Genetic phenotypes and clinical characteristics description of hereditary transthyretin patients in China

doi:10.21203/rs.3.rs-1494325/v1

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Genetic phenotypes and clinical characteristics description of hereditary transthyretin patients in China

https://doi.org/10.21203/rs.3.rs-1494325/v1

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This study described 126 Chinese patients of hereditary transthyretin amyloidosis identified through a review of 29 literatures published between 2007 and 2020. The most common genotype in the Chinese population was Gly83Arg (25, 19.8%), which most likely presented visual and neurological abnormalities without reported death. The second and third common genotype were Val30Met (22,17.4%) and Val30Ala (10,7.9%). Peripheral Neurological manifestations (91,72%) were dominant in 126 patients. The following manifestation was autonomic neurological abnormalities (73,58%). Half of the cases were reported with visual disorders and nearly one-third of the cases presented cardiac abnormalities. Among all 126 reported patients, 48.4% were classified as neurological type, 50.0% as mixed type and only 1.6% as cardiac one. In addition. Chinese patients were mostly early onset (age of onset was 41.8years), the time from onset to death was 9.4 years. Subjects with cardiac involvement had a shorter survival duration.

Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal-dominant disorder. It is characterized by the extracellular deposition of amyloid fibrils in tissues and organs such as heart, peripheral neuropathy and eyes. Amyloidosis can be life-threatening with a short duration between onset to death^1,2. hATTR has been reported in 36 countries globally³ with morbidity rate of 10,186 persons (range, 5,526–38,468)⁴, especially as an endemic in Portugal, Sweden and Japan⁵. The prevalence of hATTR in China was estimated to be 2000 (range 435-10134)⁴. The normal transthyretin(TTR) is a tetramer composed of four identical subunits. TTR gene mutations could cause abnormal depolymerization, misfolding and aggregation of TTR which lead to amyloidosis formation. More than 140 TTR mutations have been reported worldwide, leading to considerable genotype-phenotype variations among different ethnic groups. Misfolded TTR monomer deposits in the form of amyloid fibrils and leads to intractable peripheral sensory and motor neuropathy, autonomic neuropathy, cardiomyopathy and other presentations.

So far, there had been few systematical reports on hATTR patients in China, especially in mainland China,though single case or pedigrees of hATTR had been reported. In this study, we searched all related literatures on hATTR in Chinese population and analyzed clinical features and mutations to develop a more comprehensive view of the genotype and phenotype of Chinese hATTR pattients.

Literature review

The systematic review included structured searches of peer-reviewed literature published from 2007 to 2020 via the following online reference databases: PubMed, web of science and the literature database in China. The searched key words included: “transthyretin”, "amyloidosis”, “hereditary transthyretin amyloidosis” “familial amyloidotic polyneuropathy (FAP)”, “familial amyloidotic cardiomyopathy (FAC) and “ATTR cardiomyopathy”. And all the above key words retrieval were combined with “China or Chinese”. These searches were conducted without regard to language or geography.

Case eligibility, data extraction, and analysis

Reports with ensured TTR mutation, specific clinical milestones and detailed description of clinical presentations were included in our study. Duplicated reports and the reports lacked of data in milestones or symptoms were removed according to criteria.

For each identified patient, the following variables were collected: 1) personal information (sex, age, natural course, family history); 2) the age at diseases onset and diagnosis; 3)reported presentations and involved organ; 4)mutation type and the age and reason of death.

Descriptive analysis of patients’ data got the following information:1) age at disease milestones (onset, diagnosis and death) by genotype. Subjects were classifified into early or late onset group depending on the onset age before or after of 50 years old. 2) Reported presentations and involved organ were further categorized as peripheral neuropathy, autonomic neuropathy, cardiac or visual abnormality and others. Peripheral neuropathy included paresthesia, hypesthesia, and muscular atrophy or walking disability. Autonomic neuropathy consisted of gastrointestinal dysfunction(diarrhea/constipation, nausea/vomiting and weight loss/anorexia), orthostatic hypotension, syncope or dizziness and genitourinary dysfunction (erectile dysfunction and urinary disorders). Cardiac abnormality included heart failure, conduction block, ventricular wall thickness on echocardiography and amyloid deposition on pathology. Visual abnormality consisted of vitreous opacity, glaucoma and dry eye. Others were neuropsychiatric problem (stroke, TIA and mental disorders), hearing loss and leptomeningeal enhancement on magnetic resonance imaging(MRI). These clinical evaluations were used to classify subjects into one of the following three phenotypes: 1) neurological type, with peripheral or autonomic neuropathy and without cardiac involvement ;2) cardiac type, with cardiac abnormality and without or only mild neurological abnormalities, and 3) mixed type, which covered all remaining symptomatic subjects.

For descriptive analysis, mean and standard deviation (SD), and inter-quartile range (IQR) were calculated for continuous variables based on the distribution. Time between disease milestones was calculated if all the values were available.

Patients

There were 57 potentially relevant reports extracted from the databases. After applying eligibility criteria and removing duplicate reports, 28 reports were excluded after applying eligibility criteria. Among them, 4 reports were duplicate, 9 reports did not include the detailed description of presentations, and 15 reports could not discriminate the demographics and clinical data for each individual patient. In the remained 29 individual reports, 8 reports were written in Chinese and the other 21 reports were written in English (Table 1).

