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Prion Protein Mutation Database

Allele count in gnomAD: 0

Cases in literature: 278

Penetrance: Highly penetrant – 98% of cases show signs of disease by age 70

Clinical presentation:

In 1935, the Viennese neurologist J. Gerstmann and neuropathologists E Sträussler and I Scheinker reported a “curious heredo-familial disease of the central nervous system” in a young adult female1. They noted “holes in the second and third layer of the cerebral cortex, as a result of which, the architectonics appear to be markedly disturbed” – retrospectively, this description might be considered spongiform lesions. Although a preliminary clinical description of the disease, that now bears their name, was first given by Gerstmann2 in 1928. They described the original Austrian Gerstmann-Sträussler-Scheinker (GSS) family, studied in detail (covering nine generations) by Hainfellner and colleagues in 19953.

Pro102Leu (in-phase with Met129) is the most common GSS disease-causing mutation world-wide4-6. However, at least seventeen missense mutations in total have been associated with GSS (Pro84Ser, Pro102Leu, Pro105Leu/Ser, Ala117Val, Gly131Val, Ser132Ile, Ala133Val, Val176Gly, His187Arg, Phe198Ser, Asp202Asn, Glu211Asp, Gln212Pro, Gln217Arg, Tyr218Asn and Met232Thr), as well as the nonsense mutation Gln227X (see Truncating Mutations).

GSS is characterised by a slowly progressive cerebellar ataxia, associated with distal pain and loss of sensation, lower limb areflexia, mild abnormalities of frontal lobe functioning and late cognitive impairment. There is, however, considerable clinical heterogeneity among patients harbouring the Pro102Leu mutation, that is evident even between first degree relatives; furthermore, a subset of patients present with prominent cognitive and psychiatric symptoms, and others with a rapidly evolving dementia indistinguishable from sporadic CJD5 (see Table of Cases below).

We have reviewed all symptomatic and pre-symptomatic GSS Pro102Leu cases reported in the literature from 1989 to date. Case reports and case series are included; three shaded reports are excluded from analyses for lack of individual level data. We find 278 cases distributed across the world (for which individual level data is available): Japan (n = 102), China (n = 35), Italy (n = 41), UK (n = 24), US (n = 13), Germany (n = 8) , Czech Republic (n = 7), Brazil (n = 6) , Korea (n = 5) , Finland (n = 5), India (n = 4) , Hungary (n = 3) , Denmark (n = 3), Canada (n = 2), Austria (n = 2) , Israel (n = 1), France (n = 1) , Spain (n = 1), Slovenia (n = 1), Poland (n = 1), other (UK or Europe, n = 13).

The mean age of onset (n = 192) in GSS Pro102Leu is 49.0 years (range 22 to 72 years, SD 11.8) with a mean clinical duration-to-death of 55.3 months (n = 107), ranging widely from 2 to 240 months (SD 42.3). In patients with an in-phase methionine residue at codon 129, Pro102Leu-Met129, the mean age of onset (n = 136) is 50.7 years (range 26 to 72 years, SD 10.9) and clinical duration-to-death (n = 80) is 49.5 months (range 2 to 240 months, SD 39.8). Whereas, in patients with Val129 in cis, Pro102Leu-Val129, the mean age of onset (n = 12) is 34.6 years (range 25-47 years, SD 7.7), and mean clinical duration-to-death (n = 7) is 128.6 months (range 48-180 months, SD 41.4) It therefore, appears, that the Pro102Leu-Val129 genotype induces an earlier disease onset (mean 16.1 years earlier) and far slower progression to death (mean 79.1 months longer clinical duration-to-death) than the GSS phenotype associated with an in cis methionine residue at codon 129. The difference between Met129 in cis and Val129 in cis mutants reached statistical significance (independent samples t-test) with p values of 7.1 x 10-6 for age of onset and 0.002 for clinical duration-to-death.

In the Met/Val129 heterozygote cohort (either in-phase with Met or Val, n=41) mean age of onset is 44.4 years (range: 22 to 65 years, SD 11.2). Mean clinical duration-to-death for heterozygotes (n = 26) is 77.3 months (range: 7 to 240, SD 63.0). Whereas, codon 129 homozygotes, (Met/Met129 or Val/Val129, n = 107) mean age of onset is later at 50.6 years (range: 26 to 72 years, SD 11.5) and clinical duration-to-death (n = 57) is shorter at 47.5 months (range: 2 to 144 months, SD 30.7). Therefore, in our dataset the mean age of onset for Pro102Leu codon 129 homozygotes is 6.2 years later than Met/Val129 heterozygotes, and clinical duration-to-death is 29.8 months shorter: these differences reaching statistical significance with p values of 0.004 and 0.029, respectively.

Our trend towards a younger onset in Met/Val129 heterozygotes is in keeping with the studies of Krasnianski et al 7 and Minikel et al8 but in contrast to the findings of Webb et al5, wherein, age of onset was found to be seven years earlier for Pro102Leu-Met/Met129 patients compared to Met/Val129 genotypes. Of note, in the study of Webb and colleagues5, the Pro102Leu mutant was in-phase with Met129 in all heterozygotes and no Val/Val129 homozygotes were present. In our dataset, when Val129 in cis cases are removed from analyses, the age of onset remains on average 2.5 years later in Met/Met129 homozygotes than in Met/Val129 heterozygotes, and this difference does not reach clinical significance (p = 0.22). Webb et al5 noted that the earliest clinical onsets were Met/Met129 homozygotes and overall age at onset was seven years earlier for Met/Met129 cases compared to heterozygote Met/Val129 genotypes5.

The table below shows a summary of age of onset and clinical duration-to-death data, with survival analysis (Kaplan-Meier curves). Data were collated from the literature as outlined in Table of Cases.

AGE OF ONSET
Mutation Without censored data Survival curve including censored data
Mean+/-SD (years) n Median IQR Range n Log-rank test (p)
Pro102Leu 49.0 +/- 11.8 192 50.5 40-58 22-72 192  
Pro102Leu-Met/Met129 51.2 +/- 11.2 103 53 43-60 26-72 103 <0.0001
Pro102Leu-Met/Val129 44.4 +/- 11.2 41 44 38-53 22-65 41
Pro102Leu-Val/Val129 35.0 +/- 6.3 4 38.5 32-40.5 27-41 4
Pro102Leu-Met in cis 50.7 +/- 10.9 136 52 43-59 26-72 136 <0.0001
Pro102Leu-Val in cis 34.6 +/- 7.7 12 35 26.5-40.5 25-47 12
 
CLINICAL DURATION-TO-DEATH
Mutation Without censored data Survival curve including censored data
Mean+/-SD (years) n Median IQR Range n Log-rank test (p)
Pro102Leu 55.3 +/- 42.3 107 60 42-92 2-240 181  
Pro102Leu-Met/Met129 44.1 +/- 25.9 54 57 42-72 2-96 95 0.059
Pro102Leu-Met/Val129 77.3 +/- 63.0 26 72 48-156 7-240 40
Pro102Leu-Val/Val129 108 +/- 52.3 3 132 48-144 48-144 3
Pro102Leu-Met in cis 49.5 +/- 39.8 80 58 36-84 2-240 127 0.009
Pro102Leu-Val in cis 128.6 +/- 41.4 7 132 120-156 48-180 11

a) Pro102Leu Age of Onset (all codon 129 haplytes)

b) Pro102Leu Clinical Duration to Death (all codon 129 haplotypes)

c) Pro102Leu Age of Onset by Codon 129 Haplotype (p = < 0.0001, Log-rank test)

d) Pro102Leu Clinical Duration to Death by Codon 129 Haplotype (p = < 0.059, Log-rank test)

e) Pro102Leu Age of Onset by in cis codon 129 residue (p = < 0.0001, Log-rank test)

f) Pro102Leu Clinical Duration by in cis codon 129 residue (p = < 0.009, Log-rank test)

Kaplan-Meier curves for Pro102Leu age of onset and clinical duration-to-death. All codon 129 genotypes are shown in graphs a) and b), by codon 129 genotype (ignoring phase in Met/Val129 cases) graphs are shown in c) and d) and by the in cis codon 129 residue graphs are shown in e) and f). The Kaplan-Meier curve is shown as a solid line and in graphs a) and b) the 95% confidence limits are shown as dotted lines. Censored data in clinical duration graphs b), d) and f) is shown as open circles and they represent cases that were alive at last report/follow-up and for whom total clinical duration-to-death is not known.

PrPC is polymorphic at two notable positions: residues 129 and 219. Methionine or valine are found at codon 1299 and either glutamic acid or lysine at codon 219 in the Japanese population10. These polymorphisms can influence the clinicopathological phenotype resulting from a pathogenic PrPC mutation. This is seen most strikingly with the Asp178Asn mutation, which can cause FFI or CJD depending on either residue Met or Val at codon 129, respectively11. Homozygosity for either methionine or valine at codon 129 is also known to affect susceptibility to sporadic CJD12, and earlier age at onset is well recognized to be linked with codon 129 homozygosity in other forms of inherited prion disease13-14, including that which is caused by Ala117Val-Val129 (Val/Val129 homozygotes presented ten years earlier than Met/Val129 heterozygotes – see Ala117Val mutation subpage for data). This effect most likely relates to the less efficient protein-protein interactions between heterologous PrP molecules compared with homologous PrP molecules, which in turn, affects prion propagation efficiency and results in later disease onset in patients with the Met/Val129 genotype12, 15-18.

