Novel prion mutation (p.Tyr225Cys) in a Korean patient with atypical Creutzfeldt–Jakob disease

Figures & data

Figure 1 (A) Brain diffusion-weighted-MRI of the proband patient. (B) FDG PET imaging of proband patient.

Abbreviation: MRI, magnetic resonance imaging; FDG, fluorodeoxyglucose; PET, positron emission tomograp.

Figure 2 Family tree of the patient.

Note: I 1 and I 2, parents of the proband patient; II 1, proband patient; II 2, sister of the proband patient.
Abbreviation: CJD, Creutzfeldt–Jakob disease.

Figure 3 Next generation sequencing data for a patient with PRNP Tyr225Cys, verified by standard sequencing.

Figure 4 (A) ExPASY analysis of PRNP Tyr225Cys compared with normal PrP protein. (B) Comparison of normal PrP proteins with Tyr225 and mutant Cys225 in terms of distance from Met166. (C) In silico prediction of PRNP Tyr225 and Cys225. Helix-3 in prion proteins may be more flexible in the case of Cys225 due to the smaller size of cysteine.

Figure S1 EEG data of the patient.

Abbreviation: EEG, electroencephalogram.

Table 1 Examples of mutations, observed in atypical CJD cases

Mutation	Family history	AOO (y)	Disease duration	Symptoms	Imaging data/EEG	Biomarker data
Tyr225Cys	Unknown	59	5 years	Speech impairment, slow progressive dementia, rigidity myoclonic jerks	MRI: cortical signal changes in frontotemporoparietal region EEG: atypical triphasic waves	CSF: Weak positive for 14-3-3 protein CSF: reduced Aβ42 and elevated total Tau levels
Val180Ile^Citation25^–^Citation27	Negative or positive	70	More than 1 year	Neurological signs with dementia	EEG: Periodic sharp waves may be absent	Can be negative for 14-3-3 protein, but positive cases were also found
Glu196Lys^Citation28	Probably negative	75	18 months	Dementia, but no motor signs, misdiagnosed as FTD	MRI: larger cortical sulci in the frontal and temporal lobes EEG: normal	CSF: Positive for 14-3-3 protein, normal for Tau
Gly114Val^Citation29	Probable positive	24	5 years	Cognitive decline, movement impairment, aphasia, ataxia	EEG: sharp wave-like morphology MRI: restricted diffusion in the cortical ribbon	CSF: 14-3-3 protein, Total Tau and Aβ42 were normal
Octapeptide insertion^Citation30	Positive	23–35	4–13 years	CJD	NA	NA

Abbreviations: CJD, Creutzfeldt–Jakob disease; EEG, electroencephalogram; MRI, magnetic resonance imaging; CSF: cerebrospinal fluid; AOO, age of onset; NA, not available.

Table 2 Mutations, located in the C-terminal region of 3^rd helix of prion protein

Mutation	Family history	AOO (y)	Disease duration	Symptoms	Imaging/neurological
Glu217Arg^Citation44	Probable positive	45	Over 10 years	GSS, with FTD-like symptoms	MRI: mild cortical atrophy affecting the frontal, temporal, and parietal lobes, depigmentation in substania nigra Microscopy: large amyloid plaques with fibrillary cores
Tyr218Asn^Citation45	Probable positive	61	6 years	GSS, AD and FTD-like symptoms	EEG: focal frontotemporal slowing during hyperventilation, but no periodic short-wave complexes. PET: asymmetric bifrontal and parieto-occipital hypoperfusion Neuropathology: Spongiform changes, PrP^res and Tau pathology
Tyr225Cys	Unknown	59	5 years	Atypical CJD	MRI: cortical signal changes in frontotemporoparietal region
Tyr226Ter^Citation11,Citation46	Probable positive	55	27 months	AD-like dementia	EEG: generalized slowing and typical pattern of periodic synchronous wave complexes Neuropathology: amyloid deposition, CAA, Tau deposits
Gln227Ter^Citation11	Probable positive	42	72 months	FTD, extrapyramidal signs	SPECT: hypoperfusion in the left frontal and temporal cortex Neuropathology: PrP positive plaques, amyloid plaques, neurofibrillary tangles

Abbreviations: GSS: Gerstmann–Sträussler–Scheinker syndrome; FTD, frontotemporal dementia; MRI, magnetic resonance imaging; AD: Alzheimer’s disease; EEG, electroencephalogram; PET; positron emission tomography; CJD, Creutzfeldt–Jakob disease; AOO, age of onset; CAA, cerebral amyloid angiopathy.

Table S1 SF tapping profile of the proband patient

Marker	Levels	Normal values
Red blood cell count	0/mm^3
White blood cell count	0/mm^3
Glucose	108 mg/dL	70–110 mg/dL
Albumin	3.8 g/dL	3.5–5.0 g/dL
Sodium	139 mEq/L	137–145 mEq/L
Potassium	3.8 mEq/L	3.6–5.0 mEq/L
Chloride	103 mEq/L	98–107 mEq/L
CSF microalbumin	160.00 mg/L (IFCC)	Up to 350 mg/L (IFCC)

Abbreviations: CSF, cerebrospinal fluid; SF, spinal fluid; IFCC, International Federation of Clinical Chemistry.

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