p\u0026lt;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinical features\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe basic information of the probands (18 males and 3 females) in the 20 families with\u0026nbsp;Ala97Ser (p.Ala117Ser)\u0026nbsp;ATTRv-PN\u0026nbsp;is summarised in Table 1. All probands were from South Mainland China (see Figure 1). The age of onset was 56.5\u0026nbsp;±\u0026nbsp;7.2\u0026nbsp;years (range 40-66). The period from the onset to the final diagnosis was\u0026nbsp;4.9\u0026nbsp;± 3.9\u0026nbsp;years (range\u0026nbsp;0–13), and neurological assessments were performed at the time of diagnosis. Initial symptoms were numbness of the lower or upper extremities (15\u0026nbsp;patients), weakness of the lower limbs (2\u0026nbsp;patients), diarrhea and constipation (1 patient), erectile dysfunction (1 patient), Decreased exercise tolerance (1 patient),\u0026nbsp;and chest tightness (1 patient). No cranial nerve defects, such as dysphagia, dysarthria, or hypertrophy of the tongue, were observed in any of the patients.\u003c/p\u003e\n\u003cp\u003eThe clinical manifestations are shown in supplementary table 1. Fifteen patients suffered from muscular weakness and amyotrophy in the upper and lower limbs to varying degrees in a distally accentuated manner. Paraesthesia was noted in all patients. Almost half of the patients experienced pain in the upper or lower limbs, although sensory dissociation was not conspicuous. Decreased tendon reflexes and carpal tunnel syndrome were prominent in most patients. Eighteen patients complained of autonomic dysfunction during the duration of the disease. However, specific symptoms varied from patient to patient. Constipation was observed in 11 patients. Six of the 11 patients complained about alternating occurrences of diarrhea and constipation. Seventeen patients experienced weight loss. Orthostatic hypotension was seen in seven patients. Erectile dysfunction was observed in 9 /18 male patients. Only four patients had hyperhidrosis. Two patients complained of disturbances in urination (urine retention).\u003c/p\u003e\n\u003cp\u003eAdditionally, the involvement of other organs was seen in seventeen patients\u0026nbsp;by means of the multisystemic assessment described in the methods section.\u0026nbsp;Cardiac dysfunction was the most common (17\u0026nbsp;patients), specifically arrhythmia, cardiac hypertrophy, and symptomatic heart failure. Only\u0026nbsp;4\u0026nbsp;patients had renal dysfunction (manifested by abnormal 24-hour urine protein quantification).\u0026nbsp;Four\u0026nbsp;patients experienced ocular dysfunction: decreased vision (4\u0026nbsp;patients), vitreous opacity (1 patient), and cataract (1 patient). However, none of the patients had glaucoma. Other symptoms included edema (8\u0026nbsp;patients), dry cough (8\u0026nbsp;patients), and hemorrhagic rash (2 patients). The various system dysfunction scores of the probands are shown in Figure 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNeurophysiological manifestations\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNCS showed axonal-type sensorimotor polyneuropathy (detailed in Table 2). Most patients had long distal latency of the upper or lower extremities, but it was much smaller than in demyelinating neuropathies. All patients had reductions in the amplitudes of compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) from mild to severe. It is worth noting that the decline in SNAP was\u0026nbsp;\u003ca href=\"link%3Amore\"\u003emore\u003c/a\u003e \u003ca href=\"link%3Anoticeable\"\u003enoticeable\u003c/a\u003e than that in CMAP. The nerve damage of the lower limbs was more severe than that of the upper limbs. The SNAP of most of the lower extremities was not observed. Additionally, a decrease in the F wave was observed in nearly all tested nerves.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHistopathological findings\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFifteen patients underwent a sural or peroneal nerve biopsy. The main pathological changes in peripheral nerves were moderate to severely decreased myelinated and unmyelinated nerve fibers, accompanied by degenerative or regenerative changes in the axons and myelin sheath of myelinated nerve fibers, which is following the pathological characteristics of chronic active mixed peripheral neuropathy. Nerve biopsy revealed positive Congo red staining in 11/15 patients (73.3%). Congo red staining showed multiple red-stained amyloid deposits and bright apple-green coloration under a polarising microscope. MGT staining found axonal degeneration of green substances in some large myelinated fibers. The histopathologic findings of patient no. 10 are shown in Figure 3.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTc-99m Pyrophosphate (PYP) Scintigraphy\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFour patients underwent Tc-99m Pyrophosphate (PYP) Scintigraphy. Three of them demonstrated positive imaging findings indicative of transthyretin cardiac amyloidosis (ATTR-CA), meeting the 2020 AHA diagnostic criteria for cardiac amyloidosis with Grade 2-3 radiotracer uptake on visual grading. One patient did not fulfill the criteria for ATTR-CA positivity (Grade 0 per 2020 AHA classification). Representative imaging of Patient 21 is illustrated in Figure 4.