Further evidence for GSS Pro102Leu disease modification by PrPC codon 129 is provided by patients with an in cis valine at this position. We note that the most powerful modifying effect is determined by the codon 129 in cis residue: Pro102Leu-Val129 cases presented on average sixteen years earlier and their clinical course six-and-a-half years longer, than patients with an in cis methionine at codon 129 (see data given above). These cases are relatively infrequent, representing 4% of GSS Pro102Leu patients reported: twelve patients to date, of which four are Val/Val129 homozygous and eight are Met/Val129 heterozygous (see Table of Cases below: Telling GC 199519, Young K 199720, Bianca M 200321, Kojovic M 201122, Ferrer I 201123, Muona M 201524, Mumoli L 201725, Smid J 201726, Bhatia S 202027). Clinical information is available for eleven patients; all but the case reported in Telling GC 199519. These findings are aligned with GSS-associated Ala117Val and Phe198Ser cases, wherein Val/Val129 homozygosity is associated with a ten-year earlier age of onset13,28-29 compared to Met/Val129 heterozygosity at position 129 (see Ala117Val mutation subpage). In addition, the manifest phenotype in Pro102Leu-Val129 cases is markedly different (see Table of Cases below). Interestingly, two of these patients24-25 presented, clinically, with what appeared to be progressive myoclonus epilepsy, and a further two also presented with seizures20-21. The phenotypic difference in Pro102Leu-Val129 patients has been proposed to relate to different prion strain propagation originating from the valine allele5.

In a Japanese family with Pro102Leu coupled with Lys219 on the same allele (see Furukawa H 199530 in Table of Cases below), the phenotype was marked by attenuated cerebellar signs and decreased PrPSc plaque deposition in the brain, that do not stain Congo red, and it was suggested that an in cis Glu219Lys polymorphism may modify the pathology in GSS Pro102Leu10,30-31. The pathological pattern in patients with GSS Pro102Leu and Glu219Lys polymorphism on the non-mutant allele has shown Congo red staining of PrP plaques in cerebral cortices, consistent with that of patients with GSS who had a Pro102Leu mutation without the Glu219Lys polymorphism31. No further families with the Pro102Leu-Lys219 genotype are reported in the literature.

It appears that both clinical and pathological features of GSS may be influenced by the polymorphisms at positions 129 and 219 in PrPC. However, a definitive correlation between phenotype and polymorphic codons 129 and 219 in GSS Pro120Leu patients remains elusive; in view of phenotypic heterogeneity, even within a single syngeneic family, these polymorphisms cannot entirely account for the observed clinical variation. The greater proportion of this phenotypic variability is thought to be contributed by variable propagation of distinct disease-related PrP species32 generated from either PrP 102Leu33-34 or wild-type PrP35-36. Furthermore, stochastic events in the conversion of PrPC to PrPSc may also contribute to variation in age at onset of GSS33,37.

