Ala97Ser transthyretin amyloidosis-associated polyneuropathy, clinical and neurophysiological profiles in a Thai cohort

The clinical presentation of ATTRv-PN varies among patients with different genetic, ethnic, and geographic backgrounds. Whatever is known in ATTRv-PN has been mainly gathered from studies of ATTRV30M. ATTRA97S has much lesser data, but usually shows a mixed polyneuropathy-cardiopathy phenotype of late-onset manifestation [6‐10, 16]. Cardiopathy tended to become symptomatic after neuropathy in most cases [16]. ATTRA97S is mostly endemic in Taiwan (Han-Taiwanese) with male predominance [7‐10]. It is also a common TTR mutation in mainland China (Han-Chinese), particularly in southern China [17‐20]. One study from Malaysia reported ATTRA97S-PN in nine Chinese Malaysian patients [21]. In fact, this mutation has never been reported in other populations so far. Our study first described ATTRA97S-PN in Thai patients. The main clinical features in Thai patients were generally comparable to those in previous reports, however some additional characteristics were found.

Similar to previous reports, most of our patients also had a mixed polyneuropathy-cardiopathy phenotype. The core neuropathic manifestations were (1) symmetrically length-dependent sensory or sensorimotor polyneuropathy, accompanied with various degrees of autonomic neuropathy, (2) frequent bilateral median neuropathies at the wrist (CTS), occurring concurrently or precedingly to polyneuropathy, (3) insidious onset of sensory and/or autonomic polyneuropathy and subsequent motor polyneuropathy, and (4) progression over years to decades (faster worsening once motor nerves were affected). Additionally, symptomatic patients were not restricted to late adulthood and elderly individuals. Patients’ symptoms may start in their early 30 s. A review of the English literature in the PubMed search engine revealed 12 clinical studies with clinical data (including case reports) of ATTRA97S-PN [6‐10, 17‐23]. The first case was reported in 1999 [23]. Additional file 2 shows the epidemiologic data and clinical features of Thai patients in comparison to those in 12 previous reports [6‐10, 17‐23].

In this cohort, sensory and/or autonomic dysfunctions were reported as early symptoms and were objectively evident in the initial neurological assessments in all patients. In the report of Chao HC, autonomic symptoms were found in 68.5 % of patients during their first clinical evaluations [6]. In the study of Chao CC, most (21/28, 75 %) patients had sensory symptoms at onset [8]. In the same study, small sensory fiber loss and sudomotor nerve dysfunction were also revealed by pathological studies in 92.9 and 100 % of patients, respectively [8]. Because sensory symptoms are subjective and autonomic complaints can be nonspecific, objective evidence is inevitably important. In our study, comprehensive neurophysiological tests were used to confirm neuropathy and to grade the severity. In all four milder patients with normal NCS, the QST, which, in one test, assessed large and small sensory nerve functions, and the AFT, were abnormal, suggesting the lower sensitivity of NCS in neuropathic evaluation of ATTRv-PN, especially in the early stage [24]. Gastrointestinal dysfunctions and orthostatic intolerance were the most prevalent autonomic complaints. Gastrointestinal symptoms seemed to present in the early phase of disease, like previous studies [7, 10, 20]. Sudomotor dysfunction, though frequently evident by neurophysiological tests (the results of 7/7 QSART tested patients were abnormal.), was clinically unnoticeable in three patients. This was probably because the dysfunction was mild or mostly limited to the feet. Also, this might reflect that the sudomotor dysfunction is clinically less significant compared to gastrointestinal or cardiovascular autonomic involvement in this disease.

In contrast to other studies which recruited patients, who already had sensorimotor polyneuropathy or were the late stage [8, 9], the frequency of motor neuropathy in our study was comparably lower. This observation was because almost half of our patients were in the early stage of disease. Motor neuropathy appeared in the later stage of disease and was usually accompanied by significant weight reduction. Weight reduction has been hypothesized to be due to gastrointestinal dysautonomia, dysphagia and muscular atrophy [7]. Of interest, our study showed that when motor neuropathy was present, the overall worsening of neuropathy tended to progress faster than when motor neuropathy was not present in both clinical and neurophysiological aspects (Table 2). In the study of Yang, the time of progression from mild to significant motor dysfunctions, for which the patient required a wheelchair to ambulate, was 2.5 to 8 years [9]. In four patients with preserved motor nerves, clinical worsening was subtle, and the neurophysiological studies showed no significant change in the follow-up time up to four years. The mean annual rate of change in the NIS in our patients with motor neuropathy was also comparable to that found in a meta-analysis of ATTRv-PN (11.7 points/year) [25]. Long-term follow-up is necessary to clearly show the natural history of ATTRA97S-PN. Diflunisal is the only disease-modifying drug available in Thailand. Three patients had long-term diflunisal treatment with good tolerability. The remaining patients did not receive diflunisal. This was due to patients’ decisions (Two developed gastritis-related symptoms after treatment and decided to stop.).