Table 1

The baseline characteristics of the included studies
NO	Author, year	Sample size	Genotype	Title	Source
1	Xu Min, 2007¹³	7	Val30Ala	Transthyretin Val30Ala mutation in a Chinese family with familial amyloid polyneuropathy: clinical, pathological and genetic investigation	Chinese Journal of Neurology
2	Li Yanfeng, 2008¹⁰	24	Val30Met Phe33Val Gly67Glu	Clinical and genetic analysis of three families with familiar amyloid polyneuropathy	CHINESE MEDICAL SCIENCES JOURNAL
3	Xi Jianying, 2010²⁵	1	Glu54Lys	A Case of Familial Amyloid Polyneuropathy with a Transthyretin Glu54Lys Mutation	Chinese Journal of Clinical Neurosciences
4	Liu Jingyao, 2011¹²	1	Val30Ala	Clinical and histopathological features of familial amyloidotic polyneuropathy with transthyretin Val30Ala in a Chinese family	Journal of the Neurological Sciences
5	Zhang Yu, 2011³¹	1	Tyr114Cys	Transthyretin-Related Hereditary Amyloidosis in a Chinese Family with TTR Y114C Mutation	Neuro-degenerative diseases
6	Chen Lingyan, 2011⁶	2	Gly83Arg	Transthyretin Arg-83 mutation in vitreous amyloidosis	International Journal of Ophthalmology
7	Long Da, 2012¹⁶	15	Lys35Thr Leu55Arg	Vitreous amyloidosis in two large mainland Chinese kindreds resulting from transthyretin variant Lys35Thr and Leu55Arg	Ophthalmic genetics
8	Zhang Amei, 2013³⁷	9	Gly83Arg	Mutation p.G83R in the transthyretin gene is associated with hereditary vitreous amyloidosis in Han Chinese families	Molecular Vision
9	Zou Xuan, 2013¹⁷	6	Ala36Pro	Transthyretin Ala36Pro mutation in a Chinese pedigree of familial transthyretin amyloidosis with elevated vitreous and serum vascular endothelial growth factor	Experimental Eye Research
10	Xie Bing, 2017⁹	1	Gly83Arg	Family with familial vitreous amyloidosis with thyroid hormone binding protein Gly83Arg mutation	Chinese Journal of Ocular Fundus Diseases
11	Liu Tiruo, 2014⁸	12	Gly83Arg	Ophthalmic manifestations in a Chinese family with familial amyloid polyneuropathy due to a TTR Gly83Arg mutation	Eye
12	Yin Jie, 2014⁷	1	Gly83Arg	Chinese familial transthyretin amyloidosis with vitreous involvement is associated with the transthyretin mutation Gly83Arg: a case report and literature review	Amyloid
13	Fan Junping, 2014¹⁸	1	Gly47Arg	Myocardial involvement in transthyroxine protein-associated amyloidosis: a case report	Chinese Journal of Cardiology
14	Lv Wenjuan, 2014²⁶	1	Ile107Met	Multimodal retinal imaging in a Chinese kindred with familial amyloid polyneuropathy secondary to transthyretin Ile107Met mutation	Eye
15	Guan Hongzhi, 2015¹⁴	13	Val30Ala Val30Met Phe33Leu Lys35Asn Asp38Val Gly47Arg Gly53Glu Glu54Gln Glu54Lys	Clinical, neuropathological and genetic findings in patients with transthyretin-associated familial amyloid polyneuropathy	Chinese Journal of Neurology
16	Meng Lingchao, 2015²	9	Val30Met Phe33Leu Ala36Pro Val30Ala Phe33Val Glu42Gly	Hereditary Transthyretin Amyloidosis in Eight Chinese Families	Chinese Medical Journal
17	Chen Hui, 2016²⁷	1	Val50Leu	Exome Sequencing and Gene Prioritization Correct Misdiagnosis in a Chinese Kindred with Familial Amyloid Polyneuropathy	Scientific Reports
18	Cheng Qiusheng, 2016²⁷	1	Val50Met	Late-onset familial amyloid peripheral neuropathy: a case report and literature review	Chinese Journal of Nervous and Mental Diseases
19	Hu Die, 2017²²	1	Ala117Ser	Familial amyloid cardiomyopathy masquerading as chronic Guillain-Barre syndrome: things are not always what they seem	Frontiers of Medicine
20	Liu Gonglu, 2017²⁸	4	Thr49Ala Leu55Arg Tyr116Ser Ala36Pro	Clinical features of familial amyloid polyneuropathy carrying transthyretin mutations in four Chinese kindreds	Journal of the Peripheral Nervous System
21	Xu Jing, 2017²⁹	1	Leu75Pro	Transthyretin-related hereditary amyloidosis with recurrent vomiting and renal insufficiency as the initial presentation A case report	Medicine
22	Chen, H, 201732²⁷	1	Val50Leu	Exome Sequencing and Gene Prioritization Correct Misdiagnosis in a Chinese Kindred with Familial Amyloid Polyneuropathy	Scientific Reports
23	Chen Chuhong, 2017³⁰	1	Leu75Pro	Liver transplantation for the treatment of hereditary amyloidosis of transthyroid protein: a case report	Chinese Journal of Hepatobiliary Surgery
24	Zhu Peiran, 2017¹¹	1	Lys35Thr	Pathogenic gene mutation in a Han Chinese family with hereditary vitreous amyloidosis identified by Sanger sequencing	Chinese Journal of Clinical Laboratory Science
25	Chen Qian, 2018²¹	1	Ala117Ser	A Missense Variant p.Ala117Ser in the Transthyretin Gene of a Han Chinese Family with Familial Amyloid Polyneuropathy	Molecular Neurobiology
26	Hu Boling, 2018³³	1	Glu74Lys	A Family Report and Literature Review of TTR-type FAP with Eye Abnormalities	Journal of Apoplexy and Nervous Diseases
27	Yuan Zhenhua, 2019²⁴	1	Ala117Ser	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	Journal of Clinical Neuroscience
28	Fan Kuan, 2019²⁰	5	Asp18Gly	The identification of a transthyretin variant p.D38G in a Chinese family with early-onset leptomeningeal amyloidosis	Journal of Neurology
29	Miao xin, 2019³²	1	Phe84Ser	A case of amyloid peripheral neuropathy with central involvement caused by phe84ser mutation	Chinese Journal of Integrative Medicine on Cardiocerebrovascular Disease
30	Qin jin, 2019²³	1	Ala117Ser	Noninvasive diagnosis of hereditary transthyretin-related cardiac amyloidosis: A case report.	Medicine