Table of Cases

Case report Country of origin Number of DNA-confirmed Pro102Leu GSS 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
Hsiao K 1989 [6] USA (1) and UK (2) 3 Patient JJ (III-a) from a US pedigree (note, this is not the same JJ patient reported in Rosenthal 1976 as case III-32, in Adam J 1982 as case 2 and in Webb TEF 2008 as case VI.10 – that JJ patient is from UK W kindred).
Patients JB (III-20) and JC (IV-2) are of W kindred from Bedfordshire, England. JB (III-20) corresponds to case 6 JB in Watanabe R 1993 and case VI.12 in Webb TEF 2008. JC (IV-2) corresponds to case IV-58 in Rosenthal 1976, patient JC in Adam J 1982, case 5 JC in Watanabe R 1993 and case VII.4 in Webb TEF 2008.
2 F (JB/JC)
1 M (JJ)
JJ 39
JB 48
JC 40
JJ not known
JB 26
JC 72
Not reported.
(JJ is Val/Val129 codon 129 genotype reported in Telling GC 1995)
(JB Met/Val129
JC Met/Met129)
Not reported
Goldgaber D 1989 [38] Germany 3 Large German family (Sch.) was first reported in 1980 by Boellaard JW et al and described more extensively the following year in Schumm F 1981. Three patients (19-21) from the Sch. GSS family (III) in Germany reported here. These patients correspond to patients III-1, III-8 and III-17 in Brown P 1991. 2 F
1 M
52-58 30-84 Not reported. All three patients presented with a progressive ataxia and eventually severe dementia.
Doh-ura K 1989 [39] Japan 11 Eleven GSS patients; all unrelated except for two siblings. 10 Met/Met129
1 Met/Val129
Not reported
Doh-ura K 1990 [40] Japan 11 Seven Japanese patients affected by ‘sporadic CJD with congophilic kuru plaques’ (GSS) studied. Six were found to harbour the Pro102Leu mutation, and case 7 had a Pro102Pro variant. Eight unaffected family members of cases 1, 2 and 5 were also examined and five were found to have the Pro102Leu mutation; son of case 1 (age 36), brother of case 2 (age 58) and three children of case 5 (ages 39-46). 2 F
4 M
44-65 12-96 Not reported All affected cases (1-6) had clinical onset marked by spinocerebellar signs with an insidious clinical course, amnesia and disorientation for over one year before lapsing into a bedbound state.
Brown P 1991 [41] Germany 3 (6) Analysis of the Sch. GSS family in Germany. They were first reported in 1980 by Boellaard JW et al, and described more extensively the following year in Schumm F 1981. Three affected members of the Sch. family were previously found to have the Pro102Leu mutation by Goldgaber D 1989 (patients 19, 20 and 21; counted there) and confirmed here as cases III-1, III-8 and III-17 (further clinical details of III-8 given in Boellaard JW). A further three as-yet-unaffected members of this family (with an affected parent) were found to harbour the Pro102Leu mutation. They are aged, 41, 42 and 42 years.
It is probable that the three unaffected members of this family found to harbour the Pro102Leu mutant, are the same three as-yet-unaffected persons referred to in Speer MC 1991 (see below)
Gender of unaffected members not given Not reported. The clinical course in all three affected cases was that of a progressive cerebellar syndrome that was marked by cognitive or behavioural deterioration in the later stages.
Speer MC 1991 [42] Germany (3) Three asymptomatic members of the German Sch. family studied by Goldgaber D 1989 and Brown P 1991 were found to have the Pro102Leu mutation (See Brown P 1991). The ages of these relatives were 41, 42 and 42 years; below the mean age of onset (mean = 47 years) for GSS in this family.
It is probable that the three unaffected members of this family found to harbour the Pro102Leu mutant, are the same three as-yet-unaffected persons referred to in Brown P 1991 (see above)
Unaffected members of the German GSS Sch. family confirmed to harbour the Pro102Leu mutant.
Kretzschmar HA 1991 [43] Austria 1 Patient whose lineage was traced to the original GSS kindred described by Gerstmann (1936) and Seitelberger F (1962). This patient corresponds to HM (#19) in Hainfellner JA 1995. F 37 34 Met/Met129
(Glu/Glu219 as noted by Furukawa H 1995 in discussion)
Presented with abnormal weakness and fatigue, followed by disordered sleep, cognitive dysfunction and severe apraxia – cerebellar ataxia not found. Two years before death she was apallic, with permanent myoclonic jerking and frequent generalised tonic-clonic seizures.
Kretzschmar HA 1992 [44] Italy 1 First report of GSS from Italy. Pro102Leu found in a family originally from a small village in Sicily, they moved to Northern Italy after WWII. Detailed clinical information is available on two patients from three generations only.
Of the three family members with the neurological syndrome, genotyping was undertaken in only one member (patient 3). Patient 2, father of patient 3, developed symptoms aged 51 years and died aged 55. Patient 1 is the sister of patient 2, symptom onset was in her 50’s and she died aged 58 years.
M 37 Alive at time of report with a clinical duration to date of 24 months Not reported. Presented with progressive ataxia, pyramidal signs, myoclonus, spacticity, cognitive deficits with aphasia, and agnosia and apraxia.
Miyazono M 1992 [45] Japan 4 (7 patients described) Four GSS patients from unrelated Japanese families and three Japanese CJD patients with congophilic kuru plaques previously described by Koh-ura K 1990 (counted there) are described in this report. Not reported Not reported Mean = 28 One case Met/Val129 (in cis allele not known), others Met/Met All of these patients had spinocerebellar signs, a relatively long clinical course and numerous and various types of congophilic plaques.
Boellaard JW 1993 [46] Germany (1) This report gives a more detailed account of patient III-8 initially genotyped by Goldgaber D 1989 (counted there) Brown P 1991. She belongs to the German GSS Sch. family. F 52 84 Not reported. Presented with dizziness and anxiety, then cerebellar dysfunction manifest with ataxic gait and a lesser degree of truncal and upper limb ataxia. The cerebellar syndrome slowly deteriorated and she developed dementia. Neuropathological analysis demonstrated immunostaining for PrP in numerous multicentric plaques.
Goldhammer Y 1993 [47] Israel 1 Report of first Jewish family with GSS. The case is of an Ashkenazi Jewish lady. It is likely that the patient’s mother, maternal aunt and uncle, and maternal grandfather are also affected, however, no autopsy findings or DNA-analysis is available for these family members. Her mother died at age 49 after a progressive illness lasting three years, beginning with gait disturbance. The diagnosis of olivopontocerebellar degeneration was suggested. Her mother’s sister died at approximately the same age of a similar disorder, and one of her brothers had ataxia, dysarthria, intention tremor and dementia. The grandfather of index case was said to have died of an unknown brain disease. F 44 Alive at time of report with a clinical course of 36 months. Not reported. Presented developed only progressive cerebellar ataxia without sign of cognitive impairment.
Watanabe R 1993 [48] UK 4 (6) Six members of the W kindred from Bedfordshire, England are described.
JW (counted here), corresponds to propositus case III-32 in Rosenthal 1976, case JW in Adam 1982, patient 3 in Parchi P 1998 and case VI.9 in Webb TEF 2008.
SM and DJ (counted here) correspond to cases III-25 and III-38 in Rosenthal 1976, cases 1 (JM) and 2 (JJ) in Adam J 1982 and cases VI.7 and VI.10 in Webb TEF 2008, respectively.
EU (counted here) corresponds to case III-50 in Rosenthal 1976, case 3 (EU) in Adams J 1982, case III-22 in Hsiao K 1989, patient 9 in Piccardo P 1998 and case VI.13 in Webb TEF 2008.
JC, corresponds to case IV-58 in Rosenthal 1976, case 4 (JC) in Adam J 1982, patient JC (IV-2) in Hsaio K 1989 (counted there) and case VII.4 in Webb TEF 2008. JB, corresponds to patient JB (III-20) in Hsiao K 1989 (counted there), patient 8 in Piccardo P 1998, and case VI.12 in Webb TEF 2008.
2 F
2 M
42-60 13-72 Not reported.
(EU and JC are Met/Met129, JB is Met/Val129)
Clinical details are not provided in this paper, however, they can be found in the detailed analysis of this family by Webb TEF 2008.
The report focuses on the neuropathological analysis of these cases. All of whom were found to have multicentric plaques.
Hainfellner JA 1995 [3] Austria 1 (2) The pedigree of the original GSS kindred described by Gerstmann (1936) and Seitelberger F (1962) encompasses, at time of report, 221 members (111 men and 110 women) in nine generations and dates back to the 18th century. Definite cases of GSS are found in two family branches (H and Schw) that are also horizontally connected by a consanguineous marriage in the third generation. Therefore, 20 GSS patients among 221 family members are described in this report. However, only two are DNA-analysis confirmed (case #11 and HM). HM is the same intra vitam patient reported by Kretzschmar HA 1991 and is counted there. M 59 24 Met/Met129 Clinical course was that of a cerebellar ataxia, dysarthria and later dementia.
Neuropathological data available.
Young K 1995 [49] Italy (2)
Canada (1)
3 Patient 1 (NP 92_331, counted here) is from a previously undescribed Italian-American family originally from Sicily. His maternal aunt also has the Pro102Leu mutation. Further clinicopathological data on this on this patient can be found in Piccardo P 1995. Another member of this family is clinically described by Galatioto S 1995.
Patient 2 (NP 91_466, counted here) is equivalent to patient 1 in Piccardo P 1998 and case VII.10 in Webb TEF 2008. A member of the Canadian branch of the W kindred from Bedfordshire, England. Further clinicopathological data on this patient is given in Piccardo P 1995.
1 F
2 M
31 and 56 36 and 60 months Patient 1 Met/Met129
Patient’s 1 aunt is Met/Val129
Patient 2 is Met/Val129 (likely Met in cis)
Patient 1 (onset 31 years) developed cerebellar ataxia and late in the disease process was noted to have mild cognitive deficit. He became bedbound and died three years from onset (aged 34) His maternal aunt developed ataxia and was alive at time at report aged 65 years.
Onset in patient 2 (aged 56) was also marked by cerebellar ataxia and later, significant depression and mild dementia. He died five years from onset (aged 61).
Neuropathological examination undertaken in both patients. In patient 2 PrP was found to colocalise with A in brain plaques (see Piccardo P 1995)
Brown P 1995 [50] US (2) and Italy (2) 4 Study of 37 prion disease subjects residing in US or Europe (USA patients are or European or Latin descent). The four patients with GSS P102L constitute two pairs of first-degree relatives from unrelated families. A mother (case 34) and son (case 35); and an uncle (case 36) and his nephew (case 37). Cases 36 and 37 (uncle and nephew) are Italian-American and correspond to cases 5 and 6 in Piccardo P 1998. 1 F
3 M
32-66 9-50 Three cases were homozygous Met/Met129 and one (case 37) Met/Val129 with Met in cis. Clinical details given for one instructive case. Case 37 presented with confusion and difficulty in expressing himself. His behaviour became inappropriate, disinterested and cognition continued to deteriorate. He later became choreoathetotic and ataxic, a reversal of the usual GSS Pro102Leu clinical course.
Each GSS patient showed different plaque and amyloid distribution patterns on neuropathological examination.
Furukawa H 1995 [30] Japan 23 A screen of 400 unrelated patients with dementia or other neurological disorder, revealed twenty cases of Pro102Leu mutation, all were Met/Met129. These twenty patients included the propositus of the paper, patient 1 (III-2), and subsequently, three affected members of his family (patients 2, 3 and 4) were examined and found to harbour the Pro102Leu mutant. This family is composed of 12 members over three generations. 1 F
3 M
31-60 Patient 1: 48
Patients 2, 3 and 4 alive at time of report with clinical courses of 10, 5 and 0 years , respectively
23 Met/Met129
Patients 1, 2, 3 and 4 of the same family were also in cis for the Glu219Lys polymorphism (two other unrelated patients had the Glu219Lys polymorphism on the non-Pro102Leu allele)
Patient 1 (propositus) presented aged 31 years with progressive cerebellar ataxia and dusarthria, he was diagnosed with spinocerebellar degeneration. He died aged 35. Patient 2 (paternal uncle of patient 1) developed cerebellar signs aged 34 and was also diagnosed with spinocerebellar degeneration. Patient 3 (paternal aunt of patient 1) developed cognitive deficits aged 51 and at 56 years she became bedbound. Patient 4 (father of patient 1) developed mild dementia aged 60 years. [Further information on this family is given by Tanaka Y 1997]Histopathological analysis of patient 1’s brain reveals only few plaques that were not congophillic.
Telling GC 1995 [19] USA (1) Patient JJ – first reported in Hsiao K 1989 (where patient is counted) but without codon 129 genotype. M 39 Val/Val129 No clinical data in this report.
Barbanti P 1996 [51] Italy 7 Members of this large Italian family originated from a small village in Southern Sicily, where the family had been settled for more than 200 years. The pedigree of the family had been traced back to 1786 (seven generations) and includes 120 members.
Proband (VI-12), confirmed by direct sequencing. A further six (yet-unaffected family members of generations VI and VII were found to harbour the Pro102Leu mutation.
By examination of the offspring’s genotype, the authors infer the genotype of a further six family members that had died of neurologic disease (IV-1, IV-5, V-3, V-9, V-12 and VI-10).
F 52 9 Proband was Met/Val129 (Met in cis) and Glu/Glu219.
Among the six unaffected family members, four were Met/Met129 and two Met/Val129.
Proband (IV-12) presented with depression and mild unsteadiness. She progressed rapidly, two to three months from onset, she was bedbound in a decorticated state. She died nine months from onset. Post-mortem examination undertaken which showed multicentric, unicentric and kuru-like plaques distributed diffusely in the cerebellar molecular layer, cerebral cortex and subcortical structures.
Other non-genotyped family members had clinical onsets aged between 47 and 70 years, and durations ranging from 0.4 to 4 years
Tanaka Y 1997 [31] Japan (4) This paper provides further clinical details on members of the Japanese family reported by Furukawa H 1995. The mutation in this family was found to be in phase with the Glu219Lys polymorphism. Patients 1 (III-2 – propositus, deceased), 2 (II-1 [patient 4 in Furukawa H 1995[), 3 (II-4) and 4 (II-7 [patient 2 in Furukawa H 1995]) have been genotyped.
It is proposed that Glu219Lys polymorphism accompanied by the Pro102Leu mutation on the same allele modifies the pathological pattern in these patients.
4 Met/Met 129
4 in cis Glu219Lys
Among 12 family members over three generations, five had a history of progressive dementia, ataxia or both. Patients 1 (III-2) and 3 (II-4) developed progressive dementia with mild ataxia; patients 2 (II-1) and 4 (II-7) developed ataxia without significant cognitive deficits. These four patients have been genotyped as detailed in Furukawa H 1995.
Young K 1997 [20] Italy 1 One of only twelve known patients with Pro102Leu in phase with valine at codon 129 (see analysis under section clinical presentation above)
The family of this patient (Italian-American) did not wish to participate further in research. It is known that the maternal ancestors are from Italy, and there is no family history of neurodegenerative disorder in previous generations, but a maternal cousin of the case described is affected by a similar neurological syndrome.
(This paper was first published as a poster abstract in 1996 – See Young K 1996)
M 33 144 Val/Val129 This case is notable for its presentation with seizures, as well as for being Pro102Leu-Val/Val129.
His seizures were controlled for the following three years with AEDs. Three years following onset, he developed numbness in lower limbs, with difficulty in gait and re-emergence of seizure activity. He continued to deteriorate with progressive weakness and dysarthria. He did not appear to have dementia. He died aged 45, 12 years after onset.
Neuropathologically fine punctate PrP deposits were found in the substantia gelatinosa of spinal cord – See also Yamada M 1999.
Furukawa H 1998 [52] Japan 3 Three patients with GSS from three distinct families. Case G1 had apparent family history but cases G2 and G3 did not. Not stated, but G2 is male from pronoun use in-text. 57-63 50-60 3 Met/Met129 Cases G1 and G3 showed slowly progressive cerebellar ataxia followed by dementia – typical clinical features of GSS. Whereas, case G2 presented with unsteady gait, personality change and dementia, which progressed rapidly. Five months from onset he was in a state of akinetic mutism. All cases showed numerous kuru plaques in cerebrum, cerebellum and brainstem.
Imaiso Y 1998 [53] Japan 1 Atypical GSS phenotype in 64-year-old Japanese lady [Abstract only] F 64 Alive at time of report ?17 months Not reported. Presented with 5/12 history of progressive amnesia, twitching og right upper limb and difficulty in speech and gait. Examination revealed dementia, frontal lobe signs and myoclonus. She developed akinetic mutism 9 months from onset.
Parchi P 1998 [33] France (1)
Japan (1)
Italy (1)
USA (1)
4 (7) Seven GSS Pro102Leu patients from seven unrelated kindreds described. Five of these patients have previously been reported. Four are counted here.
Patient 1 reported as clinical case in 1989 and is counted here (Collard M 1989 – abstract only). Patient 2 corresponds to case HM (#19) in Hainfellner JA 1995 and Kretzschmar HA 1991 and counted in the latter. Patient 3 corresponds to propositus case III-32 in Rosenthal 1976, case JW in Adam J 1982, JW in Watanabe R 1993 (where case is counted) and VI.9 in Webb TEF 2008. Patient 7 corresponds to case ES (III-1) in Brown P 1991 and patient in Goldgaber D 1989 where case is counted. It is not possible, out of the remaining three patients, to determine which one has also previously been reported. Patients 1, 4, 5 and 6 are counted here.
2 F
2 M
26-66 30-51
(data not known for patient 5)
All patients Met/Met129 Patient 1: ataxia, pyramidal signs, dysarthria, dysphagia, dementia. Patient 4: ataxia, dysarthria, pyramidal signs, dysphagia, hallucinations, dementia. Patient 5: in terminal stages if disease, severe dementia, rigidity. Patient 6: ataxia, tremor, dementia, pyramidal signs.
Neuropathological analysis shows spongiosis, gliosis, neuronal loss and plaques in all cases, except case 6 in which diffuse atrophy and amyloid plaques were present, but no spongiosis.
Piccardo P 1998 [34] Canada (1)
UK (1)
2 (9) Nine GSS Pro102Leu patients are described in this report, of which seven are counted elsewhere, and two counted here (patients 2 and 7)
Patients 1, 2, 7, 8 and 9 belong to the W kindred. Patient 1 in this report is a patient from the Canadian branch of the W kindred and is equivalent to patient 2 (NP 91_466) in Young K 1995 and case VII.10 in Webb TEF 2008 (counted in Young K 1995). It is not clear which case patient 2 correlates to in the detailed description of this family in Webb TEF 2008, although they belong to the Canadian branch of the W kindred (patient 2 is counted here). Patient 8 corresponds to case VI.12 in Webb 2008, case 6 JB in Watanabe R 1993 and case JB III-20 in Hsiao K 1989 (counted in Hsiao K 1989). Patient 9 corresponds to III-50 in Rosenthal, case 3 EU in Adam J 1982, case 4 EU in Watanabe R 1993 and VI.13 in Webb 2008 (counted in Watanabe R 1993). Although report states that Patient 7 (counted here) belongs to a previously unreported English family, subsequent genealogical analysis does in fact reveal him to also be part of the UK W kindred and he corresponds to case VI.15 in Webb TEF 2008.
Patients 5 and 6 correspond to an uncle and nephew (cases 36 and 37) of an Italian-American family described in Brown P 1995, where these two patients are counted.
Patient 3 corresponds to Italian-American patient 1 (NP 92_331) in Young K 1995 and is counted there.
Patient 4 belongs to an Italian family reported by Barbanti P 1996 and is counted there.
Gender not reported but patient 7 is male 58 and 65 8 and 60 Patient 2: Met/Met129
Patient 7: Met/Val129
Both patients presented with gait disturbance. Patient two onset aged 65 years with a clinical duration of 5 years, whereas onset in patient 7 was aged 58 years, with a rapid course of eight months. No spongiform changes were seen in the brain of patient 2, whereas, patient 7 had severe spongiform degeneration. Both had unicentric and multicentric amyloid deposits in the cerebrum and cerebellum.
Hamasaki S 1998 [54] Japan 3 Case of GSS family with monozygotic twins.
Proband (II-8) has monozygotic twin sisters (II-4 and II-5) and six other siblings. Interestingly, one twin was unaffected (II-5) eight years after disease onset in her sister (II-4). All three harbour the Pro102Leu. The unaffected twin (II-5) had no neurological symptoms or signs at age 66 years. Monozygosity was confirmed.
3 F 43(II-8)
58(II-4)
48 (II-8)
II-4 alive at time of report. Eight years following onset she is in a state of akinetic mutism.
Not reported. Proband (II-8) presented with unsteadiness aged 43 years. Ataxic gait and dysarthria slowly progressed in a manner seen in spinocerebellar degeneration, associated with dementia. She died aged 47 years. Postmortem revealed kuru-type plaques in the cerebral cortex. Her sister (II-4), one of a mozygotic pair, noted gait disturbance aged 58. Ataxic gait slowly progressed and dementia ensued. Eight years from onset she is in akinetic mutism.
Yamada M 1999 [55] Japan 2 Immunohistochemical study of spinal cord and peripheral nervous system to elucidate pathomechanism of loss of deep tendon reflexes in GSS Pro102Leu. Two cases are described, patient 1 and her half-sister (same mother), patient 2. Their mother died of gastric cancer aged 56, with no obvious neurologic disorder.
Abnormal PrP deposits in the posterior horn of patient 2’s spinal cord, most dense in the substantia gelatinosa, were seen, which the authors relate to painful dysestheisas and areflexia in GSS Pro102Leu patients.
Fine punctate PrP deposits in the substantia gelatinosa of the spinal cord were also reported by Young K 1997 in the Pro102Leu-Val129 case.
2 F 35 and 39 36

