Allele count in gnomAD: 0
Cases in literature: 26
Penetrance: Incomplete/variable – 90% of cases show signs of disease by age 70
26 symptomatic and asymptomatic cases are reported in the literature to date. Of which, 10 exhibited the disease phenotype and 16 are asymptomatic at time of reporting (see Table of Cases below). Seven cases are Met/Val129 heterozygote and 18 are Met/Met129 homozygotes (genotype at codon 129 for one case is not known) – where the in-phase allele is reported (n = 18), all cases are Gly114Val in cis with methionine at codon 129. The mean age of onset (n = 10) is 33.7 years (range 20 to 75 years, SD 16.5) and mean clinical duration-to-death (n = 6) is 38 months (range 24 to 60 months, SD 15.9).
The table below shows a summary of age of onset and clinical duration-to-death data, with survival analysis (Kaplan-Meier curves).
|AGE OF ONSET|
|Mutation||Without censored data||Survival curve including censored data|
|Gly114Val||33.7 +/- 16.5||10||31.5||22-36||20-75||10|
|Mutation||Without censored data||Survival curve including censored data|
|Gly114Val||38 +/- 15.9||6||48||24-48||24-60||7|
a) Gly114Val-Met129 Age of Onset
b) Gly114Val-Met129 Clinical Duration to Death
Figure: Kaplan-Meier curves for Gly114Val age of onset and clinical duration-to-death. The Kaplan-Meier curve is shown as a solid line and the 95% confidence limits are shown as dotted lines. In clinical duration graph b) censored data is shown as open circles, and they represent cases that were alive at last report/follow-up for whom total clinical duration-to-death is not known.
The clinical course in mutant Gly114Val-Met129 is marked by behavioural change, progressive dementia, extrapyramidal features and myoclonus, and is phenotypically associated with CJD. In one Polish patient, generalised ataxia was also noted. Beside one South Indian gentleman, who presented aged 75 years, onset is early between 22 and 45 years of age. The 16 asymptomatic carriers ranged in age from 12 to 61 years at time of reporting (age of one asymptomatic carrier is not known), four of which, are older than the mean age of onset for this mutant, suggesting incomplete or variable penetrance that is not yet well characterised.
Table of Cases
|Case report||Country of origin||Number of DNA-confirmed Gly114Val patients||Details of kindred and family members studied||Gender||Age at onset||Duration of illness (months)||Genotype at polymorphic sites||Presentation and other clinical details|
|Rodriguez MM 2005 ||Uruguay||6||Six members of family shown to harbour Gly114Val mutant, of which three where asymptomatic (III-7, III-9 and IV-5) and three manifest the disease phenotype (III-14, III-19 and IV 2). This family has a further two clinically affected but not genotyped members (II-1 and III-16).|
The father of III-7, III-9, III-14 and III-19 (case II-8) did not carry the mutation and is it hypothesised that their mother II-6 (deceased without suggestive symptomology, age at death not given) was an asymptomatic carrier. Asymptomatic Gly114Val members III-7 and III-9 were aged 45 and 44 years, respectively at time of report.
|22-27||24-48||4 Met/Val129 (in cis allele not known)|
|Presentation of disease in this family included neuropsychiatric disturbance (mood and personality), followed by dementia associated with Parkinsonism, pyramidal signs, myoclonus and mild cerebellar signs|
No post-mortem was performed for any member of this family, although frontal lobe biopsy data is available. No multicentric plaques were noted.
|Ye J 2008 ||China||4||Second family worldwide to be described with this mutation. The index case (III-4) and the son of her cousin (IV-2) were genetically confirmed. The daughter of III-4 (case IV-10) and mother of IV-2 (case III-1) were asymptomatic carriers of mutant Gly114Val and were aged 22 and 61, respectively.||3 F|
Alive 24 months from onset (IV-2)
|4 Met/Met129||Clinical features of index case, III-4, similar to sporadic CJD including progressive neuropsychiatric symptoms, dementia, myoclonus and pyramidal signs. Cerebellar signs were observed late but became marked.|
|Liu Z 2010 |
*See note below regarding discrepancies between this paper and that of Ye J 2008.
|China||11 (15)||A re-report of the proband’s neuropathology (brain biopsy) and further analysis of the Han Chinese family reported by Ye J 2008. Cases III-4 (proband), IV-2, IV-10 and III-1 reported previously by Ye J 2008. This paper finds a further 11 asymptomatic members harbouring the Gly114Val mutant, who range in age from 12 to 41 years.||6 F|
1 Met/Val129 (case IV-14 and not known which is the in cis allele)
Glu219Lys in cases IV-1 and IV-5 (in cis allele not known). Others were Glu219Glu.
