Clinical and genetic profiles of hereditary transthyretin amyloidosis in Taiwan

Abstract

Objective The clinical and genetic profiles of hereditary transthyretin amyloidosis ( ATTR ) in Chinese populations remain elusive. We aim to characterize the features of ATTR in a Taiwanese cohort of Han Chinese descent. Methods Seventy‐nine patients with molecularly confirmed ATTR from 57 Taiwanese families were identified by sequencing the transthyretin gene ( TTR ). The clinical and electrophysiological data were scrutinized. Cardiac involvement of ATTR was evaluated by echocardiography and cardiac scintigraphy. Four microsatellite and seven single‐nucleotide polymorphism markers flanking TTR were genotyped to investigate the founder effect of the TTR Ala97Ser mutation. Results Most of the patients had a peripheral neuropathy with variable autonomic symptoms. The average age at disease onset ( AO ) was 58.2 ± 7.2 years, and the male patients had an earlier AO than female patients (56.6 ± 5.7 years vs. 61.8 ± 8.9 years, P = 0.013). Electrophysiological studies revealed a generalized axonal sensorimotor polyneuropathy and isolated median neuropathy in 84.5% and 15.5% of the patients, respectively. Up to 80% of the patients with ATTR had symptomatic or subclinical cardiac involvement. Six TTR mutations were identified in the participants including one novel mutation Glu89Asp. Among them, Ala97Ser was the most common mutation, accounting for 91.2% of the ATTR pedigrees. Detailed haplotype analyses demonstrated a shared haplotype in the 47 patients with the Ala97Ser mutation, suggesting a founder effect. Interpretation The present study delineates the distinct features of ATTR in Taiwan and provides useful information for the diagnosis and management of ATTR , especially in patients of Chinese descent.

Hereditary transthyretin amyloidosis in mainland China: a unicentric retrospective study

“…Nevertheless, the cause of chronic dry cough remains unknown, but could be attributed to deposition of amyloid in the vagal nerve or denervation hypersensitivity of the upper airways 19 . Three patients had lower cranial nerve involvement, including dysarthria or tongue fasciculation with Ala97Ser mutation, to our knowledge, which was not mentioned in previous studies with Ala97Ser mutation 9,10 …”

“…The fact that very few TTR Val30Met mutation cases have been reported before in mainland China probably means that such cases might have been greatly underestimated. As in the Taiwan cohort, our patients with the TTR Ala97Ser mutation usually presented with a late‐onset peripheral neuropathy and autonomic dysfunction 9 . Unlike the genetic situation in the north of China, TTR Ala97Ser mutation is the dominant mutation type in the south.…”

“…There is a great phenotypic variability between patients, but length‐dependent axonal, sensory‐motor and autonomic polyneuropathies with varying degrees of other organ involvement are the distinct features of ATTR 7,8 . In Taiwan, TTR Ala97Ser is the most common mutation 9,10 . However, a limited number of cases of ATTR have been reported in the form of case reports in mainland China 11–50 .…”

Early changes of nerve integrity in preclinical carriers of hereditary transthyretin Ala117Ser amyloidosis with polyneuropathy

“…Carriers with MNE at the wrist showed a reduced IENF density; a greater decline in the parameters of the ulnar, peroneal, tibial, and sural NCS; and elevated cold thresholds at the foot dorsum. Traditionally, carpal tunnel syndrome has been considered an early but nonspecific manifestation of ATTRv‐PN patients [42], and 43.8% of ATTRv‐PN patients with p.A117S mutation had sensory abnormalities compatible with carpal tunnel syndrome as their first symptoms [35]. However, the significance of median neuropathy at the wrist in ATTRv‐PN has not yet been determined.…”

Hereditary transthyretin amyloidosis

“…Большинство диссоциацией без ответа на иммуномодулирующую терапию [46]. Вариант G47A (p.G67A), эндемичный в Мексике, связан с характерным псевдосклеродерматозным поражением рук; другие распространенные мутации в этой области, S52P (p.S72P) и S50A (p.S70A), имеют тенденцию прогрессировать быстрее и имеют худший прогноз в отношении сердца [47].…”