 

(patient 1 alive at time of report with clinical duration of 48 months)

Patient 1 Met/Met129
Glu/Glu219

 

Patient 2 not reported.

Patient 1 presented aged 39 years with gait ataxia and later dysarthria. Cognition was intact at age 41, and she is alive. Patient 2 is the half-sister of patient 1, she also presented aged 35 with gait ataxia, dysarthria and intact cognition. She eventually lapsed into a bedbound state and died aged 38 years. Neuropathological analysis revealed spongiform changes and numerous kuru-type plaques.
Sugai F 2000 [56] Japan 1 Patient with GSS Pro102Leu and bilateral optic atrophy. His father and two aunts, all deceased, had been diagnosed with dementia. M Not stated 36 ‘Other mutations were not found’ Slowly progressive cerebellar ataxia, with subsequent subacute bilateral optic atrophy without retinal degeneration (see Majtenyi C 2000, Salsano E 2011 and Karmon Y 2011)
Majtenyi C 2000 [57] Hungary 3 Three Hungarian sisters with four well children between them, the oldest child was 55 years and asymptomatic at time of reporting. The family were unable to recall the clinical history pertaining to the sisters’ parents. 3 F 56-66 2 to 2.5 All three were Met/Met129 All three sisters had a rapidly deteriorating syndrome marked by cerebellar ataxia and dementia, which lapsed into an apallic syndrome with mutism. Of note, patient 1 reported to have visual disturbance and patient 3 developed total cortical blindness (See Sugai F 2000, Salsano E 2011 and Karmon Y 2011)). Death occurred in two to two-and-a-half months in all three. Neuropathological analysis undertaken in all cases.
Konaka K 2000 [58] Japan 4 Japanese family formed of 16 members over three generations. Enquiry of the propositus reveals two clinically affected aunts and genotyping was subsequently undertaken in unaffected father, and the two affected aunts which revealed the Pro102Leu mutant in all four, who are alive at time of report. 3 F
1 M
22-64 All three patients alive with clinical durations of 12 to 36 Not reported. Propositus developed clumsiness in arms and balance difficulty aged 22 years. Later ataxic gait and dysarthria developed. SPECT analysis of propositus reveals hypoperfusion of occipital lobes, with normal perfusion of cerebellum (See also Arata H 2006, Irisawa M 2007, Giovagnoli AR 2008). One paternal aunt developed dementia aged 64 and is in a vegetative state aged 66. Another paternal aunt developed cerebellar ataxia aged 46 years and is demented aged 49. Father of the propositus also harbours the Pro102Leu mutation and is unaffected (age unknown)
Muramoto T 2000 [59] Japan 1 Study of allelic origin of PrP deposits in brain tissue of Glu/Lys219 heterozygotes. Study include a GSS patient with Lys219 in cis with Leu102. No further clinical data on this patient is given. Codon 129 not reported.

