Allele count in gnomAD: 0
Cases in literature: 38
Penetrance: Highly penetrant – 100% of cases show signs of disease by age 70
There are 38 genetically confirmed symptomatic (n = 22) and pre-symptomatic (n = 16) Ala117Val cases, from ten families, reported in the literature (reports for which individual level data are not available are excluded and shown shaded in the Table of Cases below). Of these cases, the genotype at polymorphic codon 129 was reported in 33 cases: 26 were Met/Val129 and 7 Val/Val129 and (where the in-phase allele was reported; n = 28) the mutation occurred exclusively on a Val129 background. Mean age of onset (n = 22) is 39.3 years (range: 20 to 64 years; SD 11.1) and mean clinical duration-to-death (n = 16) is 50.6 months (range: 24 to 108 months; SD 24.5). Patients with Met/Val129 heterozygosity had a mean age-of-onset of 42.6 years (n = 14, range: 20 to 64 years, SD 11.9) with mean clinical duration-to-death of 54.7 months (n = 9, range 24 to 108 months, SD 27.6), whereas patients Val/Val129 homozygous, had a ten-year earlier mean age of onset in patients with Val/Val129 homozygosity of 32.6 years (n= 7, range 26-43 years, SD 7.1), with a slightly shorter mean clinical duration-to-death of 47 months (n=6, range: 24 to 84 months, SD 22.3). The difference in age of onset between heterozygotes at codon 129 and homozygotes reached statistical significance, with a p value of 0.03. However, mean clinical duration to death did not (p = 0.60).
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|
|Ala117Val||39.3 +/- 11.1||22||39.5||33-43||20-64||22|
|Ala117Val-Met/Val129||42.6 +/- 11.9||14||40.5||35-53||20-64||14|
|Ala117Val-Val/Val129||32.6 +/- 7.1||7||29||26-41||26-43||7|
|Mutation||Without censored data||Survival curve including censored data|
|Ala117Val||50.6 +/- 24.5||16||48||36-84||24-108||22|
|Ala117Val-Met/Val129||54.7 +/- 27.6||9||48||36-84||24-108||14|
|Ala117Val-Val/Val129||47 +/- 22.3||6||48||30-84||24-84||7|
a) Ala117Val Age of Onset (all codon 129 haplotypes)
b) Ala117Val Clinical Duration to Death (all codon 129 haplotypes)
c) Ala117Val Age of Onset by Codon 129 Haplotype (p = 0.038, Log-rank test)
d) Ala117Val Clinical Duration by Codon 129 Haplotype (p = 0.502, Log-rank test)
Figure: Kaplan-Meier curves for Ala117Val age of onset and clinical duration-to-death. All codon 129 genotypes are shown in graphs a) and b). The Kaplan-Meier curve is shown as a solid line and the 95% confidence limits are shown as dotted lines. Graphs c) and d) show the effect of codon 129 haplotype, either Met/Val129 or Val/Val129. Censored data in clinical duration graphs b) and d) is shown as open circles, they represent cases that were alive at last report/follow-up and for whom total clinical duration-to-death is not known.
The prion disease associated with mutant Ala117Val was initially mis-attributed to Alzheimer’s disease1 prior to the advent of PrP immunohistochemistry2 and the subsequent identification of the Ala117Val mutation by PRNP sequencing3. As is commonly seen in other inherited prion diseases, phenotypic diversity is observed both clinically and pathologically in patients with the Ala117Val mutant, and it is associated with the Gerstmann-Straussler-Scheinker phenotype. Often, mood and personality changes precede the development of a recognisable neurological disorder. In some patients, a Parkinsonian extrapyramidal syndrome occurs early in the clinical course, in others the disease manifests with a progressive hemiparesis. Pyramidal, cerebellar and pseudobulbar syndromes also occur, in addition to dementia. (see Table of Cases and Neurological Examination below).