The retained reports included 126 cases contributed by 58 pedigrees of Han Chinese descent. Genotypes were accurately identified in the above reports. Among the 126 cases, the description analysis was conducted by different genotype including the age of onset, death and duration between onset to diagnosis or death (Table 2). Of all 126 cases, 85 (67.4%) patients were male, and 102(81.0%) had family history. The mean age at onset (AO) and disease duration from presentation to diagnosis were 41.8 ± 8.9 years and 5.9 ± 3.6 years respectively. The mean duration from presentation to death was 9.4 ± 5.5 years with mean age of death (AD) of 47.2 ± 10.2 years.

Table 2

Characteristics of 126 hATTR cases
	All	Gly83Arg (p.Gly103Arg)	Val30Met (p.Val50Met)	Val30Ala (p.Val50Ala)	Leu55Arg (p.Leu75Arg)	Ala36Pro (p.Ala56Pro)	Lys35Thr (p.Lys55Thr)	Gly47Arg (p.Gly67Arg)	Asp18Gly (p.Asp38Gly)	Gly47Glu (p.Gly67Glu)	Ala117Ser (p.Ala137Ser)	Other^a
N	126	25	22	10	9	9	8	6	6	4	4	23
% of Samples	100%	19.8%	17.4%	7.9%	7.1%	7.1%	6.3%	4.8%	4.8%	3.2%	3.2%	18.3%
% Male	85(67.4%)	13(52.0%)	15(68.2%)	4(40.0%)	7(77.8%)	7(77.8%)	5(62.5%)	5(83.3%)	4(66.7%)	4(100%)	3(75%)	18(85.7%)
% Family History	102(81.0%)	25(100%)	11(50%)	10(100%)	9(100%)	6(66.8%)	8(100%)	5(83.3%)	6(100%)	4(100%)	2(50%)	16(69.6%)
Age at presentation onset, years, mean (SD)	41.8(8.9)	39.4(4.1)	47.0(8.6)	34.2(3.5)	33.9(5.4)	38.8(8.8)	44.3(2.9)	29.5(6.0)	31.3(6.7)	40.0(6)	60.8(4.8)	40.3(8.2)
Late -onset,n(%)	23(18.3%)	9(36.0%)	6(27.3%)	0(0)	0(0)	0(0)	0(0)	0(0)	0(0)	0(0)	4(100%)	4(17.4%)
Time from presentation onset to diagnosis, years, mean (SD)	5.9(3.6)	8.5(5.3)	8.6(2.3)	4.0(2)	6.3(2.3)	2(0.9)	2.4(0.6)	3(0.8)	4.5(0.5)	3.5(0.5)	3.5(1.5)	4.6(2.9)
Age at Death, years, mean (SD)	47.2(10.2)	—	54.3(3.8)	37.3(1.8)	53.6(7.8)	58.7(1.8)	57.7(3.1)	32.3(2.9)	39(4.0)	45.5(6.5)	—	44(10.5)
Time from presentation Onset to death,years, mean (SD)	9.4(5.5)	—	8.7(0.6)	4.3(2.0)	22.2(7.7)	10(1.3)	12.7(3.1)	4.7(1.1)	7.5(5.3)	4.5(0.5)	—	5.5(2.3)
# All other genotypes with <_3 subjects in total. These are genotypes: Glu54Lys,Phe33Val (three subjects each); Phe33Leu,Val50Leu,Thr49Ala,Leu75Pro ( two subjects each), Tyr114Cys,Ile107Met, Lys35Asn, Asp38Val, Gly53Glu,Glu54Gln,Glu42Gly,Tyr116Ser,Phe84Ser one subject each)