 

Lys/Glu219 (Lys in cis with Leu102)

Clinical details not given
Finckh U 2000 [60] Germany 2 Case found in a screen of patients with early-onset dementia, all of whom had been diagnosed with dementia of unknown type or probable AD. Family history in index case reveals five affected members over three generations, of which her brother is one and is the only other living affected member. The brother was also found to harbour the Pro102Leu mutation. Age of onset in the four deceased affected members ranged from 51 to 67 years, and age of death from 55 to 68 years. 1 F
1 M
40 and 40 168 and 240 2 Met/Val129 (Met in cis) Index patient, developed symptoms aged 40 had a diagnosis of early onset dementia with no overt neurological signs in the early stages. She died aged 60 years. Brother was given an antemortem biopsy-based histopathological diagnosis of AD in 1987 (two years before the first report on a familial PrP mutation was published – see Hsiao 1989). He died aged 54, 14 years from onset.
Kulczycki J 2001 [61] Poland 1 First reported case of GSS in Poland. 54-year-old gentleman with a rapidly progressing dementia and ataxia. Family history was positive in the father and sister. The father had a similar disorder at a similar age and died one year from onset, and the patient’s sister died six years from onset of a neurological disorder diagnosed as MS. M 53 18 Met/Met129 One year history of rapidly progressing ataxia of arms and legs. Six months after hospitalisation the patient died, aged ?54.
Takase K 2001 [62] Japan 1 Japanese family in which three out of six siblings, as well as their father, developed cerebellar ataxia and cognitive deterioration in their fifth decades. M 70 Alive at time of report with clinical duration of 48 months Codon 129 genotype not known but Glu219Lys polymorphism was found on the non-mutant allele Case of 74-year-old with late onset GSS. He presented aged 70 years with unsteady walk and tingling pain in the legs. He was found to have truncal and limb ataxia, ataxic speech, sensory impairment and areflexia.
Ishizawa K 2002 [63] Japan 2 Japanese gentleman with disease onset aged 38 years and death aged 44. He reports a negative family history. The Pro102Leu mutation was also detected in his mother, although she was asymptomatic at time of reporting – her age is not given. M 38 72 Not reported. Presented with forgetfulness. The following year a postural tremor emerged. The symptoms progressed slowly. Four years from onset he had a severe dementia. He eventually lapsed into a state of akinetic mutism and died aged 44, 6 years from onset. Cerebellar signs were not part of his clinical syndrome. Neuropathological analysis undertaken. Tauopathy also noted (See Ferrer I 2011)
Bianca M 2003 [21] Italy 1 Sicilian family from Catania. Index patient with symptom onset aged 41 years, he died aged 45. His father and brother died following a similar neurological syndrome. The clinical history in this family is notable for its prominent psychiatric onset. Consent was not obtained for autopsy of the index case. M 41 48 Val/Val129 Disease onset heralded by apathy and depression. Two years later developed cerebellar ataxia, psychorganic syndrome, dysarthria and seizures. Progressive cognitive decline and dementia then developed.
De Michele G 2003 [64] Italy 2 Large previously unreported Italian family over four generations. Five patients described.
Only two patients (III-8 and IV-II) were genotyped.
The mean age at onset for all five affected members 41.4 years and mean disease duration to death in the four deceased patients was 5.5 years.
F (IV-11)
M (III-8)
71 (III-8) and 22 (IV-11) 72 (III-8)
IV-11 alive a time of report with clinical duration 108 months
III-8 Met/Met129
IV-11 Met/Val129 (not known which is the in cis allele)
Two distinct clinical patterns were noted in this family: 1) cognitive impairment with minimal neurological features or 2) ataxia following by cognitive impairment. Of note, III-8 (Met/Met129) developed ataxia followed by dementia, whereas disease onset for case IV-11 (Met/Val129) was marked by dementia with minimal neurological features.
Sasaki K 2003 [65] Japan 4 Cases I-5, II-1, II-3 and II-4 of this Japanese family genotyped – the index case, her two brothers and father. All harbour the Pro102Leu mutant in cis with Met129, but of note, her two brothers are as-yet unaffected (their ages are not given). 1 F (II-3)
1 M (I-5)
53 (I-5) 96 (I-5) All Met/Met129 The index case, II-3, developed severe psychiatric disease aged 20 years that was diagnosed as schizophrenia and sadly, committed suicide aged 50 years – likely before any clinical signs of GSS had developed. Neuropathological analysis showed no GSS-linked pathology or PrP deposition, unlike in her father. Her father (I-5) was GSS confirmed post-mortem. He developed cerebellar ataxia aged 53 and died aged 61 years.
Wang Y 2006 [66] China 1 First report of Chinese family with GSS Pro102Leu (although the first cases of GSS in China were reported in Jilin in 1993 using biopsied brain tissue by Lin SH 1993). This family comes from Eastern China.
Brother of index case died aged 40, he had a ten-year history of progressive ataxia and dementia in the late stages; diagnosed as hereditary cerebellar ataxia. Her grandfather died aged 48 and had a history of ataxic gait in his 40’s and later developed dementia.
F 33 13 Met/Val129 (Met in cis)

 

Glu/Glu219

Index case is patient with clinical onset aged 33 years manifest by cerebellar ataxia followed by cognitive impairment; she died 13 months from onset. Neuropathological analysis undertaken.
Arata H 2006 [67] Japan 11 11 patients from nine families all from the Kagoshima Prefecture, South Japan, confirmed to harbour the Pro102Leu mutation. Seven patients (4, 6-11) were living at time of report. Three patients (1, 3 and 6) did not have a family history suggestive of GSS or of neurological disorder. 6 F
5 M
38-70 36-96

 

Seven patients are alive, current durations unclear only duration from onset to clinical examination noted

11 Met/Met129
11 Glu/Glu129
Initial symptoms were gait disturbance in nine patients, dysesthesia of the lower limbs in one, and dysarthria in one. The deceased patients were in a vegetative state during the advanced stages of disease.
SPECT analysis was undertaken in five patients that uniformly showed hypoperfusion in bilateral occipital lobes, with normal cerebellar perfusion, although there were no definitive visual symptoms in these patients (See also Konaka K 2000, Irisawa M 2007, Giovagnoli AR 2008)
Misumi M 2006 [68] Japan 1 Case of Japanese lady with clinical onset aged 58 years. Case it notable for MR brain DWI findings of high-signal intensity lesions in bilaterally in the cerebral cortex and basal ganglia. F 58 Alive aged 59 at time of report Not reported. Slowly progressive gait disturbance and ataxia followed by dementia and myoclonus. MR DWI brain images revealed high signal intensity lesions in the bilateral cerebral cortex and basal ganglia.
Hill AF 2006 [69] UK 5 Seven cases of Pro102Leu patients. Case 1929 (counted here) belongs to the UK W kindred and is the same 1929 in Wadsworth JDF 2006, corresponding to case IV-12 in Hsiao K 1989 and case VII.7 in Webb TEF 2008. Case 1756 is the same 1756 (case 3) in Wadsworth JDF 2006, corresponding to patient 7 in Piccardo P 1998 (where it is counted) and case VI.15 in Webb TEF 2008. Case 2179 corresponds to case 19 (HM) in Hainfellner JA 1995 and initially reported by Kretzschmar HA 1991, where it is counted. The remaining four cases (1911/3070/6271/6202) are counted here. Therefore, out of a total of seven cases, the genotype for two have previously been reported (1756/2179) 1929, M 1929, 36 1929, 33 4 Met/Met129
1 Met/Val129 (Met in cis)
Not given.
Wadsworth JDF 2006 [35] UK and Austria (6) Six cases whose genotypes all previously reported.

 

1929 (case 1) belongs to UK W kindred and is the same case 1929 in Hill AF 2006, corresponding to case IV-12 in Hsiao K 1989 and case VII.7 in Webb TEF 2008 (counted in Hill 2006). 2179 (case 2) is the same case 2179 in Hill AF 2006 corresponds to case 19 (HM) in Hainfellner JA 1995 and initially reported by Kretzschmar HA 1991, where it is counted. 1756 (case 3) is the same 1756 in Hill AF 2006, patient 7 in Piccardo P 1998 (where it is counted) and corresponds to case VI.15 in Webb TEF 2008. 11722 corresponds to case #11 in Hainfellner JA 1995, counted there. PM E3/76 corresponds to case III-50 in Rosenthal 1976, case 3 (EU) in Adams J 1982, case III-22 in Hsiao K 1989, EU in Watanabe R 1993 (counted there), patient 9 in Piccardo P 1998 and case VI.13 in Webb TEF 2008. PM 4/80 corresponds to IV-58 in Rosenthal 1976, patient JC in Adam J 1982, case IV-2 in Hsiao K 1989, case 5 JC in Watanabe R 1993 and case VII.4 in Webb TEF 2008 (counted in Hsiao K 1989).