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eATTRv-PN appears relatively rare in South Mainland China, while our study provides the largest cohort of Ala97Ser (p.Ala117Ser) mutation cases. In the 1990s, a family with ATTRv-PN was first diagnosed at the Peking Union Medical College Hospital\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. It is estimated that there are approximately 1997 cases in China\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Over 40 case reports have been published recently, including reports of multiple ATTRv-PN families. Studies describe a mutation in the \u003cem\u003eTTR\u003c/em\u003e gene, different from that observed in Europe\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Shortly before, a unicentric retrospective study reported that \u003cem\u003eTTR\u003c/em\u003e Val30Met (p.Val50Met) remains mainland China's most common mutation type\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. However, \u003cem\u003eTTR\u003c/em\u003e Ala97Ser (p.Ala117Ser) mutations are relatively rare. Based on previous studies, the \u003cem\u003eTTR\u003c/em\u003e Ala97Ser (p.Ala117Ser) mutation was one of the most common variants in the Chinese population, especially in Chinese kindreds from the Taiwan area. This mutation has never been reported in Caucasian populations. Detailed haplotype analyses demonstrated a shared haplotype in most patients with the Ala97Ser (p.Ala117Ser) mutation in the Taiwan area, suggesting a founder effect\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. This may be related to the late onset of ATTRv-PN and the early onset of symptoms, which are mild and do not interfere with fertility. Except for the first report of the ATTRv-PN family with a proven \u003cem\u003eTTR\u003c/em\u003e Ala97Ser (p.Ala117Ser) mutation from mainland China\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e, our study reported another 20 pedigrees with the same mutation. Furthermore, all cases were from south China, especially Hunan and Guangdong provinces. Despite the lack of genetic verification, we speculate that the \u003cem\u003eTTR\u003c/em\u003e Ala97Ser (p.Ala117Ser) mutation originated in South Mainland China.\u003c/p\u003e \u003cp\u003eOur study demonstrated the characteristics of ATTRv-PN with the \u003cem\u003eTTR\u003c/em\u003e Ala97Ser (p.Ala117Ser) mutation in mainland China. Similar to previous reports, significantly more men than women were diagnosed with this mutation. However, it is unclear whether there is a protective factor for women due to the small sample size and the possibility of selection bias. The Ala97Ser(p.Ala117Ser) patients showed late onset \u0026ndash; almost all were over 50 years of age. It differed from Val30Met(p.Val50Met) patients, which showed early or late onset\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. The course from the onset to final diagnosis ranged from 0 to 13 years, while there was no significant correlation between this and the severity of clinical manifestations. Numbness of the lower or upper extremities was among the most common initial symptoms.\u003c/p\u003e \u003cp\u003eDue to its insidious onset, there is usually a delay in the diagnosis of this disease, which makes it difficult to treat. Apart from peripheral nerve dysfunction, autonomic dysfunction was also particularly prominent. Constipation was more common than orthostatic hypotension, and it (constipation) often manifested as alternating between diarrhea and constipation. Remarkably, almost all males had erectile dysfunction at an early stage, which is an important feature that differentiates them from female patients. Cardiac dysfunction was the most common involvement of other organs. One of the 21 patients died of a cardiac incident shortly after the diagnosis. A unique phenotype of ATTRv-PN has been reported in a case report describing a distinctive chronic dry cough\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. In our study, eight patients had similar symptoms. It occurs at different stages of the disease.\u003c/p\u003e \u003cp\u003eFurther research is needed to confirm this mechanism. Although nerve biopsy helped diagnose the disease, not all patients in our study underwent a nerve biopsy. Only 11/15 (73.3%) patients showed positive Congo red staining. Patients with ATTRv-PN negative Congo red staining might get misdiagnosed. Interestingly, Neurophysiological examinations\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e, vagus nerve ultrasonography\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e, neurofilament light chain\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e, and skin biopsy\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e also helped with the diagnosis. The final diagnosis was based on genetic and pathological examinations. In the absence of definitive amyloid deposits, a definitive diagnosis needs to be made in the context of the previously described clinical manifestations of multisystem involvement, genetic evidence, and the exclusion of other diseases.\u003c/p\u003e \u003cp\u003eIn addition, many factors, such as the rarity of the disease in the general population, physicians\u0026rsquo; lack of understanding of various clinical features, and limited diagnostic tools (i.e., histopathology and gene screening), lead to a high misdiagnosis rate and poor prognosis. ATTRv-PN is often misdiagnosed as chronic idiopathic axonal polyneuropathy, chronic inflammatory demyelinating polyneuropathy, and lumbar spinal stenosis. Diabetes or chronic alcoholism may cause polyneuropathies similar to ATTRv-PN. It may also be misdiagnosed as Charcot-Marie-Tooth or motor neuron disease. Delayed diagnosis is the main obstacle to the optimal management of ATTRv-PN in China. There is usually an interval of several years from the initial clinical symptoms of the disease to the final diagnosis. Because of the significant unmet medical needs for this rare and fatal disease, there is an urgent need to raise disease awareness to facilitate early diagnosis and timely treatment.