DNA analysis

Genotype analysis revealed 26 TTR mutations, including Gly83Arg^6–9(25 cases), Val30Met^10,11(22), Val30Ala^12–14(10), Leu55Arg^15,16(9), Ala36Pro¹⁷(9), Lys35Thr¹⁶(8), Gly47Arg^14,18(6) Asp18Gly^19,20(6),Gly47Glu¹⁴(4), Ala117Ser^21–24(4) and other mutations less than 4 subjects each, including Glu54Lys²⁵, Phe33Val² (three subjects each); Phe33Leu^18,26, Val50Leu²⁷, Thr49Ala²⁸, Leu75Pro^29,30 (two subjects each) and Tyr114Cys³¹, Ile107Met²⁶, Lys35Asn¹⁶, Asp38Val¹¹, Gly53Glu¹¹, Glu54Gln¹¹, Glu42Gly², Tyr116Ser²⁸, Phe84Ser³², Glu74Lys³³ (one subject each). The three most common genotypes were Gly83Arg (19.8%), Val30Met (17.4%)and Val30Ala (7.9%). Gly83Arg mutation was the most common mutation in our study

Clinical course and milestone

Summary of meaningful milestones was listed in Table 2. The mean AO was 41.8 years .The Ala117Ser cases were all late-onset and mean AO was 60.8 ± 4.8 years. The average AO of other mutations was less than 50 years old. Nine cases(36%) of Gly83Arg mutation, six (27.3%) of Val30Met, one of Phe33Leu (50%) and Tyr116Ser, Lys35Asn and Ile107Met mutation( 1/1) were late-onset, while other mutations (Val30Ala,Leu55Arg, Ala36Pro, Lys35Thr, Gly47Arg, Asp18Gly, Gly47Glu, Glu54Lys, Phe33Val, Val50Leu, Thr49Ala, Leu75Pro,Tyr114Cys,Asp38Val, Gly53Glu,Glu54Gln, Glu42Gly, Phe84Ser and Glu74Lys)were only early-onset.

Patients of hATTR had poor prognosis and the average AD was 47.2 years. Patients with Gly47Arg mutation had the lowest AD (29.5 ± 6.0 years) and Ala36Pro had the maximum AD (58.7 ± 1.8 years), No death was reported in patients with Gly83Arg and Ala117Ser mutation. Patients with Leu55Arg mutation had the longest duration from onset to death ( 22.2 ± 7.7 years). Patients with Lys35Thr and Ala36Pro had longer survival time (12.7 and 10 years respectively), while Val30Ala, Gly47Glu and Gly47Arg had worse prognosis ( survival time was 4.3, 4.5 and 4.7 years respectively). Patients with Val30Ala mutation had the shortest time from presentation onset to death (4.3 ± 2.0 years). Gly47Arg mutation had the lowest AO (29.5 ± 6.0 years), AD (32.3 ± 2.9 years) and shorter duration from onset to death (4.7 ± 1.1 years).

Clinical presentations

The proportions of every phenotype stratified by different genotype were listed in the Table 3. Cardiac, autonomic neurological, peripheral neurological, visual and the other abnormalities were calculated both in total and in specific mutations.

Table 3

Presentations distributions of 126 hATTR cases
Feature	All	Gly83Arg	Val30Met	Val30Ala	Leu55Arg	Ala36Pro	Lys35Thr	Gly47Arg	Asp18Gly	Gly47Glu	Ala117Ser	Other
Feature	All	(p.Gly103Arg)	(p.Val50Met)	(p.Val50Ala)	(p.Leu75Arg)	(p.Ala56Pro)	(p.Lys55Thr)	(p.Gly67Arg)	(p.Asp38Gly)	(p.Gly67Glu)	(p.Ala137Ser)	Other
N	126	25	22	10	9	9	8	6	6	4	4	23
Cardiologic	39(30.95%)	1	2	10	0	2	0	6	0	4	2	11
Autonomic	73(57.94%)	0	21	10	4	4	0	6	0	4	3	21
Sensory/Motor	91(72.22%)	10	21	10	4	7	6	6	1	4	4	18
Visual	63(50.00%)	25	1	1	9	7	7	3	0	0	0	10
Other	18(14.29%)	0	0	4	2	0	0	2	5	0	0	5
Skin problem	3(0.02%)	0	0	1	0	0	0	0	0	0	0	2
Neuropsychiatric problem	6(0.05%)	0	0	0	0	0	0	0	5	0	0	1
Hearing loss	5(0.04%)	0	0	2	2	0	0	0	1	0	0	0
Leptormeningeal	7(0.06%)	0	0	1	0	0	0	2	2	0	0	2
enhancement	7(0.06%)	0	0	1	0	0	0	2	2	0	0	2
Main
Neurological	60(47.6%)	9	19	0	4	4	6	0	6	0	2	10
Cardiac	3(2.4%)	0	1	0	0	0	0	0	0	0	0	2
Mixed	38(30.2%)	1	2	10	0	2	0	6	0	4	2	11
# All other genotypes with <_3 subjects in total. These are genotypes: Glu54Lys,Phe33Val (three subjects each); Phe33Leu,Val50Leu,Thr49Ala,Leu75Pro ( two subjects each), Tyr114Cys,Ile107Met, Lys35Asn, Asp38Val, Gly53Glu,Glu54Gln,Glu42Gly,Tyr116Ser,Phe84Ser one subject each