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|
|Tateishi J 1990 ||France||1||Alsatian (AND) family. At least eight members over four generations were affected. The disease in this family is characterised by onset during the 3rd or 4th decade with progressive difficulty in walking and dementia. Fatality is reached after a mean of 3 years. Cerebral biopsies of three members of this family showed multicentric amyloid plaques. (See Warter JM 1982) However, the patient reported here (V-17) is the first member of this family to be genetically confirmed. Further genotyping of this family was undertaken by Tranchant C 1992.||M||20||48||Met/Val129 (Val in cis)||Presented with difficulty walking and speaking. Examination revealed pseudobulbar syndrome, incoordination and pyramidal syndrome in all four limbs. Over the following two years, he dramatically deteriorated, his speech was incomprehensible, walking impossible and dementia ensued. Numerous multicentric plaques which were PrP +ve to immunohistochemical stains, were found post-mortem.|
|Hsiao KK 1991 ||Germany||5||Study of American GCSA kindred who are of German descent. 24 members over five generations are clinically affected. Five members are confirmed to harbour the Ala117Val mutant. One of which, the proband V-8, is symptomatic. Two children of V-6 (VI-1 and VI-2) and two children of V-10 (VI-11 and VI-12) are asymptomatic carriers aged less than 36 (masked gender) at time of report. Detailed clinical and pathological findings of family GCSA are presented in Nochlin D 1989, the proband, V-8, correlates to member V-31 in Nochlin D 1989.||M
(gender of asymptomatic carriers is masked)
|58||36||Met/Val129 (Val in cis)||Marked steady decline in intellectual function. Examination aged 59 was unremarkable. He had no evidence of rigidity, focal weakness, tremor, ataxia or sensory deficits, and his gait was normal. He became bed-ridden, the family reported a probable generalised seizure and he died aged 61 years.
Neuropathological examination reveals widespread amyloid plaques in the cerebral cortex, hippocampus, putamen, thalamus and subcortical and deeper white matter.
|Tranchant C 1992 ||France||14 (15)||Further characterisation of Alsatian (AND) family first genotyped by Tateishi J 1990. Family tree now includes 76 subjects over six generations. Case IV-28 correlates to the patient genotyped by Tateishi J 1990, and is counted there. Members IV-9, III-3, IV-25 and III-11 are confirmed in this report, all of whom are alive. Cases IV-25 and IV-28 are children of case III-11. IV-9 is the daughter of III-3. Of note, the disease started in the children before onset in the affected parent.
A further ten asymptomatic members of this family are carriers of Ala117Val aged between 11 and 38 years, whose case number and gender have been masked.
|33-64||All cases are alive at between 12-132 months from onset.
Case III-3 died aged 73 (108 months from onset) and IV-25 died aged 39 (72 months from onset) as per report of Tranchant C 1997
|Met/Val129 (Val in cis)||In the third generation, the clinical syndrome is composed of dementia followed by progressive hemiparesis which then becomes bilateral and accompanied by pseudobulbar syndrome. In the fourth generation, there, the syndrome is dementia, a pseudobulbar syndrome, and the appearance of more complex neurological signs associating a cerebellar syndrome, an extrapyramidal syndrome, motor neuron signs with fasiculations and amyotrophy, myoclonia and generalised seizures IV-9 alive 11 years from onset, and biopsy showed multicentric or unicetric amyloid plaques that were PrP +ve to immunohistochemical stain.|
|Mastrianni JA 1995 ||US||1||American kindred unrelated to that reported by Hsaio KK 1991. Proband is case IV-E, his family history is notable for several phenotypically similar relatives who had died between the ages of 30 and 50 years, although no specimens were available for these members.||M||35||30||Val/Val129||Presented with dysarthria and ataxia, Parkinsonism and pseudobulbar signs. Dementia developed late in the disease course and he died two-and-a-half years from onset.|