\u003c/p\u003e \u003cp\u003eHistorically, mutations in the \u003cem\u003eTTR\u003c/em\u003e gene have predominantly been associated with symptoms affecting the peripheral nerves and cardiac system. Consequently, existing literature has visually represented the proportion of peripheral nerve and cardiac impairments across various mutation sites, facilitating people's understanding of the clinical manifestations associated with different \u003cem\u003eTTR\u003c/em\u003e gene mutation locations. However, it is important to note that \u003cem\u003eTTR\u003c/em\u003e gene mutations can also impact other organs and systems, including the kidneys, eyes, and autonomic nervous system. Our study introduces a more comprehensive radar chart for multidimensional assessment, enhancing the graphical representation of clinical symptoms associated with different \u003cem\u003eTTR\u003c/em\u003e gene mutation sites.\u003c/p\u003e \u003cp\u003eNonetheless, our study's sample size remained insufficient for robust statistical analysis, and all cases were sourced exclusively from southern China. Consequently, these findings may not be representative of the rest of China or the world, thereby constraining the generalizability and precision of the results.\u003c/p\u003e \u003cp\u003eMoreover, this study was conducted retrospectively, which introduced challenges such as incomplete data and selection bias. Notably, there was a disproportionate male-to-female ratio among the participants, and a significant delay was observed between the onset of symptoms and the final diagnosis. The retrospective design further precluded the possibility of patient follow-up, resulting in a deficiency of information regarding patient treatment and prognosis. These limitations may have impeded the precise assessment and comprehensive understanding of the disease under investigation.\u003c/p\u003e \u003cp\u003eAlthough the \u003cem\u003eTTR\u003c/em\u003e gene was examined in all participants of this study, other potential genetic variants and gene-environment interactions were not analyzed or discussed. These aspects need further investigation in more comprehensive and detailed studies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur findings elucidate the clinical spectrum of ATTRv-PN associated with the \u003cem\u003eTTR\u003c/em\u003e Ala97Ser (p.Ala117Ser) mutation in Southern China, underscoring the need for more extensive, multi-centric studies to fully delineate the disease's impact.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupported by grants from Horizontal projects funded by Pfizer（74310325）and the Nanfang Hospital Baiyun Branch Dean\u0026rsquo;s Fund (BYYZ24007).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data sets generated and analyzed during the current study are available from the corresponding author upon reasonable request. All data generated and analyzed during this study are included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the patients who participated in this study. We thank the professors of Peking University First Hospital, Third Xiangya Hospital of Central South University, for providing valuable cases. We thank the technicians in the Neuromuscular Pathologic Team, Electron Microscope Room, and Neurophysiology Room of Nanfang Hospital of Southern Medical University, Department of Neurology, for their assistance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u003c/strong\u003e\u003cstrong\u003eInformation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAffiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of Neurology, Southern Medical University Nanfang Hospital, Southern Medical University, Guangzhou, China\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYeli Zhu, Jingxian Fan,Wei Li, Zhaoyong Zhang, Hui Zheng, Haishan Jiang\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of Neurology, Central South University Third Xiangya Hospital, Central South University, Hunan, China\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXiying Zhu, Ruxu Zhang\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of Neurology, Peking University First Hospital, Peking University, Beijing, China\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLingchao Meng\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDepartment of Neurology,\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eThe First affiliated Hospital of Guangdong Pharmaceutical University,\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eGuangzhou, China\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZhihua Zhou\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYZ, JF and XZ wrote and edited the manuscript. WL contributed pathological assessment. ZZ and HZ designed the figures and tables. ZZ, LM, RZ and HJ provided clinical samples and information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding Author\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to Lingchao Meng, Ruxu Zhang\u0026amp; Haishan Jiang\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there is no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eApproved by Medical Ethics Committee of Southern Medical University Southern Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublisher\u0026rsquo;s Note\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eADAMS D, KOIKE H, SLAMA M, et al. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease [J]. Nat reviews Neurol. 2019;15(7):387\u0026ndash;404.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eANDRADE C. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves [J]. Brain. 