Table 4

Neurological presentations distributions of hATTR cases
Feature	All	Gly83Arg	Val30Met	Val30Ala	Leu55Arg	Ala36Pro	Lys35Thr	Gly47Arg	Asp18Gly	Gly47Glu	Ala117Ser	Other
Feature	All	(p.Gly103Arg)	(p.Val50Met)	(p.Val50Ala)	(p.Leu75Arg)	(p.Ala56Pro)	(p.Lys55Thr)	(p.Gly67Arg)	(p.Asp38Gly)	(p.Gly67Glu)	(p.Ala137Ser)	Other
N	126	25	22	10	9	9	8	6	6	4	4	23
Sensory/Motor	91	10	21	10	4	7	6	6	1	4	4	18
Lower Limbs numbness	80	4	21	6	4	6	6	6	1	4	4	18
Upper Limbs numbness	80	10	21	2	4	7	5	6	0	4	3	18
Muscular atrophy/weakness	69	0	21	4	4	4	6	6	0	4	4	16
Autonomic	73	0	21	10	4	4	0	6	0	4	3	21
Diarrhea/constipation	52	0	19	8	4	3	0	2	0	0	2	14
Nausea/vomiting	29	0	16	8	0	0	0	0	0	0	0	5
Weight loss/anorexia	26	0	2	8	0	0	0	2	0	0	1	13
Orthostatic hypotension	41	0	4	9	0	3	0	4	0	4	1	16
Syncope/dizziness	15	0	0	2	0	0	0	4	0	4	1	4
Erectile dysfunction	21	0	12	0	0	0	0	0	0	4	0	5
Urinary	25	0	16	1	0	0	0	0	0	0	0	8

Table 5

Cardiologic presentations distributions of hATTR cases
Feature	All	Gly83Arg	Val30Met	Val30Ala	Leu55Arg	Ala36Pro	Lys35Thr	Gly47Arg	Asp18Gly	Gly47Glu	Ala117Ser	Other^a
Feature	All	(p.Gly103Arg)	(p.Val50Met)	(p.Val50Ala)	(p.Leu75Arg)	(p.Ala56Pro)	(p.Lys55Thr)	(p.Gly67Arg)	(p.Asp38Gly)	(p.Gly67Glu)	(p.Ala137Ser)	Other^a
N	126	25	22	10	9	9	8	6	6	4	4	23
Cardiologic	39	1	3	10	0	2	0	6	0	4	2	11
Ventricular wall thickness	36	1	2	9	0	2	0	6	0	4	2	10
AV block/bundle-branch block	10	1	1	6	0	0	0	0	0	0	1	1
Heart failure	9	0	0	0	0	1	0	0	0	4	2	2
Pericardial effusion	1	0	0	0	0	0	0	0	0	0	0	1
Amyloid deposition	1	0	0	1	0	0	0	0	0	0	0	0
# All other genotypes with <_3 subjects in total. These are genotypes: Glu54Lys,Phe33Val (three subjects each); Phe33Leu,Val50Leu,Thr49Ala,Leu75Pro ( two subjects each), Tyr114Cys,Ile107Met, Lys35Asn, Asp38Val, Gly53Glu,Glu54Gln,Glu42Gly,Tyr116Ser,Phe84Ser one subject each)

Neurological phenotype was the most common one in the 126 patients. Ninety-one cases (72.22%) presented peripheral neurological problems which were higher in the Val30Ala (100%), Gly47Arg (100%), Gly47Glu (100%), Ala117Ser (100%), Val30Met (95.5%), Ala36Pro (77.8%) and other (78.2%), compared with Leu55Arg (44.4%), Gly83Arg(25%)and Asp18Gly (16.7%) category. Autonomic neurological presentations (57.9%) were the second common. Val30Ala (100%), Gly47Arg (100%), Gly47Glu (100%), Val30Met (95.5%) and Ala117Ser (75%) had obviously higher rate of this autonomic abnormalities compared with Gly83Arg (0), Lys35Thr (0) and Asp18Gly (0) categories. Thirty-nine cases (31%)presented cardiac abnormality. All patients with mutations of Val30Ala (100%), Gly47Arg(100%) and Gly47Glu(100%) had cardiac problems while those with Leu55Arg(0%), Lys35Thr(0%), Asp18Gly(0%)and Gly83Arg(4%) had no or very few cardiac abnormalities. Sixty-three cases ( 50%) were reported with visual disorders. Gly83Arg(100%) and Leu55Arg(100%) contributed most of visual presentations, followed by Lys35Thr(87.5%), Ala36Pro(77.8%) and Gly47Arg(50%). Asp18Gly(0), Gly47Glu(0), Ala117Ser(0), Val30Met(4.5%) and Val30Ala(10%) had no or very few visual problems. Eighteen cases were reported with other presentations, followed by leptomeningeal enhancement(5.6%), neuropsychiatric problem(4.8%) and hearing loss(4.0%). Asp18Gly mutant was liable to have neuropsychiatric problem(83.3%) and leptomeningeal enhancement (33.3%), and Gly47Arg also had leptomeningeal enhancement (33.3%).