In ATTRA97S-PN, concurrent cardiopathy was not unusual [16]. It was also the leading cause of death in this cohort. Cardiac manifestations included progressive heart failure, conduction defects, arrhythmias, and sudden cardiac arrest. In ATTRA97S, cardiac involvement may be asymptomatic or pauci-symptomatic, at the time neuropathy is clearly evidenced. Cardiopathy preceding neuropathy was comparatively rarer [16]. In other mutations, such as ATTRV122I and ATTRT60A, cardiopathy may precede neuropathy or be a core clinical feature [12]. Systemic involvement, such as central nervous system, eye, and kidney involvement, was also uncommon in ATTRA97S. Concurrent monoclonal gammopathy could lead to misdiagnosis of paraproteinemic neuropathies or light-chain amyloidosis, potentially delaying the diagnosis [5]. In this study, serum/urine immunofixations were also done in all patients. Only one patient had monoclonal gammopathy. This patient was initially misdiagnosed with paraproteinemic neuropathy. In this case, bone marrow biopsy was performed to exclude plasma cell dyscrasia and light-chain amyloidosis. Because all patients had a positive family history, most bypassed tissue biopsy and underwent genetic tests.

Of interest, the age of onset appeared lower in this cohort and neuropathy can be evident in middle adulthood. ATTRA97S-PN has usually been found to manifest with late-onset (> 50 years) polyneuropathy [4, 6, 7]. However, two reported patients from mainland China had early-onset (38 and 23 years) disease [18, 19]. Both carried a heterozygous variant. One patient had slowly progressive autonomic neuropathy for two decades before developing muscular weakness at 58 years [19]. Another patient had had autonomic neuropathy at 23 and developed sensory and motor polyneuropathy two years later [18]. In our study, 3/9 patients had neuropathy starting in their early 30 s. The neuropathy of three patients manifested in the form of sensory and/or autonomic neuropathy. The course of disease during their 30 s (and until the 40 s in patient D1) seemed to be protracted without motor involvement. In two patients, whose parents were also examined, the age of onset was at least 20 years lower in the younger generation. In ATTRV30M, diversity in the age of onset among different populations is a recognized phenomenon [5, 26]. Anticipation (younger onset in the offspring, usually with increased severity) has also been repeatedly reported in ATTRV30M but is not common in ATTRA97S [18, 27‐31]. Similar to patients from Malaysia [21], the paternal or maternal ancestors of our patients migrated from southern China in the 19th century. It is possible that ATTRA97S-PN patients residing in Southeast Asian countries share a similar ancestor with Han-Taiwanese/Han-Chinese patients. Hence, these may reflect the common founder among those patients, rather than “hot-spot” mutation. Another supportive reason was that this mutation has not been reported in non-Han Chinese-related populations (excluding some cases with undocumented ethnicity). Further studies should be carried out to confirm this hypothesis. Population and genetic admixtures as well as environmental changes may contribute to modifying some phenotypes in Thai patients. However, whether anticipation is a biological phenomenon in ATTRA97S-PN still needs more evidence.

The treatment of ATTRv has expanded significantly during recent years, from symptomatic treatments and liver transplantation to increasing numbers of approved pharmacological options and their increasing availability. For current medications, research has emphasized the benefits of early treatment, prior to amyloid accumulation in tissues. Because the clinical manifestations of ATTRv-PN vary, diagnosis may not always be straightforward. In early onset ATTRV30M-PN, autonomic symptoms are prominent, resulting in easier recognition [5]. In ATTRA97S-PN, patients can present in their 30 s with relatively milder autonomic or sensory symptoms. As a result, physicians may overlook those apparently nonspecific autonomic complaints, particularly when some investigations were also negative. In such cases, we stress the importance of careful history taking, including a family history and detailed physical examination. In clinically suspicious cases, noninvasive neurophysiological tests (QST/AFT) objectively yield valuable neuropathic assessments.

This study had some limitations. First, due to the retrospective nature, some clinical data were lacking. Some data prior to clinical assessment were based merely on patient reports. However, in the authors’ opinion, the COMPASS-31 questionnaire had helped to systematize the collected autonomic symptoms. Second, to demonstrate the natural history of disease, a longer follow-up time is better. Diflunisal, a TTR tetramer stabilizer, was also given to three patients with motor nerve involvement, which may have modified the natural history of disease. Third, this study mainly focused on neuropathy, and less data on cardiopathy were discussed. Additionally, myocardial scintigraphy with the bone avid tracer ^99mtechnetium pyrophosphate, which has high sensitivity and specificity in the diagnosis of cardiac amyloidosis, was performed in only one case [12]. Finally, this study did not evaluate the quality of life, which could reflect the impact of disease.