1952;75(3):408\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eARAKI S, MAWATARI S, OHTA M, et al. Polyneuritic amyloidosis in a Japanese family [J]. Arch Neurol. 1968;18(6):593\u0026ndash;602.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eANDERSSON R. Familial amyloidosis with polyneuropathy. A clinical study based on patients living in northern Sweden [J]. Acta Med Scand Suppl. 1976;590:1\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRYU JK, BAIK H W BAEJS, et al. Familial amyloid polyneuropathy in Korea: the first case report with a proven ATTR Lys35Asn gene [J]. Amyloid: Int J experimental Clin Invest : official J Int Soc Amyloidosis. 2005;12(1):62\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZHEN D B, SWIECICKI P L, ZELDENRUST S R, et al. Frequencies and geographic distributions of genetic mutations in transthyretin- and non-transthyretin-related familial amyloidosis [J]. Clin Genet. 2015;88(4):396\u0026ndash;400.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLIU G, NI W, WANG H, et al. Clinical features of familial amyloid polyneuropathy carrying transthyretin mutations in four Chinese kindreds [J]. J peripheral Nerv system: JPNS. 2017;22(1):19\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePASUTHARNCHAT N, TAYCHARGUMPOO C, VORASETTAKARNKIJ Y, et al. Ala97Ser transthyretin amyloidosis-associated polyneuropathy, clinical and neurophysiological profiles in a Thai cohort [J]. BMC Neurol. 2021;21(1):206.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePARMAN Y, ADAMS D. Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP [J]. Curr Opin Neurol. 2016;29(Suppl 1):S3\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBENSON M D, KINCAID JC. The molecular biology and clinical features of amyloid neuropathy [J]. Muscle Nerve. 2007;36(4):411\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSARAIVA M J, COSTA P P BIRKENS, et al. Family studies of the genetic abnormality in transthyretin (prealbumin) in Portuguese patients with familial amyloidotic polyneuropathy [J]. Volume 435. Annals of the New York Academy of Sciences; 1984. pp. 86\u0026ndash;100.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLIU Y T, LEE Y C, YANG C C et al. Transthyretin Ala97Ser in Chinese-Taiwanese patients with familial amyloid polyneuropathy: genetic studies and phenotype expression [J]. J Neurol Sci, 2008, 267(1\u0026ndash;2): 91\u0026thinsp;\u0026ndash;\u0026thinsp;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYANG N C, LEE M J, CHAO C C, et al. Clinical presentations and skin denervation in amyloid neuropathy due to transthyretin Ala97Ser [J]. Neurology. 2010;75(6):532\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCHAO C C, HUANG C M, CHIANG H H, et al. Sudomotor innervation in transthyretin amyloid neuropathy: Pathology and functional correlates [J]. Ann Neurol. 2015;78(2):272\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHSU H C, LIAO M F HSUJL, et al. Phenotypic expressions of hereditary Transthyretin Ala97Ser related Amyloidosis (ATTR) in Taiwanese [J]. BMC Neurol. 2017;17(1):178.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYUAN Z, GUO L, LIU X, et al. Familial amyloid polyneuropathy with chronic paroxysmal dry cough in Mainland China: A Chinese family with a proven heterozygous missense mutation c.349G\u0026thinsp;\u0026gt;\u0026thinsp;T in the transthyretin gene [J]. J Clin neuroscience: official J Neurosurgical Soc Australasia. 2019;60:164\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuan HZ, Liu Q, Chen L, Qian M, Liu Z, Guan YZ, Ren HT, Zhao YH, Chen M, Tian Z, Zou X, Cui LY. The clinical, pathological and genetic studies of transthyretin familial amyloid polyneuropathy. Chin J Neurol. 2015;48(1):7\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSCHMIDT H H, WADDINGTON-CRUZ M, BOTTEMAN M F, et al. Estimating the global prevalence of transthyretin familial amyloid polyneuropathy [J]. Muscle Nerve. 2018;57(5):829\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLIU J Y, GUO Y J, ZHOU C K et al. Clinical and histopathological features of familial amyloidotic polyneuropathy with transthyretin Val30Ala in a Chinese family [J]. J Neurol Sci, 2011, 304(1\u0026ndash;2): 83\u0026thinsp;\u0026ndash;\u0026thinsp;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLYU MENGLC, ZHANG H. Hereditary Transthyretin Amyloidosis in Eight Chinese Families [J]. Chin Med J. 2015;128(21):2902\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCHEN H, ZHOU X, WANG J et al. Exome Sequencing and Gene Prioritization Correct Misdiagnosis in a Chinese Kindred with Familial Amyloid Polyneuropathy [J]. Scientific reports, 2016, 6(26362.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDU K, LI F, WANG H, et al. Hereditary transthyretin amyloidosis in mainland China: a unicentric retrospective study [J]. Ann Clin Transl Neurol. 2021;8(4):831\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCHAO H C, LIAO Y C, LIU Y T, et al. Clinical and genetic profiles of hereditary transthyretin amyloidosis in Taiwan [J]. Ann Clin Transl Neurol. 2019;6(5):913\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMISU K, HATTORI N, NAGAMATSU M et al. Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan. Clinicopathological and genetic features [J]. Brain, 1999, 122 (Pt 10)(1951-62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCASTRO J, MIRANDA B, DE CASTRO I, et al. Changes in nerve conduction studies predate clinical symptoms onset in early onset Val30Met hereditary ATTR amyloidosis [J]. Eur J Neurol. 2022;29(3):826\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDU K, XU K, CHU X, et al. Vagus nerve ultrasound in transthyretin familial amyloid polyneuropathy: A pilot study [J]. J neuroimaging: official J Am Soc Neuroimaging. 