Not given 36-59 9-72 5 Met/Met129
1 Met/Val129 (Met in cis)
Not given
Irisawa M 2007 [70] Japan 1 Family history was unremarkable. M 31 Alive at time of report, and was in a state if akinetic mutism at 25 months following onset Not reported. Onset with inattention, dysarthria, dysgraphia and ataxia; later myoclonus and dementia ensued, lapsing into akinetic mutism. SPECT showed decreased blood flow in the occipital lobes (See Konaka K 2000, Arata H 2006, Giovagnoli AR 2008)
Yamamoto S 2007 [71] Japan 1 Family history not reported. M 71 Alive at time of report, twenty-eight months from onset Not reported. Presented with progressive bilateral limb weakness, aphasia and apathy. 20 months from onset he developed mutism, akinesia and spastic paraplegia.
Webb TEF 2008 [5] UK (12)
Other (13)
25 W kindred from Bedfordshire, England, first reported in 1974 by Cameron and Crawford with an unusual inherited neurodegenerative disease (Cameron and Crawford 1974). Cameron and Crawford described seven generations of the W family, comprising 131 members (56 male, 75 female) of which 21 had the described (as yet unidentified GSS) neurological disease (Cameron 1974).
This is a large international series of 84 patients, 58 of which belong to the UK W kindred. The remaining 26 belong to eight small unrelated pedigrees. Genetic data was available for a total of 31 patients (six of whom have previously been reported)
Eighteen genetically confirmed patients from the UK W kindred described by Webb et al and include cases: VI.1-2, VI.12-15, VII.1, VII.4-8, VII-10, VIII.1-6. The following six cases: VI.12 (Hsiao K 1989), VI.13 (Watanabe R 1993), VI.15 (Piccardo P 1998), VII.4 (Hsiao K 1989), VII.7 (Hill AF 2006) and VII.10 (Young K 1995) have been previously reported and counted in their respective papers. Therefore, 12 W kindred cases are counted here.
A further 13 patients from nine unrelated families (six from the UK and two families from elsewhere in Europe – family 10 origin not stated), of which none are related to the W kindred, where also genetically confirmed in this study. However, as it is not known which are the UK patients and from which European countries the other patients belong to they are classified as ‘other’.
16 F
9 M
27-63 7-96 W kindred:
6 Met/Met 129
6 Met/Val129
Nine further unrelated families:
10 Met/Met129
3 Met/Val129
All heterozygous patients were Met129 in phase the Pro102Leu allele
The most commonly occurring presenting features were unsteadiness, cognitive symptoms and leg weakness. The most common clinical syndrome was progressive cerebellar ataxia associated with leg weakness and areflexia, accompanied by cognitive impairment late in the disease course – classic GSS. There was, however, considerable heterogeneity regarding clinical features.
Met/Met129 homozygotes were noted to have an earlier age at onset, compared with Met/Val heterozygotes.
Cagnoli C 2008 [72] Italy 1 In a screen of 206 unrelated Italian patients diagnosed with adult-onset cerebellar ataxia of unknown origin, one patient (case 5854) was found to harbour the Pro102Leu mutant. This female patient had disease onset aged 52 and died five years later. She is of Sicilian origin, with no family history of note. Retrospective review of her case confirms that the clinical course was compatible with the classical description of GSS characterised by predominant progressive ataxia with cognitive deterioration in the late stages of disease F 52 60 Met/Met129 Onset with cerebellar ataxia with dementia in late stages of disease. Of note, she was diffusely hyper-reflexic. She deteriorated to the point of akinetic mutism. Post-mortem was not performed.
Kanata A 2008 [73] Japan 1 51-year-old lady Pro102Leu GSS and noted to have high intensity lesions in the bilateral pulvinar on DWI MR brain. F 45 Alive at time of report aged 51, six years from onset. Not reported. Initially developed gait disturbance with lower limb muscle atrophy. Subsequently an ataxic gait manifest with refractory lower limb pain. She then demonstrated rapidly progressive cognitive dysfunction.
Giovagnoli AR 2008 [74] Italy 3 Previously unreported Italian GSS family. Proband is female patient, with disease onset aged 46 years; her mother died aged 59 years following cognitive deterioration and progressive palsy; her maternal grandfather died aged 65 years following a five-year period of progressive ataxia; a maternal uncle also died in pre-senile age following a period of progressive ataxia. The patients two brothers also developed a neurological syndrome in keeping with GSS (currently aged 45 and 48 years) and were found to have the Pro102Leu mutation. Of note, sequence analysis of the progranulin gene (GRN) revealed a previously undescribed missense mutation in all three family members: Ala505Gly. This is thought to be a non-pathogenic variant. 1 F
2 M
44-46 Proband alive at time of report aged 52, seven years from onset. Both brothers also alive 12 and 18 months from onset. 3 Met/Val129 (all Met in cis) Three members of same family, one with strikingly different phenotype. Onset in proband, aged 46, was heralded by changes in initiative, motivation, affect and behaviour. A progressive frontotemporal-type dementia emerged that resulted in loss of autonomy two years from onset in the absence of severe motor dysfunction. SPECT showed hypoperfusion of the left superior parietal and temporal cortex, and left thalamus (see Konaka K 2000, Arata H 2006, Irisawa M 2007). In contrast, her two brothers (onset aged 45 and 46) showed progressive cerebellar ataxia in the absence of cognitive decline (currently, they are 12 and 18 months into their clinical course, respectively). SPECT analysis in the brothers revealed normal perfusion.
Provini F 2009 [75] Italy 2 Polysomnographic study in two sisters with Pro102Leu mutation. They have a positive family history for ataxia in their mother and maternal grandfather. 2 F 31 and 24 Both sisters alive at time of reporting, five years from onset aged 36 and 32 Not reported. Patient 1, clinical onset aged 31 years with ataxia; reflexes were brisk. Her sister, patient 2, onset was aged 24 years with cognitive impairment and later progressive ataxia. Sleep study reveals preserved sleep organisation.
Webb TEF 2009 [37] UK (2) Two pairs of homozygotic twins from the UK W kindred, studied in detail in Webb TEF 2008. Twin pair A correspond to cases VIII.5 and VIII.6 in Webb TEF 2008 (counted there), and are likely related to the UK W kindred through a recent common ancestor. Twin pair B correspond to cases IV-3 and IV-4, genetic analysis is not available for this pair.
Further clinicopathological data is provided on twin pair A in this report.
2 F Twin 1, 53 and Twin 2, 60
(Not known for twin pair B)
Twin 1, 84
Twin 2, 48
2 Met/Val129 The clinical phenotype in twin pair A is notable for twin 2 having a disease onset seven years (aged 60) after her sister, twin 1 (aged 53). Twin one died seven years from onset aged 60. Twin 2 died aged 64, four years from onset and underwent neuropathological analysis.
Monozygosity was confirmed by analysis of multiple unlinked microsatellite markers.
Bergström AL 2009 [76] Denmark 1 Study of morphology and localisation of PrP in Danish patients with different subtypes of sporadic CJD and GSS. No clinical information given. Patient diagnosed with Pro102Leu. No frozen tissue was available for patient to permit genotyping for codon 129. Not reported.
Beck JA 2010 [77] Italy 2 Small pedigree from Sicily, Italy. The proband’s sister, brother and mother were affected with a similar illness, dying at 54, 57 and 60 years of age, respectively but genetic analysis not performed. A healthy descendant of the proband was found to possess the P102L on one chromosome and a 1-OPRI in trans on the other chromosome (no further clinical information given) M 56 60 Met/Met129 Typical GSS presentation with progressive cerebellar ataxia and late cognitive impairment
Takazawa T 2010 [78] Japan 1 This family comes from the Gunma Prefecture, East Japan. Family history shows the grandfather (I-1) and mother (II-2) of proband (III-1) had unsteadiness and cognitive changes. The mother became unsteady in walking aged 32 years; clinical record reveals evidence of cerebellar ataxia and brisk lower limb reflexes, personality changes developed aged 36 years and she died of pneumonia at 37 years. F 33 Alive at time of report at five years from onset in a state of akinetic mutism Met/Met129
Glu/Glu219
Index case presented with cerebellar ataxia and dysarthria. Her presentation is notable for lower limb hyperreflexia at an early stage in the disease process. At five years from disease onset she developed intractable insomnia and nocturnal howling, two months later she has verbal perseveration, somnolence, myoclonus and akinetic seizure.
Nozaki I 2010 [79] Japan 39 Prospective ten-year study (from 1999) of patients with prion disease registered by the Japanese Creutzfeldt-Jakob Disease Surveillance Committee. Pro102Leu was found to be the second most common mutation in familial prion disease (18.1%), preceded by Val180Ile (41.2%) 23 F
16 M
Mean 54
(range 22-75)
Mean 36.7 (range 3-96) 29 Met/Met129
3 Met/Val129
(31 Glu/Glu219 and 1 Glu/Lys219)
Park MJ 2010 [80] Korea 3 The first confirmed case of GSS in Korea.
Proband is Korean lady with disease onset aged 43. Two of the proband’s sisters (of seven siblings) developed similar symptoms in their fourth and fifth decades, respectively, and both died approximately five years after onset. Genotyping of her three children, revealed two (age and gender not given) to carry the Pro102Leu mutation.
F 43 Alive at time of reporting in a nursing home > three years from onset Not reported. Presented with slowly progressive gait ataxia and dysarthria. Cognitive decline ensued two years from onset becoming severe dementia. Her neurological deficits deteriorated to the point of becoming bedbound three years from symptom onset, aged 46.
Chi N-F 2010 [81] China (Taiwan) 9 Study of a large Han Chinese family from Taiwan (first Taiwanese GSS family). 34 members spanning five generations were examined.
Three surviving patients (III-3, IV-3 and V-2) and six unaffected family members (III-4, IV-1, IV-5, V-3, V-4 and V-5) were confirmed to harbour the Pro102Leu mutation.
Clinical information is available for a further four affected, now deceased, family members. Of which, two (III-1 and III-2) were said to have developed seizures as part of the disease phenotype, however, no genotyping is available.
Gender has been masked 27-64 Alive at time of report but current clinical courses range from 18 months to 13 years 9 Met/Met129
9 Glu/Glu219
In two patients (III-3, IV-3), disease onset was heralded by ataxia, followed insidiously by dementia. Clinical onset in patient V-2 was marked by a rapidly progressive dementia, followed later by ataxia.
Kojovic M 2011 [22] Slovenia 1 De novo Pro102Leu mutation in a Slovene patient, without family history of neurological disease. At the time of death her parents were in their sixties, without any major medical disorder. Her parents did not harbour the Pro102Leu mutation and both were Met/Val129 and Glu/Glu219. A paternity test performed on both parents yielded a 99.999% likelihood of paternity. Spontaneous demethylation of cytosine to thymidine at codon 102 (CpG site) has been suggested as mechanism for de novo mutation. F 27 132 Val/Val129
Glu/Glu219
Diseaase onset aged aged 27, with sporadic progressive spastic-ataxia with deafness. There was no evidence of any cognitive deficit throughout her illness. She dies eleven years from onset, aged 38. Neuropathological analysis undertaken showing typical GSS changes.
Ferrer I 2011 [23] Spain 1 Case of Pro102Leu-129Val. Initial working diagnosis was of a hereditary spastic paraparesis based on similar pyramidal signs in the family, although no further family history is given. F 47 120 Met/Val129
Val129 in cis with Pro102Leu.
48-year-old lady hospitalised for the previous ten years due to a progressive neurological disability categorised as hereditary spastic paraparesis of Strümpell-Lorrain disease-type, cognitive impairment and eventually, severe dementia. Neuropathological analysis showed typical GSS changes as well as tauopathy (see Ishizawa K 2002)
Karmon Y 2011 [82] USA 2 Case of GSS masquerading as MS. Index case initially misdiagnosed with primary progressive multiple sclerosis. Family history was positive for an early onset rapidly progressive neurological disease in both the father (in his mid-40s) and an older sister (in late 20s) characterised by early cognitive decline and behavioural change; they were given a presumptive diagnosis of Alzheimer’s disease at the NIH. Eventually, another sister revealed that a cousin related through the paternal grandfather had a molecular diagnosis of GSS. This eventually led to genetic testing that confirmed GSS Pro102Leu in this case. F 40 Alive at time of report >18 months from onset Not reported. Index case presents with progressive unsteadiness over one year. She also had dysarthria and myoclonic jerks. 18 months from onset, dementia ensued, and ataxia deteriorated. An initial working diagnosis of MS was supported by increased signal intensity in periventricular region on MR FLAIR, OGBs in CSF and abnormal VEPs. OCT demonstrated bilateral atrophy of retinal nerve fibre layers (see Sugai F 2000, Majtenyi C 2000 and Salsano E 2011)
Salsano E 2011 [83] Italy 7 Report of seven novel Italian GSS102 patients. Five patients belonged to three Sicilian families and two were sporadic cases, one from Southern (Calabria) and one from Northern (Emilia-Romagna) Italy. In the two patients without family history, non-paternity was not excluded.
Authors propose that areflexia, in the presence of normal NCSs and SEPs, could be considered a highly suggestive feature of GSS (see Yamada M 1999)
2 F
5 M
30-53 Not reported but all patients alive and evaluated at between 12 and 48 months into the disease process. 4 Met/Met129
3 Met/Val129
Presenting symptom was ataxia or lower limb weakness in all cases. They were also all areflexic. Four also complained of lower limb dysesthesia. Cognitive deficiency was not a prominent feature of their presentation.
Some cases had abnormalities of electroretinogram and visual evoked potentials suggesting involvement of retina and optic tract (see Sugai F 2000, Majtenyi C 2000 and Karmon Y 2011)
Monaco S 2012 [36] Italy 3 (8) Study designed to investigate the contribution of mutant PrP and wild-type PrP in the generation of PrPSc conformers. Eight patients from four unrelated kindreds are described, of which five have been previously reported. Three by this group in Piccardo P 1998. It is not stated where cases 4 (98-196) and 5 (98-197) are reported and we are unable to locate them in the literature.
Case 1 (91-466) corresponds to patient 1 in Piccardo P 1998, is a patient from the Canadian branch of the W kindred and is equivalent to patient 2 (NP 91_466) in Young K 1995 and case VII.10 in Webb TEF 2008 (counted in Young K 1995). Case 2 (92-331) is equivalent to patient 3 in Piccardo P 1998 and corresponds to Italian-American patient 1 (NP 92_331) in Young K 1995 where it is counted. Case 3 (96-422) is equivalent to patient 2 in Piccardo p 1998 (counted there) and they belong to the Canadian branch of the W kindred.
1 F
2 M
41-50 5-72 Two (cases 6 and 8)
Met/Met129
One (case 7) Met/Val129
Case 6 presented with behavioural change, mild ataxia and mild cognitive impairment and developed abnormal sleep and agitation. Case 7 presented with ataxia and developed dementia. Case 8 presented with cognitive decline and developed dementia without cerebellar signs.
Popova SN 2012 [84] Finland 5 First verified Finnish GSS family. Ancestors of this family were born in Eastern Finland in 1872 and 1873. The pedigree consists of five generations with forty members, of which ten are clinically affected.
The index case (III-11) was a member of the third generation. Two family members of the second generation (II-1 and II-4) and three from the third (III-1 and III-2), displayed symptoms that retrospectively are likely to have been due to GSS – they died aged between 48 and 58 years and genetic analysis was not undertaken.
The Pro102Leu mutant was confirmed in five members of this family (III-7, III-11, III-12, IV-2 and IV-7).
4 F
1 M
38-62 36-84