|Tranchant C 1997 ||France||(2)||Further clinicopathological detail of two patients from the Alsatian AND family. The patients detailed here, cases IV-4 and V-15 correspond to patients III-3 and IV-25 in Tranchant C 1992, respectively and are counted there. These patients were both alive at time of report in 1992, now are deceased.||1 F
|33 and 64||72 and 108||Met/Val129 (Val in cis)||–|
|Heldt N 1998 ||France||1||Report of a second family from the French region of Alsace. Proband’s mother and maternal grandmother both died aged 38 of neurological disease. A parietal biopsy was taken from proband in life which showed multicentric PrP plaques. No post-mortem undertaken and no material available for genetic analysis. His two children underwent genetic testing, one of whom was found to harbour the Ala117Val mutant on a Val129 background||Proband: M
Gender of asymptomatic carrier not given
|Proband: 40||Asymptomatic carrier: Met/Val129 (Val in cis)||Proband presented aged 37 with symptoms mimicking alcoholism. His cerebellar syndrome progressed rapidly, with the emergence of pyramidal and extra-pyramidal signs and eventual dementia. He died aged 40, three years from onset. Not genetically confirmed, although one of his asymptomatic children|
|Piccardo P 1998* ||US and Germany||2 (3)||Patient 12 corresponds to the proband V-8 from GCSA family reported by Hsaio KK 1991, as is counted there. Patient 10 also belongs the GCSA family however, their genetic confirmation has not been previously reported and are counted here. Patient 11 is from a new American family (AS kindred, as described in Piccardo P 2001) and is also counted here.||1 F
(gender of patients in Piccardo P 2001)
|26 and 41||48 and 84||Val/Val129||Initial symptom in both patients, one from GCSA kindred (patient 10) and one from AS kindred (patient 11), was memory loss.|
|Mallucci GR 1999** ||UK (5) and Ireland (1)||6||Report of a British and Irish family, likely to be from the same kindred due to being haplotypically identical for several uncommon polymoprhisms around PRNP. 14 affected members of the English family (family 1) and four affected members of the Irish family (family 2) are examined. Five affected individuals from the English family (III-12, III-15, III-22, III-24 and III-33) and one affected member of Irish family (iii-6) were genetically confirmed.||5 F
|III-12 and III-15 Val/Val129
III-22, III-24, III-33 and iii-6 Met/Val129 (Val in cis)
(All cases were APOE e3/e3, apart from III-12 who was e2/e3)
|Clinical syndrome is of a progressive cortical dementia and varying degrees of cerebellar ataxia with neuropsychiatric features.|
|Kovacs GG 2001 ||Hungary||1||Hungarian family. Several members of the propositus’ (III-2) family on her father’s side were clinically affected. Her father, II-1, died aged 45 following three years of progressive left-sided hemiparesis with Babinski’s sign, Parkinsonism, depression and intellectual decline – histological examination of father undertaken in this report showing focal spongiform change, PrP plaques in cerebrum and cerebellum. No tau pathology.||F||29||Alive (72 months)||Val/Val129||Initial presentation with depression. Later developed cerebellar ataxia, left-sided hemiparesis, pyramidal signs, rigidity and intellectual decline.|
|Piccardo P 2001 ||US (1) and Germany (2)||3 (6)||Six cases are reported here from two families.
Four patients from the American GCSA kindred of German descent (Hsiao K 1991), termed SG kindred in this report. Of these four patients, two (patient 1 and patient 3) have previously been reported. Patient 1 corresponds to the proband V-8 in Hsiao K 1991 (counted here) and patient 12 in Piccardo P 1998. Patient 3 corresponds to patient 10 in Piccardo P 1998, and is counted there. Genetic confirmation of patients 2 and 4 from the GCSA family has not been previously reported.