2022;32(2):285\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLUIGETTI M, DI PAOLANTONIO A, GUGLIELMINO V, et al. Neurol sciences: official J Italian Neurol Soc Italian Soc Clin Neurophysiol. 2022;43(4):2845\u0026ndash;8. Neurofilament light chain as a disease severity biomarker in ATTRv: data from a single-centre experience [J].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLEONARDI L, ADAM C, BEAUDONNET G, et al. Skin amyloid deposits and nerve fiber loss as markers of neuropathy onset and progression in hereditary transthyretin amyloidosis [J]. Eur J Neurol. 2022;29(5):1477\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;1\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;The\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eclinical\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003efeatures\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ethe\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003cstrong\u003eroband\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;with p.Ala117Ser TTR-FAP\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"735\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003ePatient No.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eNationality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eBirthplace\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 102px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003eInterval (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eInitial complaints\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 114px;\"\u003e\n \u003cp\u003eMuscle power (MRC)， upper/lower limbs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eTissue proof\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003eOnset\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003eDistal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003eProximal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eChangsha, Hunan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of upper extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e3- / 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e4- / 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eZhuzhou, Huan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of limbs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e5 / 4+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e4+/ 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eLoudi, Hunan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eDiarrhea and constipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e5 / 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e5 / 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eSural N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eChenzhou, Hunan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eChest tightness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e5 / 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e5 / 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eShanghai\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of upper extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e1 / 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e3+/3+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eSural N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eChaozhou, Guangdong\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eWeakness of lower extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e1 / 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e4 / 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eSural N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eHengyang, Hunan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eErectile dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e4- /4-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e4 / 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eSural N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eHengyang, Hunan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of lower extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003eNK/0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e4 / 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eSural N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eShenzhen, Guangdong\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of upper extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e5 / 5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e5 / 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eSural N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eHengyang, Hunan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of upper extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e4 / 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e4- / 4-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eSural N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eShenzhen, Guangdong\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of lower extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e2 / 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e4- / 4-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003ePeroneal N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eJieyang, Guangdong\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of upper extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e2 / 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e4- / 4-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003ePeroneal N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eLoudi, Hunan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of lower extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e5 / 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e5 / 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003ePeroneal N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eJiangmen, Guangdong\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of lower extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e4+/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e5/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003ePeroneal N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eChenzhou, Hunan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of limbs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e5/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e5/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eNanping, Fujian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of upper extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e3/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e4/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003ePeroneal N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eNanping, Fujian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eDecreased exercise tolerance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e5/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e5/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eFuzhou, Fujian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eWeakness of lower extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e4/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e4/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eHeyuan, Guangdong\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of limbs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e5/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e5/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003ePeroneal N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eChaozhou, Guangdong\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of limbs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e5-/4+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e5-/4+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eSural N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eHan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003eXiangtan,Hunan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003eNumbness of lower extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e5-/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e5/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003ePeroneal N\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003eAverage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e61.2\u0026plusmn; 8.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e56.5 \u0026plusmn;\u0026nbsp;7.2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp\u003e4.9 \u0026plusmn; 3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 148px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;M: male. F: female. N: nerve. NK:\u0026nbsp;unknown.None: without biopsy. Sural N: sural nerve. SP N: superficial peroneal nerve.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eC-: Congo red staining negative. C+: Congo red staining positive.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 Clinical presentations of the\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eprobands\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;with\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ep.Ala117Ser\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eATTR-PN in\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003evarious\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;report\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"106%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eReferences\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eLai et al.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7px;\"\u003e\n \u003cp\u003eYang et al.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eLiu et al.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eChao et al.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eTachibana et al.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eKlein et al.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eChen et al.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6px;\"\u003e\n \u003cp\u003eYuan et al.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eOur study\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eOrigin \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003ethe Taiwan area, China\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7px;\"\u003e\n \u003cp\u003ethe Taiwan area, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003ethe Taiwan area, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003ethe Taiwan area, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003ethe Taiwan area,\u003c/p\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eMainland China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6px;\"\u003e\n \u003cp\u003eMainland China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eMainland China\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eGender (M/F) \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e14/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7px;\"\u003e\n \u003cp\u003e16/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e3/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e25/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e1/0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e1/0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e1/0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6px;\"\u003e\n \u003cp\u003e1/0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e18/3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eAge of onset (years) \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e65.2 \u0026plusmn; 5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7px;\"\u003e\n \u003cp\u003e59.5 \u0026plusmn; 5.