|Beck JA 2010 ||India (1)|
|2||75-year-old South Indian gentleman had no relevant family history of neurological disease.|
No clinical information for Turkish female patient given.
|Not reported||Met/Val129 (in cis allele not reported)||75-year-old South Indian gentleman presented with excessive fatigue, perceived left-sided weakness and sensory disturbances of his feet. He rapidly deteriorated and experienced recurrent falls. Second patients was a 34-year-old Turkish lady – no further clinical details given|
|Cali I 2018 (first reported in abstract form in Mikhail F 2015) [5-6]||Poland||1||Polish-American gentleman. Patient’s father (III-B) died at age 34 with a similar phenotype and “autopsy proven CJD”, no genetic analysis available. Apart from proband’s father (III-B) no other family member over four generations known to have a neurological disorder. Genetic testing undertaken in five asymptomatic family members – 81-year-old paternal grandmother (II-E), three of the father’s siblings aged between 40 and 59 (III-C/D/E) and the proband’s sister (IV-B) – showed that none harboured the Gly114Val mutant**.||M||24||60||Met/Met129||Progressive dementia, aphasia and ataxia|
|Margolesky J 2018 ||US||1||Proband is African American. Proband’s mother and father, aged 51 and 49, respectively, are alive and well. Her brother aged 23 is well. Her paternal and maternal grandparents reached their ninth decades f life without neurodegenerative disease. Genetic testing was only undertaken in the proband and no further family members were tested.||F||20||Alive (duration of clinical course to date not given)||Not reported||Presented with involuntary movements and cognitive decline.|
|Cousyn L 2019 ||France||1||No known family history. Proband’s brother dies aged 25 years from a limb-girdle dystrophy; his parents both 74 years old and his maternal half-sister were neurologically intact.||M||36||48||Met/Met129||Developed attention deficit leading to difficulties in work as a computer engineer. Memory loss and spatial and temporal disorientation then developed and worsened rapidly.|
In the column of DNA-confirmed cases, the number in brackets represents the total number of cases contained within the report. They may not have all be counted due to cases being reported in a previous publication, the details of which will be given in the table. F, female; M, male. * This is the same family described by Ye J 2008, yet there is no reference to this paper in this report and data is presented as the first report of this family. The authors of these two papers are affiliated with the same hospital. It is of note that in the Ye J 2008 paper the proband was known to have been deceased at age 47, however, this same proband is reported contemporaneously here with no indication that she is in fact deceased. Although, the Liu Z 2010 paper identifies further asymptomatic Gly114Val members of the family, there are inconsistencies between these two papers. In Ye J 2008, the asymptomatic carrier daughter of proband (case IV-10) is said to be 22 years of age and Met/Met129 homozygous. In this paper, the age of the proband’s daughter (same IV-10 individual) is given as 17 years, and we are told she is Met/Val129 heterozygous. The original reporting of this case as Met/Met129 is the one taken into account. Furthermore, age of asymptomatic Gly114Val case, III-1 (mother of patient IV-2), was given as 61 years in Je Y 2008, and is given as 60 years in the Lui Z 2010 paper. Patient IV-2 was reported by Ye J 2008 as being 34, his age is still given as 34 in this paper. Asymptomatic carriers IV-4 and IV-5 are sisters (not twins) and are both reported as being aged 31 years. **Since the paternal grandmother (II-E) was Val/Val129 and the Gly114Val variant is allelic with Met129, the paternal grandfather would be predicted to have a Met/Val129 genotype and be a silent carrier of Gly114Val in cis with Met129 – he died without dementia aged 84 years. However, surprisingly, the genotype of the proband’s aunt (III-E) was Met/Val129 but with a normal Met129 allele. Therefore, it is suggested that either the mutation has arisen de novo in the paternal grandfather’s germline or a non-paternity event has skewed the genetics of this family.