Two cases are from the American AS kindred (patients 5 and 6). Patient 5 was previously reported in Piccardo P 1998, and corresponds to patient 11 in that report, where they are counted. Patient 6 is an asymptomatic carrier, counted here.
|28 and 36||36 and 60||Met/Val129 (patient 2, in cis allele not reported)
Val/Val129 (patient 4)
|No clinical details given|
|Saenz-Farret M 2016 ||Argentina||2||First report of Ala117Val mutant in Latin America. Two patients from an Indigenous Argentine family are reported. A sister (case 1) and brother (case 2) and sister (of a total 13 siblings) are genotyped.||1 F
|34 and 37||Both siblings alive at 12 and 24 months from onset||Met/Val129 (in cis allele not reported)
***Both patients were also found to be heterozygous for a variant of unknown pathogenic significance at codon 165: c.494C>A leading to Pro165His.
|Presenting symptoms were upper limb paraesthesia, frequent falls, and right hemi-paresis, followed by dysphagia, dysarthria and myoclonic jerks. In case 1, the gag reflex was severely diminished.|
|Takada LT 2017 ||US||6||Patients referred to UCSF rapidly progressive dementia prion disease centre between 2001 and 2016 with confirmed Ala117Val mutation. Two patients are from families known to harbour the mutation. One patient had not family history||Not given||14-49||27-78||In cis with Val129 (full codon 129 genotype not given)||Individual level data not reported.|
|Malek N 2017 ||UK||1||Positive family history spanning two previous generations. Maternal first cousin of index case had a similar neurological syndrome and had a mutation in PRNP (history provided by relative). His mother was diagnosed with corticobasal syndrome and encephalitis lethargica in his maternal grandfather. His sister was diagnosed with MS and died in her 40s.||M||41||84||Met/Val129 (in cis allele not reported)||Presented with bilateral Parkinsonism, early cognitive impairment and behavioural problems.
Family consent not given for neuropathological analysis.
|Jiang AA 2019 ||Germany-Ireland||1||Patient of Irish and German descent. No family history of relevant neurological disease. His mother died in her 30s due to accidental drowning, therefore, it is possible that she harboured the mutation but died before the phenotype was declared.||M||40||36||Not reported||Early behavioural symptoms including paranoia and perseveration on his chronic pain and depressive symptoms, which lead to an initial diagnosis of psychogenic aetiology.|
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. Shaded reports are excluded from total counts for each mutant and further analyses due to lack of individual level data. *Patient 11 in Piccardo P 1998 is from a new American family found to harbour the Ala117Val mutant. This family has been reported in the following paper which we have been unable to locate: Ghetti B, Young K, Piccardo P, Dlouhy SR, Pahwa R, Lyons KE, Koller EC, Ma MJ, De Carli C, Rosenberg RN. Gerstmann-Straussler-Scheinker disease (GSS) with PRNP A117V mutation: neuropathological and molecular studies of a new family. Neuropathology and Applied Neurobiology 1999; 25: 57. **There is a typographical error in this manuscript regarding patient III-15, who is female Val/Val129 homozygous with onset aged 26 years and death aged 28. In table 1 she is mistakenly inserted as III-14 (case III-15 in Table 1 is in fact case III-16) and in Table 2, the same error is found, case III-15 is entered as III-14 and case III-16 is entered as III-15. ***Reported as Arg165His variant in paper by Saenz Farret M 2016. Codon 165 in PrP is a proline. c.494 cytosine is the second base of CCC Pro165, therefore, a C>A base change at this position would result in a CCC-to-CAC Pro165His variant. This variant is not found in the gnomAD dataset.
