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Rare genetic Creutzfeldt-Jakob disease with T188K mutation: analysis of clinical, genetic and laboratory features of 30 Chinese patients
  1. Qi Shi1,2,
  2. Wei Zhou1,2,
  3. Cao Chen1,2,
  4. Kang Xiao1,2,
  5. Yuan Wang1,2,
  6. Chen Gao1,2,
  7. Xiao-Ping Dong1,2
  1. 1National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
  2. 2State Key Laboratory for Infectious Disease Prevention and Control,Collaborative Innovation Center for Diagnosis and Treatment of InfectiousDiseases (Zhejiang University, Hangzhou), National Institute for Viral DiseaseControl and Prevention, Chinese Center for Disease Control and Prevention,Chang-Bai Rd 155, Beijing 102206, China, Beijing, China
  1. Correspondence to Professor Xiao-Ping Dong, Chinese Center for Disease Control and Prevention, National Institute for Viral Disease Control and Prevention, ChangBai Rd 155, Beijing 102206, China; dongxp238{at}

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Genetic human prion diseases include genetic or familial Creutzfeldt-Jakob disease (gCJD or fCJD), fatal familial insomnia (FFI) and Gerstmann-Sträussler-Scheinker syndrome (GSS). T188K gCJD was first described in Germany in 2000.1 The first Chinese patient with T188K gCJD was identified in 2009.2 By March 2016, 30 Chinese cases with T188K gCJD were identified and genetically diagnosed via national CJD surveillance programme. T188K gCJD is now the second-most frequent genetic prion disease among Chinese (next to FFI),3 however, is rarely reported in the other countries besides China.

All cases with 30 T188K gCJD in this report were Han-Chinese without sibship. The gender ratio (male to female) was 1:0.76. The onset ages of the patients varied from 40 to 85 years old, with the median age of 59 years. More patients (13 cases) were in the group of 50–59 years old, followed by those of 60–69 and 70–79 years old.

Clinical features

The interval from onset to reporting to CJD surveillance centre differed from 1 to 9 months (median: 2.5 months). All patients appeared more than one symptom at onset. Progressive dementia was noticed in 2/3 patients (20/30), followed by cerebellum symptoms and walk unstable (12/30), mental (10/30) and extrapyramidal (9/10) symptoms. In the whole clinical courses, progressive dementia was described in 93.3% (28/30) cases. Pyramidal or extrapyramidal dysfunction, myoclonus, visual or cerebellar disturbance and akinetic mutism appeared in 80% (24/30), 60% (18/30), 73.3% (22/30) and 43.3% (13/30) of the patients, respectively.

Cerebrospinal fluid (CSF) 14-3-3, electroencephalogram (EEG) and MRI

Lumber puncture was performed in 29 cases. Western blots of CSF protein 14-3-3 showed positive in 72.3% cases. Higher ratios of the patients with CSF 14-3-3 positive (11/21, 52.4%) display more numbers of neurological manifestations (≥four sporadic CJD (sCJD)-related symptoms) than those with CSF 14-3-3 negative (2/8, 25.0%), showing statistical difference (see online supplementary figure 1).

Supplementary Material

Supplementary figure 1

EEG was recorded in 29 cases. Only five cases revealed sCJD related periodic sharp wave complexes (PSWCs). 83.3% (25/30) cases received MRI scanning showed at least one of the two abnormalities (high signal in caudate nucleus and/or putamen, symmetric or asymmetric cortical ribbon syndrome on diffusion-weighted imaging (DWI)). The rates of MRI typical abnormality showed age-dependent increase. Higher ratios of the patients with MRI abnormality (12/25, 48.0%) displayed more numbers of neurological symptoms. Cortical ribbon syndrome on DWI was frequently detectable (77.8%). 81.0% (17/21) cases with CSF 14-3-3 positive showed MRI abnormality. All five cases with PSWC in EEG were MRI abnormal, while four cases with PSWC in EEG were CSF 14-3-3 positive (see online supplementary figure 2).