Neurological examination and clinical investigations
|Rodriguez MM 2005 ||Ye J 2008 ||Beck JA 2010 ||Cali I 2018 ||Margolesky J 2018 ||Cousyn L 2019 |
|Age on onset (years)||27||22||22||45||32||75||24||20||36|
|Clinical duration to death (months)||24||24||48||24||Alive||Not reported||60||Alive||48|
|Examination findings||Corticospinal syndrome, hyperreflexia with bilateral Babinski signs, marked extrapyramidal syndrome, myoclonus and incontinence. Frontal signs.||Corticospinal syndrome, hyperreflexia (plantars flexor), bilateral extrapyramidal syndrome, frontal signs, myoclonus and incontinence. Mild cerebellar signs.||Marked extrapyramidal syndrome, myoclonus||Corticospinal dysfunction, generalised hyperreflexia and bilateral Babinski signs, extrapyramidal signa, myoclonus. No cerebellar signs.||Extrapyramidal syndrome, left-sided extensor plantar response and positive palmomental reflexes predominant on the right.||Asymmetric akinetic rigid syndrome, broken pursuit eye movements, myoclonic jerks and mild apraxia||Extrapyramidal syndrome with cogwheel rigidity, stooped posture and reduced arm swing, generalised ataxia and myoclonus||Facial and limb myoclonic jerks, asymmetric action and postural tremor (affecting left > right arm), slow gait and decreased arm swing.||Extrapyramidal syndrome, hyperreflexia and myoclonus.|
|Neuropsychological deficits||Panic attacks, visual hallucinations, apathy and self-neglect||Hallucinations, indifference, apathy, asomatognosia, dementia. Folstein score 12 months from onset 17/30||Puerility, progressive dyspraxia, tendency to mutism and restlessness. Insomnia.||Generalised dementia, emotional lability, severe apathy and insomnia||Progressive memory impairment and insomnia leading to inability to work. MMSE score 17/30.||Cognition well preserved||Progressive cognitive decline with language impairment and loss of motor skills leading to three car accidents, withdrawal and agraphia. MMSE 20/30||Paucity of spontaneous speech output, bradyphrenia, incongruent smiling facial expression, emotional lability||Dysexecutive syndrome and impaired episodic memory with spatial disorientation suggestive of hippocampal dysfunction|
|CSF 14-3-3 protein||Not performed||Not performed||Not performed||Negative||Not performed||Negative||Negative||Not performed||Negative
(total tau was increased)
|EEG||Diffuse cerebral damage||Background 5-6 Hz activity, bilateral sporadic medium amplitude spike discharges||Background activity with a theta rhythm at 6-7 Hz||Background 5-6 Hz activity||Not performed||Not performed||Grade 2 dysrhythmia||Diffuse delta frequency slowing||Diffuse theta activity|
|MR brain||Not performed||Moderate diffuse encephalic atrophy||Diffuse cerebral atrophy||Moderate diffuse atrophy. Hyperintensities on DWI in caudate nucleus, putamen and periventricular regions||No obvious abnormalities on MR brain including DWI||Hyperintensities in putamen and caudate nuclei bilaterally||Left greater than right cortical atrophy in addition to restricted diffusion within the cortical ribbon on DWI||Signal hyperintensities in the cortex and striatum bilaterally on DWI||Hyperintensities of the parieto-occipital cortex on DWI associated with reduced apparent diffusion coefficient|
|Neuropathology||Moderate spongiform change, neuronal loss, gliosis and the absence of amyloid plaque deposits, however, synaptic PrPSc deposits were seen.||Not performed||Not performed||Neuronal loss and spongiform change, with synaptic PrP staining on immunohistochemical analysis.||Not performed||Not performed||Diffuse spongiform degeneration with PrP plaque-like collections in basal ganglia, thalamus and cerebellar molecular layer.||Not performed||Moderate spongiosis, moderate gliosis. Diffuse synaptic PrP staining on immunohistochemical analysis.|
|Codon 129 (in cis allele)||Met/Val129 (not reported)||Met/Val129 (not reported)||Met/Met129 (Met)||Met/Met129 (Met)||Met/Met129 (Met)||Met/Val129
|Not reported||Met/Met129 (Met)|
c.341G>T leading to GGT-to-GTT change at codon 114, resulting in Gly114Val missense mutation.
Case III-4 from Yen J 20082 (also reported in Liu Z 20103): Neuronal loss and spongiform change was seen. Deposits of PrPSc were restricted mostly to the neuronal cytoplasm, and no obvious PrPSc deposits were observed in extracellular areas. No tau pathology was seen. Three PK-resistant PrPSc bands ranging from 21 to 27 kDa were detected with predominance of monoglycosylated PrPSc (type 1).
Proband from Cali I 20185: Widespread spongiform degeneration and gliosis were most severe in the frontal, temporal and parietal cortices, and least severe in the occipital lobe and hippocampus. Severe spongiform degeneration was also present with the putamen but no globus pallidus, and within the medial nuclei of thalamus but not the lateral thalamus. The midbrain, cerebellum, pons and medulla were also free from spongiosis. Immunohistochemistry reveals fine diffuse PrP staining and occasionally larger granules within the cerebral cortex and neostriatum, as well as plaque-like (globular) PrP deposits in the putamen and cerebellum. There was intense astrogliosis in the frontal and temporal lobes.