|Kindred||Report||Case||Gender||Age at onset||Clinical duration to death (months)||Neuro-psychiatric disturbance||Dementia||Pyramidal signs||Cerebellar signs||Extra-pyramidal signs||Pseudobulbar syndrome||Seizure/
|AND family from Alsace, France||Tateishi J 1990 ||V-17 (IV-28)||M||20||48||–||+||+||+||+||+||+|
|Tranchant C 1992 ||III-3||F||64||108||–||+||+||+||+||+||+|
|III-11||F||57||Alive (12 months)||–||+||–||–||–||+||–|
|IV-9||F||35||Alive (132 months)||–||+||+||+||+||+|
|American GCSA kindred of German descent||Hsaio KK 1991 ||V-8 (V-31)||M||58||36||–||+||–||–||–||–||+|
|Piccardo P 1998 ||10||M||26||84||–||+||Not known||+||Not known||–||Not known|
|American family||Mastrianni JA 1995 ||IV-E||M||35||30||–||+||–||+||+||+||–|
|Hag family from Alsace, France||Heldt N 1998 ||–||M||37||36||+||+||+||+||+||–||–|
|American AS family||Piccardo P 1998 ||11||F||41||48||–||+||Not known||+||Not known||Not known||–|
|British-Irish family||Mallucci GR 1999 ||III-12||F||43||36||+||+||–||+||–||–||+|
|Hungarian family||Kovacs GG 2001 ||III-2||F||29||Alive (72 months)||+||+||+||+||+||–||+|
|Argentinean family||Saenz-Farret M 2016 ||Case 1||F||34||Alive (24 months)||–||–||+||–||–||–||+|
|Case 2||M||37||Alive (12 months)||–||+||–||–||–||–||–|
|N/A||Malek N 2017 ||–||M||41||84||+||–||+||–||+||–||+|
|N/A||Jiang AA 2019 ||–||M||40||36||+||+||+||–||+||+||+|
The Ala117Val mutation is created by a dinucleotide change in codon 117. One of the changes is a non-coding third base polymorphism, c.351A>G, which is present in 10% of the population17. The second base change is a coding c.350C>T change resulting in the substitution of valine for alanine and occurs at the CpG dinucleotide mutation hotspot. The mutational event generating the valine-encoding sequence thus differs from the normal allele by two bases: GCA-to-GTG10.
Neuropathology shows many multicentric PrP amyloid plaques throughout the cerebral cortex, basal ganglia and thalamus. In the cerebellum, plaques may be absent2 or present in variable amounts4,6. Spongiform degeneration is not a prominent feature2,4. Amyloid- deposits, associated with PrP plaques have been noted in one patient7. Neurofibrillary tangles have also been reported2,7.
Proteinase K-resistant PrPSc from brain homogenate is seen to comprise 7 kDa and 14 kDa species on Western blotting9,12.
Structure-based protein function annotation:
Alanine 117 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 Ala117Val mutant18.
PrPC is unusual in its ability to adopt multiple membrane topologies. The greater proportion of PrPC molecules are attached to the outer leaflet of the plasma membrane through the C-terminal GPI anchor19-20. However, when synthesised in vitro or in cells, some PrPC molecules assume a transmembrane orientation, that spans the bilipid layer once through the highly conserved hydrophobic region (aa 112-134, see Architecture of PrP), with either the N- or C-terminus (NtmPrP or CtmPrP, respectively) on the extracytoplasmic side of the membrane (ER lumen)21. These species form a small proportion of the total PrP generated (< 10 of the total PrPC; 0.5% to 1% CtmPrP22) during biosynthesis of wild-type PrP in the endoplasmic reticulum. The relative proportion of CtmPrP can be manipulated with mutations within the hydrophobic region, including Ala117Val, which increase the transmembrane topological variant to as much as 20-30% of the total PrPC synthesised21-23 – but mutants outside of this region do not affect CtmPrP production24. A plausible explanation for the effect of Ala117Val on increased CtmPrP is that the amino acid change increases the hydrophobic and other physical properties of the central region to make it a more suitable transmembrane segment24.