Among all 126 reported patients, 48.4% were classified as neurological type, 50.0% as mixed type and only 1.6% as cardiac one. One of Val30Met and both Leu75Pro mutants mainly presented cardiac abnormality. Gly83Arg mutant mainly had visual problems, partly combined with peripheral neurology and only one had the cardiac hypertrophy and abnormal late enhancement on magnetic resonance imaging. Leu55Arg and Lys35Thr mutants had neurological and visual abnormalities without any cardiac involvement. Val30Met and Ala36Pro mutants mainly has neurological problems with a few cardiac abnormalities. Val30Ala, Gly47Arg and Gly47Glu mutants had nearly equal neurological and cardiac problems. Asp18Gly mutant mainly had neuropsychiatric problem without cardiac involvement.

According to the data, Gly83Arg was the most common mutant genotype in the Chinese population. The difference of clinical feature between Gly83Arg and the other genotype were statistically significant. All patients with Gly83Arg mutation had family history, while only 71.93% of non-Gly83Arg genotype had family history. The AO in the Gly83Arg and non-Gly83Arg genotype showed no statistic significance. When compared with non-Gly83Arg mutants, patients with Gly83Arg had more visual presentations, less autonomic, peripheral neurological and cardiac presentations. No death was reported in Gly83Arg. The AD in the non-Gly83Arg was 37.4 years, and the year of onset to death is 5.79 years.

More than 140 TTR mutations have been reported worldwide, with varied clinical presentations and disease progression. The distribution of genotypes and phenotypes of 126 Chinese patients with hereditary TTR amyloidosis were analyzed in the study aiming at better understanding the clinical and genetic characteristics of Chinese hATTR patients.Hereditary transthyretin amyloidosis was classified to three phenotypes (neurological, cardiac and mixed), and our patients mainly presented with the mixed type (50%). Most patients were early-onset. Peripheral neuropathy was the most-common (72.2%) clinical presentation. And the Chinese hTTR patients had the same poor prognosis with mean age of death less than 50 years old.

Similar to previous studies^34,35, we discovered a male predominance and not 100% family history. The gender predominance and the lack of insured family history may be explained by variety of mutation penetration. Among the overall identified 26 mutations in our study, Gly83Arg (19.8%) was the most common gene mutation, and Val30Me (17.4%)was the second common one, while Val30Met was the most common mutation in many other countries³⁴. Two widely reported mutations (Ile68Leu and Val122Ile) were not found in our study. This finding suggests that geography and race can cause heterogeneity in genotypes. Other common gene mutations in Chinese population include Asp18Gly, Ala36Pro, Gly47Arg et al. Some infrequent gene mutations were also been reported in the Chinese population. A potentially highly heterogeneous mutations might occur in China.

Gly83Arg, the most common genotype in China, showed some general features. The AO was 39.4 years and one third was late-onset. The most common main symptom was visual abnormality. The second common presentation was sensory/motor neurological and mostly presented with upper limbs numbness. Only one patient had cardiac involvement, and none of them had autonomic or other presentations. No death data had been reported in this genotype. There were a few reports on Gly83Arg outside China, making it difficult to make a comparison. In many countries, Val30Met was the most common gene mutation. According to Transthyretin Amyloidosis Outcomes Survey (THAOS) registry, 99.1% of cases in Portugal were Val30Met mutation, following by 90.1% in Sweden.

In our study, the neurological phenotype was mainly in patients with Val30Ala, Gly47Arg, Gly47Glu, Ala117Ser and Val30Met, while it is mainly seen in Val30Met mutation worldwide³⁶. Sensory and motor neurological presentations turned out to be the most common abnormality in China and other countries. Val30Ala (100%), Gly47Arg (100%), Gly47Glu (100%) and Ala117Ser(50%) were prone to have cardiac involvement. While according to THAOS³⁴, Val30Met and Val122Ile³⁴ were the most to present cardiac phenotype. As for visual involvement, Gly83Arg(100%), Leu55Arg(100%), Lys35Thr(87.5%) and Ala36Pro(77.8%) were the most common ones. While according to previous epidemiological researches, genetic mutation with visual impairment varies, including Gly83Arg³⁷ and Ala36Pro¹⁶ in Chinese, Ala36Pro in Greek³⁸.

There were also important findings regarding to the timing of disease milestones. The mean AO in Chinese hATTR patients was 41.8 years, whereas onset age reported was 53 to 61 years in Western Europe³⁴ and 70 in United States³⁵. According to THAOS reported from Japan, hATTR patients were 51.1 (33.3–72.3) years³⁹. 18.3% of patients in our study had symptoms after 50 years old (late-onset phenotype) and this phenotype was mostly seen in Gly83Arg (9/23), Val30Met (6/23) and Ala117Ser (4/23) genotype. While according to THAOS registry, late-onset phenotype was mostly seen in Val30Met, followed by Val122Ile³⁴, Thr60Ala and Ile68Leu in Western Europe and United States³⁴. The time from onset to death was 9.4 years in our study, ranged from 4.3 years in Val30Ala mutation to 22.2 years in Leu55Arg mutation. Subjects with cardiac involvement as in Val30Ala,Gly47Arg and Gly47Glu had a shorter survival duration.

The diagnosis of hATTR was not optimistic in China. Time from symptom onset to diagnosis was 5.9 years. Val30Met had the longest duration between onset to final diagnosis. The delay of of proper diagnosis, even for patients with a defined family history, may be the reason for poor prognosis in Chinese hATTR patients. Therefore, it is very important and urgent to raise awareness of hATTR in China.