Molecular typing of proteinase K-resistant PrP revealed a mixture of type 1 (21 kDa) and type 2 (19 kDa) conformations with only two, rather than the usual three PrPSc glycoforms5. The brain homogenate lacked the high molecular weight diglycosylated band, exhibiting only prominent monoglycosylated, and less prominent unglycosylated bands. Interestingly, a similar pattern has been reported for Pro105Ser9, CJD-associated Thr183Ala10 and Val180Ile11. Intracerebral inoculation of patient brain homogenate to CJD-susceptible transgenic mice that express human PrP-Met129 did not develop clinical or pathological signs of prion disease after nearly 700 days of observation, therefore displaying a lack of transmissibility.
Proband from Cousyn L 20198: Moderate spongiosis in most cortical areas, the caudate nucleus and the thalamus. The hippocampus was spared, contrasting with severe impairment of the entorhinal cortex. There was no confluence of the vacuoles, and gliosis was moderate. Diffuse synaptic labelling of PrP was noted by immunohistochemistry.
Structure-based protein function annotation:
Glycine 114 is located in the hydrophobic region of the N-terminal domain of PrP, participates in the highly conserved palindromic sequence, aa 113-AGAAAAGA-120 aa, and directly participates in the formation of the PrPC-PrPSc complex that leads to propagation of PrPSc, thereby, supporting the pathogenicity of the Gly114Val mutant12.
The hydrophobic region (residues 112-134, see Architecture of PrP) has a predicted propensity to form β-sheet secondary structure13, thought to undergo significant structural transition following prion infection – as antibodies directed toward mouse PrP residues 90-120 detect PrPC but not PrPSc 14 – and is proposed to be involved in PrPc-PrPSc interaction, as a misfolding initiation site that effects prion propagation12,15. Indeed, cells transfected with a PrP transgene that expresses mutant PrP with a deletion of the AGAAAAGA palindrome (residues 114-121) cannot be infected with PrPSc 16, indicating the necessity of the palindrome for conformational conversion of PrPC to PrPSc. When synthesised as peptides, the PrP region comprising amino acid residues 109 to 122 and 106 to 126, has a high intrinsic ability to polymerise into amyloid-like fibrils in vitro17-18, with the internal palindromic AGAAAAGA sequence displaying the highest tendency to form amyloid18. Furthermore, peptides that include the AGAAAAGA region antagonise the in vitro conversion of PrPC to PrPSc in a cell-free conversion model, again underlining the importance of these amino acids in the PrPC-PrPSc interaction and subsequent prion propagation19-20.
In addition to the amyloidogenic palindrome, the hydrophobic core itself is glycine rich, arranged in GXXXG motifs; a frequent motif in transmembrane α-helices that is reported to stabilise helix-helix associations and permit close packing of transmembrane domains21. The glycine residues in this region show perfect conservation across all mammalian species identified to date22-23 (see mammalian sequence alignment in Architecture of PrP). Relatively conservative amino acid substitutions of the glycine residues in this region (Gly119, Gly123, Gly126, Gly131) have been shown to diminish prion propagation and infectivity – reinforcing, the importance of the hydrophobic region in conversion of PrPC to PrPSc 24. Mouse homologue of the pathogenic Gly114Val mutation (mouse numbering: Gly113Val), leads to the formation of an altered prion strain characterised by decreased protease resistance but a higher degree of neurotoxicity25. Furthermore, the most neurotoxic deletion mutant in mice, as determined by the relative amount of wild-type expression required to rescue the phenotype, involves deletion of the hydrophobic region, however, these PrPC mutants do not form PrPSc 26-28.
Mouse homologue mutant Gly113Val, as expected, does not have an effect on the global structure, stability or dynamics of native monomeric mouse PrP29, but it has been shown to accelerate misfolding and aggregation relative to wild-type mouse PrP by inducing structure in the palindromic region29 which appears to be the site for inter-molecular association in PrP oligomers12,16,29. Valine is hydrophobic and being a Cβ-branched residue like isoleucine and threonine, it is known to be preferentially found in β-sheet structures30.
Therefore, it is possible that mutant Gly114Val, in a similar mechanism to mutant Ala117Val enhances β-sheet formation in the amyloidogenic palindrome, that drives PrPSc conversion.
In silico Pathogenicity predictions:
- Probability of pathogenicity: 0.672
- Standard error: 0.062
- Prediction: Unknown
- Score: 0.781
- Prediction: Pathogenic
A stringent REVEL score threshold of 0.75 is applied, above which the variant is classified as pathogenic.
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- Grasbon-Frodl E, Lorenz H, Mann U et al. Loss of glycosylation associated with the T183A mutation in human prion disease. Acta Neuropathologica 2004; 108(6): 476-484. (PMID: 15558291)
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