 

Cases III-7 and IV-2 alive at time of report with clinical durations of 84 and 36 months, respectively

4 Met/Met129
1 (IV-7) Met/Val129
Three cases (III-7, III-11 and IV-7) with ages of onset 62, 61 and 38 years, respectively, had ataxic onset. Two cases (III-12 and IV-2) displayed dementia at onset that was reminiscent of FTD.
Neuropathological examination was undertaken in patients III-11, III-12 and IV-7, which showed differential pathology in those with ataxic compared to dementia onset.
Higuma M 2013 [85] Japan 57 Japanese patients known to the national system for surveillance of prion diseases from April 1999 to August 2011. 45 cases classified as GSS-type and 12 as CJD-type. 22 patients had a definite family history, in which a family member also harbours the Pro102Leu mutation 30 F
27 M
Mean 55.1 GSS-type
Mean 55.4 CJD-type
Mean 58 GSS-type
Mean 27 CJD-type
43 Met/Met129
5 Met/Val129
47 Glu/Glu219
Rusina R 2013 [86] Czech Republic 1 First genetically established case of GSS in the Czech Republic (however, three cases of histopathologically confirmed GSS were reported by Jirasek A 1988).
Index case died 15 months following onset of nonspecific behavioural changes and six months following the first verified neurological signs. She has a positive family history involving her mother who died aged 49 years of progressive ataxia and dementia lasting two years (not genotyped). Post-mortem was not undertaken in the mother.
This patient (counted here) corresponds to patient 1 in Tesar A 2019
F 44 15 Met/Met129
Glu/Glu219
This case is notable for its rapid course, early cognitive impairment and late onset ataxia. She was also hyper-reflexic. MR brain and EEG (generalised sharp complexes) findings were very similar to those of sporadic CJD patients.
Neuropathological hallmarks of GSS were found post-mortem.
Iwasaki Y 2014 [87] Japan 1 Japanese lady born in the Kagoshima Prefecture in the Southern part of the Kyushu region of Japan.
It is known that the father of the index case had senile-onset dementia and became bed-bound after several years, but no further details are known and there is no other known neurological disorder in the family.
F 54 62 Met/Met129
Glu/Glu219
Disease onset was marked by dementia and gait disturbance. It was rapidly progressive, reaching akinetic mutism in 11 months.
Riudavets MA 2014 [88] Italy 1 First Latin American GSS kindred to be reported, with Italian origins.
This Argentinian family was originally from a small village in Sicily (San Piero, Messina), who left Italy to settle in Argentina (near Buenos Aires) in the early 20th century. Several unrelated GSS Pro102Leu families have been reported in Sicily – see Kretzschmar HA 1992, Young K 1995, Barbanti P 1996, Bianca M 2003, Cagnoli C 2008 and Salsano E 2011.
The family is formed of eighteen members over four generations. The proband is case IV-7, and is the only member of this family in whom the Pro102Leu mutation is confirmed.
Proband family members IV-6 (brother), III-3 (father) and II-2 (grandmother) died age 52, 54 and 52 years with diagnoses of frontotemporal dementia, dementia and Pick’s disease, respectively. His cousin (IV-5) died aged 45 years with a diagnosis of Pick’s disease, his DNA could not be sequenced.
M 44 72 Met/Val129
(Met in cis)
Glu/Glu219
44-year-old physician presented with ataxia and months later developed fronto-temporal pattern dementia. Neuropathological features of GSS were found post-mortem.
Muona M 2015 [24] Italy 1 Case identified as part of whole-exome sequencing from a multi-centre study of 84 unrelated individuals which aimed to identify the causative genes for unsolved progressive myoclonus epilepsy. Father of case (PME86-1) was similarly affected, but genotype unavailable. His illness began aged 30 years and died aged 47. F 25 180 Met/Val129