This study was a patient-pool study with incomplete data which brought limitations in three aspects. First, many reports were pedigrees, which would affect the distribution of genotype. Second, the data were biased for lacked of a comprehensive examination in disease involvement among some studies. Third, follow-up information was limited and only parts of studies reported survival information.

Despite some limitations, these case reports are important resources to know the current situation of hATTR in China. The epidemiological characteristics of diseases vary greatly in different countries and regions. There were few cohort studies on this rare disease in China and our study might partially make up for this shortcoming.However, prospective cohort studies with more samples are needed to know the characteristics of Chinese hATTR patients .

This study focused on the 126 Chinese hATTR patients obtained from the literature review. The most common genotype in the Chinese population was Gly83Arg, which most likely presented with visual and neurological abnormalities without reported death. Another common genotypes were Val30Met and Val30Ala. As for phenotype, 48.4% were classified as neurological type, 50.0% as mixed type and only 1.6% as cardiac one. Peripheral neurological manifestations (72%) were dominant phenotype in 126 patients. The following manifestations were autonomic neurological abnormalities (58%)and visual disorders(50%). Nearly one-third cases presented cardiac abnormalities. Chinese hATTR patients were mostly early onset (AO 41.8years), the time from onset to death was 9.4 years. Subjects with cardiac involvement had a shorter survival duration.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

All data generated or analysed during this study are included in this published article [and its supplementary information files]

Competing interests

The authors declare that they have no competing interests

Funding

This study was funded by CAMS Innovation Fund for Medical Sciences（CIFMS 2021-1-I2M-003）and China Alliance for Rare Diseases, Beijing Society for Diagnosis, Treatment and Guarantee of Rare Diseases---Research Project on ATTR

Authors' contributions

HXY, TZ, GHZ, ZSY conceived and supervised the work. HXY, TZ, GHZ wrote the manuscript and made figures. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work, and have given final approval for the version to be published. All authors read and approved the final manuscript.