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e51.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e59.9 \u0026plusmn; 6.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e56.5\u0026plusmn;7.2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eWeakness \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7px;\"\u003e\n \u003cp\u003e19 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e5 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e28 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e+\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e15 (21)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eParesthesia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7px;\"\u003e\n \u003cp\u003e19 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e5 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e28 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026minus;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e21 (21)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eAllodynia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7px;\"\u003e\n \u003cp\u003e11 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e15 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026minus;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026minus;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026minus;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e10 (21)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eAutonomic dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7px;\"\u003e\n \u003cp\u003e19 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e5 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e22 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e18(21)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eCardiac dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e3 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e17 (21)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eGastrointestinal symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7px;\"\u003e\n \u003cp\u003e18 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e5 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e13 (21)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003eRenal dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e1 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026minus;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e4(21)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003eOcular dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026minus;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e4(21)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026ldquo;+\u0026rdquo;with the symptom, \u0026ldquo;\u0026minus;\u0026rdquo; without the symptom, NA: not applicabl\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hereditary transthyretin amyloidosis (ATTRv), TTR gene mutation, clinical feature, scoring model","lastPublishedDoi":"10.21203/rs.3.rs-5950252/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5950252/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eOur study aimed to report the clinical features and epidemiological characteristics of hereditary transthyretin amyloidosis-polyneuropathy(ATTRv-PN) with \u003cem\u003eTTR\u003c/em\u003e Ala97Ser(p.Ala117Ser) mutation from South Mainland China.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe identified 21 patients from 20 families diagnosed with Ala97Ser(p.Ala117Ser) ATTRv-PN based on strict clinical and electrophysiological criteria from three centers. Clinical and laboratory data were retrospectively retrieved for analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA 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\u0026thinsp;\u0026plusmn;\u0026thinsp;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%).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eATTRv-PN appears relatively rare in South Mainland China, with our study providing the largest cohort of Ala97Ser(p.Ala117Ser) 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.\u003c/p\u003e","manuscriptTitle":"Clinical features of familial amyloidotic polyneuropathy with transthyretin p.Ala117Ser mutation in South Mainland China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-03 08:16:25","doi":"10.21203/rs.3.rs-5950252/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-04-01T16:53:50+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-01T09:42:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-01T06:58:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2025-03-29T10:56:27+00:00","index":"","fulltext":""},{"type":"decision","content":"Minor revision","date":"2025-02-28T08:00:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"96798c00-a999-473c-be91-cd9a8daffadf","owner":[],"postedDate":"April 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-05T16:00:11+00:00","versionOfRecord":{"articleIdentity":"rs-5950252","link":"https://doi.org/10.1186/s13023-025-03733-0","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2025-04-28 15:57:21","publishedOnDateReadable":"April 28th, 2025"},"versionCreatedAt":"2025-04-03 08:16:25","video":"","vorDoi":"10.1186/s13023-025-03733-0","vorDoiUrl":"https://doi.org/10.1186/s13023-025-03733-0","workflowStages":[]},"version":"v1","identity":"rs-5950252","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5950252","identity":"rs-5950252","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}