Clinical and Genetic Features of Transthyretin-Related Familial Amyloid Polyneuropathy in China
Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is an autosomal dominant, life-threatening, and treatable disorder caused by mutations in the transthyretin (TTR) gene. This condition is characterized by the deposition of amyloid in peripheral nerves and major organs, including the heart, kidneys, and eyes. Over 130 TTR mutations have been identified globally, with p.Val30Met being the most common in endemic countries. TTR-FAP has been reported in 29 countries, including many in Europe, the USA, Japan, China, and India. While the clinical and genetic features of TTR-FAP are relatively well-documented in Europe and Japan, there is a need for further research in China. This study reports the clinical and genetic features of eight Chinese TTR-FAP families, providing valuable insights into the disease’s presentation and genetic landscape in this population.
Study Design and Methodology
The study recruited 396 unrelated inherited peripheral neuropathy (IPN) families from the Neurology Department of The Third Xiangya Hospital and Xiangya Hospital between 2006 and 2019. All patients were evaluated by two experienced neurologists and met the diagnostic criteria for IPN. Genomic DNA was extracted from peripheral blood using phenol-chloroform procedures, and TTR mutations were screened using Sanger sequencing. Amino acid changes in TTR were numbered according to the mature protein sequence, excluding the 20-amino acid signal sequence. The severity of TTR-FAP was assessed using the neuropathy impairment score (NIS). Informed consent was obtained from all participants, and the study was approved by the Ethics Committee of The Third Xiangya Hospital of Central South University.
Genetic Findings
Five TTR mutations were identified in eight unrelated IPN families, encompassing 15 symptomatic patients and seven presymptomatic individuals. The mutations included c.112G>A (p.Asp18Asn), c.161G>C (p.Arg34Thr), c.165G>C (p.Lys35Asn), c.200G>A (p.Gly47Glu), and c.349G>T (p.Ala97Ser). Notably, c.112G>A and c.161G>C were reported for the first time in the Chinese population. The c.112G>A mutation was associated with peripheral neuropathy and cardiomyopathy, while c.161G>C was linked to pure peripheral neuropathy.
A unique finding was the coexistence of homozygous and heterozygous c.349G>T mutations in Family 1. The proband (III-1), who harbored the homozygous mutation, experienced alternating constipation and diarrhea at age 47 and developed distal numbness and weakness in the limbs at age 50. Clinical examination revealed distal weakness in the upper and lower limbs, hypalgesia below the wrists and ankles, and generalized areflexia. Electromyogram (EMG) studies indicated axonal polyneuropathy with upper limb predominance, and his NIS score was 77. Other family members with heterozygous c.349G>T exhibited similar symptoms, with one individual (II-3) dying of malnourishment caused by severe diarrhea at age 70. The NIS scores for heterozygous carriers II-1 and IV-1 were both 75, while IV-2 remained asymptomatic at age 20.
Clinical Features
The mean age at onset for the 15 symptomatic patients was 46.0 ± 15.3 years, ranging from 23 to 80 years. The most common initial symptoms were diarrhea or constipation, affecting six patients, while the most prevalent manifestation was limb weakness, observed in 13 patients. Paresthesia in the limbs was reported by 11 patients, and postural hypotension was present in 11 patients. Cardiac involvement was suspected in seven patients with c.112G>A, c.200G>A, and c.349G>T mutations. Renal involvement was detected in two patients carrying c.165G>C and c.200G>A mutations, and vitreous opacity was suspected in one patient with the c.165G>C mutation.
Phenotypic Variation and Genetic Hotspots
The study highlighted the phenotypic variation associated with TTR mutations. For instance, c.112G>A, first detected in the Chinese population, was associated with peripheral neuropathy and cardiomyopathy, contrasting with an American family harboring the same mutation, which presented with pure cardiac involvement. Similarly, c.161G>C, first reported in China, was linked to pure peripheral neuropathy, differing from an Italian family where it was associated with restrictive cardiomyopathy.
The c.165G>C mutation, previously reported to cause late-onset axonal polyneuropathy with prominent pain and autonomic dysfunction, was also associated with renal failure and vitreous opacity in this study. The c.200G>A mutation exhibited length-dependent peripheral polyneuropathy with cardiomyopathy, consistent with findings in Macau families. The c.349G>T mutation was related to late-onset sensory-dominant polyneuropathy and minor cardiac involvement, aligning with phenotypes observed in Taiwanese patients.
A significant observation was the coexistence of homozygous and heterozygous p.Ala97Ser mutations in one family, with no phenotypic difference between the two genotypes. This contrasts with other mutations, such as p.Val30Met, where homozygosity has been associated with vitreous amyloidosis and less autonomic involvement in Swedish, Japanese, and Turkish patients. Additionally, an African American family with homozygous and heterozygous p.V122I mutations exhibited earlier onset of amyloid cardiomyopathy in homozygous individuals.
Epidemiology and Mutation Prevalence in China
The study reviewed 32 literature reports of 86 Chinese TTR-FAP families with 32 mutations from 1994 to 2019. Including the eight families reported here, there are now 94 Chinese families with 34 different TTR mutations. The most frequent mutation was p.Ala97Ser (31.9%), followed by p.Val30Met (6.4%) and p.Val30Ala (6.4%). This suggests that p.Ala97Ser may be a hotspot mutation in China, differing from other endemic regions where p.Val30Met, p.Val122Ile, and p.Thr60Ala are more common.
The mean age at onset in the Chinese population (44.62 ± 13.63 years) was earlier than in American (59.6 years), Swedish (56.7 ± 13.2 years), and Cypriote (48.6 ± 15.0 years) populations but later than in Portuguese (42.8 ± 15.0 years), Turkish (40.4 ± 13.9 years), and Brazilian (32.5 years) populations. Early-onset TTR-FAP accounted for the majority of Chinese patients (60.4%), similar to Portugal (71.3%), while late-onset disease was predominant in the American population (79.2%).
Clinical Characteristics in China
The main clinical features of Chinese TTR-FAP patients included axonal peripheral polyneuropathy with predominant autonomic dysfunction (84.6%) and organ involvement such as cardiomyopathy (35.2%), vitreous opacity (25.3%), renal failure (5.6%), and meningeal involvement (2.5%). These findings underscore the importance of routine TTR screening in IPN patients, as TTR-FAP is a treatable disorder.
Conclusion
This study provides a comprehensive overview of the clinical and genetic features of TTR-FAP in China. It highlights the importance of routine TTR screening in IPN patients and reports novel mutations, such as c.112G>A and c.161G>C, in the Chinese population. The coexistence of homozygous and heterozygous c.349G>T mutations without phenotypic differences was a unique finding. The p.Ala97Ser mutation emerged as a potential hotspot in China, and the clinical features of Chinese TTR-FAP patients were characterized by early-onset axonal peripheral neuropathies with autonomic dysfunction predominance.
doi.org/10.1097/CM9.0000000000001094
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