Acknowledgments

Not applicable

Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry. 2015;86(9):1036-1043.
Meng LC, Lyu H, Zhang W, Liu J, Wang ZX, Yuan Y. Hereditary Transthyretin Amyloidosis in Eight Chinese Families. Chin Med J (Engl). 2015;128(21):2902-2905.
Cruz MW, Schmidt H, Botteman MF, et al. Epidemiological and clinical characteristics of persons with transthyretin hereditary amyloid polyneuropathy: a global synthesis of 532 cases. Amyloid. 2017;24(sup1):109-110.
Schmidt HH, Waddington-Cruz M, Botteman MF, et al. Estimating the global prevalence of transthyretin familial amyloid polyneuropathy. Muscle Nerve. 2018;57(5):829-837.
Yamashita T, Ando Y, Okamoto S, et al. Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy. Neurology. 2012;78(9):637-643.
Chen LY, Lu L, Li YH, et al. Transthyretin Arg-83 mutation in vitreous amyloidosis. Int J Ophthalmol. 2011;4(3):329-331.
Yin J, Xia X, Shi Y, et al. Chinese familial transthyretin amyloidosis with vitreous involvement is associated with the transthyretin mutation Gly83Arg: a case report and literature review. Amyloid. 2014;21(2):140-142.
Liu T, Zhang B, Jin X, et al. Ophthalmic manifestations in a Chinese family with familial amyloid polyneuropathy due to a TTR Gly83Arg mutation. Eye (Lond). 2014;28(1):26-33.
Xie B, Cai SJ, Jiang M, Li H, Su G. Familial vitreous amyloidosis resulting from transthyretin variant Gly83Arg. Acta Ophthalmol. 2017;95(6):e520-e521.
Li YF, Ng H, Sun IU, Leong W. Clinical and genetic analysis of three families with familiar amyloid polyneuropathy. Chin Med Sci J. 2008;23(4):230-233.
Zhu PW, QY. Yu, MM. et al. Pathogenic gene mutation in a Han Chinese family with hereditary vitreous amyloidosis identified by Sanger sequencing. Chinese Journal of Clinical Laboratory Science. 2017;35(03):181-183.
Liu JY, Guo YJ, Zhou CK, et al. Clinical and histopathological features of familial amyloidotic polyneuropathy with transthyretin Val30Ala in a Chinese family. J Neurol Sci. 2011;304(1-2):83-86.
Xu MJ, JP. Li, CJ. Wang, XB. et al. Transthyretin Val30Ala mutation in a Chinese family with familial amyloid polyneuropathy: clinical, pathological and genetic investigation. Chinese Journal of Neurology. 2007;40(03):173-176.
Guan HL, Q, Chen, L. et al. Clinical, neuropathological and genetic findings in patients with transthyretin-associated familial amyloid polyneuropathy. Chinese Journal of Neurology. 2015;48(01):7-12.
Liu G, Ni W, Wang H, et al. Clinical features of familial amyloid polyneuropathy carrying transthyretin mutations in four Chinese kindreds. Journal of the Peripheral Nervous System. 2017;22(1):19-26.
Long D, Zeng J, Wu LQ, Tang LS, Wang HL, Wang H. Vitreous amyloidosis in two large mainland Chinese kindreds resulting from transthyretin variant Lys35Thr and Leu55Arg. Ophthalmic Genet. 2012;33(1):28-33.
Zou X, Dong F, Zhang S, Tian R, Sui R. Transthyretin Ala36Pro mutation in a Chinese pedigree of familial transthyretin amyloidosis with elevated vitreous and serum vascular endothelial growth factor. Exp Eye Res. 2013;110:44-49.
Fan J, Wu W, Chen W, et al. [Familial transthyretin amyloidosis with Gly47Arg mutation and cardiac involvement: a case report]. Zhonghua Xin Xue Guan Bing Za Zhi. 2014;42(9):784-785.
Fan K, Zhu H, Xu H, Mao P, Yuan L, Deng H. The identification of a transthyretin variant p. D38G in a Chinese family with early-onset leptomeningeal amyloidosis. Journal of neurology. 2019;266(1):232-241.
Fan K, Zhu H, Xu H, Mao P, Yuan L, Deng H. The identification of a transthyretin variant p.D38G in a Chinese family with early-onset leptomeningeal amyloidosis. J Neurol. 2019;266(1):232-241.
Chen Q, Yuan L, Deng X, et al. A Missense Variant p.Ala117Ser in the Transthyretin Gene of a Han Chinese Family with Familial Amyloid Polyneuropathy. Mol Neurobiol. 2018;55(6):4911-4917.
Hu D, Liu L, Yuan S, Yi Y, Peng D. Familial amyloid cardiomyopathy masquerading as chronic Guillain-Barre syndrome: things are not always what they seem. Front Med. 2017;11(2):293-296.
Qin J, Zhan C, Li H, et al. Noninvasive diagnosis of hereditary transthyretin-related cardiac amyloidosis: A case report. Medicine (Baltimore). 2019;98(30):e16566.
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 Clin Neurosci. 2019;60:164-166.
Xi JL, JH. Luo, SS. et al. A Case of Familial Amyloid Polyneuropathy with a Transthyretin Glu54Lys Mutation. Chinese Journal of Clinical Neurosciences. 2010;18(04):401-406.
Lv W, Chen J, Chen W, Hou P, Pang CP, Chen H. Multimodal retinal imaging in a Chinese kindred with familial amyloid polyneuropathy secondary to transthyretin Ile107Met mutation. Eye (Lond). 2014;28(4):452-458.
Chen H, Zhou X, Wang J, et al. Exome Sequencing and Gene Prioritization Correct Misdiagnosis in a Chinese Kindred with Familial Amyloid Polyneuropathy. Sci Rep. 2016;6:26362.
Liu G, Ni W, Wang H, et al. Clinical features of familial amyloid polyneuropathy carrying transthyretin mutations in four Chinese kindreds. J Peripher Nerv Syst. 2017;22(1):19-26.
Xu J, Yang M, Pan X, et al. Transthyretin-related hereditary amyloidosis with recurrent vomiting and renal insufficiency as the initial presentation: A case report. Medicine (Baltimore). 2017;96(10):e5737.
chen CY, QF. Wang YF. et al. Liver transplantation for the treatment of hereditary amyloidosis of transthyroid protein: a case report. Chinese Journal of Hepatobiliary Surgery. 2017;23(04):221-222.
Zhang Y, Deng YL, Ma JF, et al. Transthyretin-related hereditary amyloidosis in a Chinese family with TTR Y114C mutation. Neurodegener Dis. 2011;8(4):187-193.
Miao XZWMFea. A case of amyloid peripheral neuropathy with central involvement caused by phe84ser mutation. Chinese Journal of Integrative Medicine on Cardiocerebrovascular Disease 2010;17:956-959.
Hu BL, XQ. Qi, XL. Ding, WJ. A Family Report and Literature Review of TTR-type FAP with Eye Abnormalities. Journal of Apoplexy and Nervous Diseases. 2018;35(06):555-556.
Damy T, Kristen AV, Suhr OB, et al. Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS). Eur Heart J. 2019.
Maurer MS, Hanna M, Grogan M, et al. Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;68(2):161-172.
Waddington-Cruz M, Schmidt H, Botteman MF, et al. Epidemiological and clinical characteristics of symptomatic hereditary transthyretin amyloid polyneuropathy: a global case series. Orphanet J Rare Dis. 2019;14(1):34.
Zhang AM, Wang H, Sun P, Hu QX, He Y, Yao YG. Mutation p.G83R in the transthyretin gene is associated with hereditary vitreous amyloidosis in Han Chinese families. Mol Vis. 2013;19:1631-1638.
Jones LA, Skare JC, Harding JA, Cohen AS, Milunsky A, Skinner M. Proline at position 36: a new transthyretin mutation associated with familial amyloidotic polyneuropathy. Am J Hum Genet. 1991;48(5):979-982.
Sekijima Y, Mundayat R, Ishii T, Ando Y. The current status of the Transthyretin Amyloidosis Outcomes Survey (THAOS) in Japan. Amyloid. 2019;26(sup1):61-62.

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Genetic phenotypes and clinical characteristics description of hereditary transthyretin patients in China

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Abstract

Figures

Introduction

Methods

Literature review

Case eligibility, data extraction, and analysis

Results

Patients

DNA analysis

Clinical course and milestone

Clinical presentations

Discussion

Conclusion

Declarations

Ethics approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding

Authors' contributions

Acknowledgments

References

Status:

Version 1