Hedge et al23 hypothesise that the generation of CtmPrP represents a final common pathway for neurodegeneration in both transmissible and familial forms of prion disease. The prion disease inherited by the Ala117Val mutation is proposed to cause neurodegeneration in the absence of PrPSc, with pathogenesis mediated by aberrant production of CtmPrP21, and that PrPSc accumulation in other forms of prion disease may cause pathology by inducing the synthesis of CtmPrP de novo23. This idea is based upon their observation that transgenic mice expressing CtmPrP-favouring mutations at high levels, such as Ala117Val, develop a spontaneous neurodegenerative illness in the absence of PrPSc, and that the amount of CtmPrP increases during the course of scrapie infection of mice expressing wild-type PrP21,23-24. Therefore, by the model of Hedge and colleagues, the disease caused by Ala117Val is defined as a prion proteinopathy whose pathogenesis is the result of an aberrant topological form of PrP.
Several lines of evidence counteract a model wherein CtmPrP is the obligate neurotoxic intermediate. First, most pathogenic PrP mutations are topologically inert and fail to alter the amount of CtmPrP, arguing against the notion that PrPSc causes prion disease by inducing CtmPrP production22,24. Second and most importantly, Asante and colleagues25 have demonstrated that Ala117Val is an authentic, transmissible, prion disease by showing that inoculation of Ala117Val patient brain into transgenic mice expressing mutant human PrP 117Val (117VV Tg30 and Tg31 mice) not only results in transmission of abundant PrP amyloid plaque pathology in brain (associated with a characteristic disease-related PrP assembly generating an approximately 8 kDa protease-resistant PrP fragment analogous to that detected in Ala117Val brain, but also results in propagation of classical PrPSc assemblies (generating proteolytic fragments corresponding to PrP 27-30), which are pathognomonic of prion disease25. The Asante group also go on to demonstrate that brain PrP plaques in uninoculated old-aged 117VV Tg30 mice are associated with spontaneous production of disease-related PrP assemblies, having molecular and phenotypic transmission properties that mirror those generated in Ala117Val patient brain26.
Mouse homologue mutant Ala116Val, as expected, does not have an effect on the global structure, stability or dynamics of native monomeric mouse PrP27, but it has been shown to accelerate misfolding and aggregation relative to wild-type mouse PrP by inducing structure in the palindromic region27 which appears to be the site for inter-molecular association in PrP oligomers18,27-28. However, Jones et al29, compared the fibril formation of a wild-type PrP fragment (aa 23-144) with Pro102Leu, Pro105Leu and Ala117Val fragments, and found that that these mutants converted to amyloid fibrils with kinetics very similar to wild-type, suggesting a mechanism for increased amyloidogenicity that is not intrinsic or proximal to the mutation site.
Alanine is a small aliphatic residue, due to its very short side-chain it is not particularly hydrophobic, and its substitution to valine is significant. Valine is more hydrophobic, prefers to be buried and is Cβ branched, therefore, more bulkiness is introduced near the protein backbone that restricts the conformations the main chain can adopt. The most pronounced effect of an alanine-to-valine substitution is that it becomes easy and even preferred for valine to lie within β-sheets30. Indeed, molecular dynamic simulation of Ala117Val indicate that this mutant induces a local structural change that parallels the two PrP β-strands (β1: aa 128-131, β2: aa 161-162), resulting in extension of the -sheet and abolition of the first α-helix (α1: aa 144-154)31.
Therefore, it is likely that valine at position 117, in a similar mechanism to mutant Gly114Val contributes to pathogenicity through enhanced β-sheet formation in the amyloidogenic PrP palindrome, that drives PrPSc conversion.
In silico Pathogenicity predictions:
- Probability of pathogenicity: 0.790
- Standard error: 0.053
- Prediction: Pathogenic
- Score: 0.602
- Prediction: Non-pathogenic
A stringent REVEL score threshold of 0.75 is applied, above which the variant is classified as pathogenic.
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- Saenz-Ferret M, Ramirez-Gomez CC, Araoz-Olivos N et al. Gerstmann-Straussler-Scheinker syndrome in an Argentinean family due to mutation at codon 117 of the Prion Protein Gene (PrP A117V). Journal of the Neurological Sciences 2016; 364: 50-52. (PMID: 27084215)
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