Supplementary Material

Supplementary figure 2

PRNP sequencing and family history

PRNP sequencing of those 30 cases revealed the same missense mutation from cytosine (C) to adenine (A) at the position of nt 563 in one PRNP allele, leading to a change from threonine (T) to lysine (K) mutation at residue 188. All 30 cases were methionine homozygous genotype at codon 129 (M129M) and glutamic acid homozygous at codon 219 (E219E) of PRNP.

Only four cases were recalled to have possible disease-associated family histories. The mother of case three was recalled appearing ataxia, walk unstable, alalia and hypermyotonia at 53 years old and died roughly 2 years afterwards without definite diagnosis. The sister (uncertain age) of case 10 was reported to die of CJD in Australia. The father (uncertain age) of case 13 and the mother (54 years old) of case 29 were recalled to have had similar clinical manifestations, but without referable neurological diagnosis.

Some health persons from five families had conducted PRNP sequencing. Except the second family, the other four families denied disease-related history. PRNP assays of the first family were described,4 3 out of the 11 tested persons containing T188K mutation. In the second family with possible disease history, three family members conducted PRNP sequencing without any mutation. In the third family, one (proband’s child) out of three members contained T188K mutation. Only one (proband’s child) from the fourth family conducted PRNP sequencing, not revealing T188K mutation. In the fifth family, three T188K mutation carries (one proband’s sibling and two proband’s children) were detected among four tested persons (figure 1). All asymptomatic T188K carriers maintained healthy by March 2016.

Figure 1

Medical histories and T188K mutations in PRNP sequencing in four tested families. Open square: male; open circle: female; filled square with arrow: proband case; square or circle with prolonged diagonal lines: deceased cases; square or circle with overstriking double diagonal lines: persons with neurological signs according to medical records; square or circle with fine line: asymptomatic carriers with the T188K mutation; square or circle with dot: persons having been confirmed not carrying the T188K mutation. I–IV in Roman numerals on the left indicate the different generations of the families.

Survival time

Up to March 2016, 24 cases died, 5 were alive and 1 was lost contact. The clinical duration varied from 2 to 13 months (median: 4 months). 83.3% (20/24) cases died within 5 months after onset. Female patients (median: 4.5 m) seemed to have long duration than male (median: 3.75 m). There was no significant difference in duration between young (<60 years old) and elder patients, and between the patients with more (≥four) and less (≤three) numbers of sCJD-related symptoms. The durations of the patients with CSF 14-3-3 positive, PSWC in EEG and typical abnormalities in MRI were relatively short (see online supplementary table 1).

Supplementary Material

Supplementary Table1


The clinical features of Chinese T188K gCJD are alike as that of sCJD, so that all 30 cases were suspected and considered as sCJD prior to PRNP sequencing. The disease-related family history of T188K gCJD seems to be unusual. The median onset age of T188K patients is slightly younger than that of Chinese patients with sCJD (61 years), but remarkably older than that of Chinese patients with FFI (47 years).3 CSF 14-3-3 positive and MRI abnormality are frequent, whereas PWSC in EEG is unusual. The durations of cases with T188K gCJD are short compared with that of patients with Chinese sCJD (median: 7.1 months).

The distributions of the subtypes of genetic prion diseases are different among China, Japan and Korea. There is a case with T188K gCJD and a few cases with FFI reported in Japan and Korea.5 On the contrary, V180I gCJD, M232R gCJD and P105L GSS are frequent in Japanese,5 but rare in Chinese.3 Chinese underwent several times of large ethnic migration and fusion in history. Most of the residents in the large cities of China emigrated from different parts of countryside in the 20th century. Although no fixed association of T188K mutation with ethnical characteristics of Chinese is proposed, further study for the potential linkage of PRNP mutations with ethnical differences would be interesting.


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  • Contributors QS and X-PD wrote the paper, conceived and designed the experiments. WZ and YW collected the samples and done the follow-up. WZ and KX performed the experiments. CG and CC analyzed the data. CC and KX contributed reagents/materials/analysis tools.

  • Funding This work was supported by Chinese National Natural Science Foundation Ggrants (81630062, 81572048), National Key Research and Development Plan (2016YFC1202700), and SKLID Development Grant (2016SKLID603, 2015SKLID503).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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