 

Val129 in cis
(residue at position 129 in non-mutant allele is not reported)

Onset aged 25 with ataxia, daily myoclonus from age 28, monthly tonic-clonic seizures, progressive decline from 34 years. Tetraparesis and bedridden aged 39, deceased aged 40 years. Progressive myoclonus epilepsy is a rare presentation of GSS (see Mumoli L 2017)
Ando R 2016 [89] Japan 1 The patient’s mother, two older sisters and a brother had clinical symptoms consistent with GSS disease. F 62 Alive at time of report – unclear duration but at least 6 years Met/Met129
Glu/Glu219
Initial presentation was numbness in the feet followed by ataxia; dementia ensued six years from onset.
Umeh CC 2016 [90] US 6 Seven family members had symptoms consistent with GSS. Five of whom (including index case) were positive for the Pro102Leu mutation. A further asymptomatic member (aged 23) was also found to harbour the mutation. The mean age of symptom onset in this family was 45 years. Clinical phenotypes of the four affected (now deceased) family members included ataxia, cognitive impairment and dysarthria. No further details and codon 129 genotype for these four members not reported. M 56 7 Mat/Val129 (Met in cis) Presentation of index case is notable for rapidly progressing Parkinsonism and dystonia. He died seven months following symptom onset. Severe PrPSc deposition and spongiform change in the basal ganglia, substantia nigra, striatum, and cerebellum were found post-mortem.
Krasnianski A 2016 [7] Germany 8 Patients were captured following report to the CJD Surveillance Unit in Gottingen between June 1993 and January 2005.
All cases had a positive family history.
Individual level data not available.
3 F
5 M
38-62
(Mean 49.8)
24-100
(Mean 65.0)
4 Met/Met129
4 Met/Val129
(Met129 homozygotes were found to have later age of onset and shorter disease durations compared to Met/Val129 cases, in contrast to Webb TEF 2008)
Pro102Leu patients were found to have a younger age of onset and longer disease duration than other prion disease-causing mutations. GSS patients mostly had invariably monosymptomatic onset with ataxi, with dementia manifesting late in the disease course. The eight patients in this study did not develop akinetic mutism.
Takada L 2017 [29] US 13 Patients referred to UCSF rapidly progressive dementia prion disease centre between 2001 and 2016, with confirmed Pro102Leu mutation. 13 were evaluated. Among the nine probands in this report, six had a positive family history Mean 44
(Range 24-57)
Mean 44
(Range 28-60)
Cis Met129 in all where information available (n not known) Individual level data not available.
Smid J 2017 [26] Brazil 6 Six patients in two unrelated Brazilian kindreds (family A and family B) are genetically confirmed to have the Pro102Leu mutation. Four cases from family A over two generations and two in family B.
In the first generation of family A, the father of three affected children died after the seventh decade of life, while the mother died in her forties, without symptoms of GSS. Three further siblings from the second generation, aged 61 to 69 years, are asymptomatic as are fifteen relatives of the third generation, aged 27 to 51 years. Disease onset in the mother (IIa-3) of index case (IIIa-1) was 66 years, whereas, in the index case it was age 27.
Family B is of Portuguese descent and has six probably-affected individuals. The first known case was the paternal grandfather (Ib-1) of the index case (IIIb-1). In the next generation there were reports of at least three individuals with likely similar neurological syndrome who died around the fourth decade. The father (IIb-1) of index case died aged 33 years. In the third generation two patients were evaluated (IIIb-1 and IIIb-2).
Six genotyped patients are: IIa-2, II-a-3, IIIa-1 and IIIa-2 of family A and IIIb-1 and IIIb-2 of family B. Neuropathological data available for three cases: IIa-1, IIIa-1, IIIa-2
5 F
1 M
25 to 66 48 to 180 months in the three deceased patients. IIa-3, IIIb-1 and IIIb-2 are alive with disease durations at time of reporting of 24, 48 and 96 months, respectively Family A: 2 Met/Met129 and 2 Met/Val129 (Met in cis with Leu102)
Family B: 2 Val/Met129 with Val in cis with Leu102
Patient IIIa (index case) of family A presented aged 27 years with rapid cognitive decline progressing to severe dementia within two years. Ataxia and dysarthria emerged five years from onset. Reflexes were brisk. She died 15 years from onset.

 

Patient IIIb-1 (index case) of family B presented aged 35 years with cognitive decline and balance deficit. Severe dementia with frontal syndrome and global cerebellar ataxia was established at three years from onset. Brisk reflexes were also present. No seizure activity reported. Her brother (IIIb-2) presented classically with ataxia and later dementia. Without seizure activity.
Phenotypic variability present within the families, with no correlation to genotype at polymorphic sites. Earliest clinical onsets noted in patients Met/Val heterozygous patients in cis with methionine cf. Webb TEF 2008.

Sugiyama A 2017 [91] Japan 2 Two unrelated Japanese patients are reported.
Case 1 had no family history of GSS but father had been diagnosed with ALS and dies aged 70 years.
The mother of case 2 had been diagnosed with cerebellar degeneration and died aged 54 years. Her elder brother had a diagnosis of GSS.
2 F 53 and 58 Both alive at time of report with durations of 2.5 and 8 years. Not reported. Case 1 presented with preogressive cerebellar ataxia; no cognitive impairment 2.5 years from onset.

 

Case 2 also presented with ataxia and later severe dementia. At time of reporting, she is in a state of akinetic mutism.

MR brain imaging in both patients shows atrophy and decreased blood flow of the thalamus.

Marino S 2017 [92] Italy 3 Family history of index case reveals that his mother had similar progressive symptoms, and in whom the Pro102Leu mutation was identified. In addition, an un-affected younger sister also harboured the same mutant. No further clinical details of mother and sister given in report. M 40 Alive at time of report, with no given information on duration. Not reported Slowly progressive cerebellar ataxia accompanied by spastic paraparesis, and cognitive impairment.
Mumoli L 2017 [25] Italy 1 Her father died at the age of 45 years of the same disease, which had started at the age of 35 years. No further family information given. F Mid-20s (taken as 25) 156 (died age 38) Met/Val129 with Val129 on the mutant allele Initially developed unsteadiness, slowed movements and difficulty speaking. Aged 29 she developed myoclonic jerks and at 32 years cognitive deterioration ensued as well as generalised tonic-clonic seizures. She was also hyper-reflexic in all four limbs. Death occurred in the ITU at age 38 years due to refractory convulsive status.
Her electroclinical findings were highly suggestive of progressive myoclonus epilepsy (See Muona M 2015)
Li H-F 2017 [93] China 9 Study of eight distinct South Eastern Chinese families in which members presented with cerebellar ataxia. Of these eight, the probands of five families 1 (II-5), 3 (II-2), 6 (II-3), 7 (III-5) and 8 (III-2) were found to harbour the Pro102Leu mutant. Other live affected members of these five families were also confirmed Prol102Leu: 1 (II-6), 3 (II-4), 7 (III-2) and 8 (III-7). 5 F
4 M
37-59 Probands and affected family members alive at time of reporting but clinical courses ranged from 2 to 10 years All Met/Met129 and Glu/Glu219 All five probands presented with cerebellar ataxia and later developed dysarthria, dysphagia and cognitive impairment. Hyperreflexia was noted in three probands (1, II-5; 3, II-2; 6, II-3). Affected members had similar clinical courses.
Long L 2017 [94] China 1 Proband is female patient from Jianxi Province, Southern China.
Family history reveals evidence of ataxia in seven family members over three generations, all of whom are deceased. The proband’s mother was hospitalised with similar symptoms aged 55. Her diagnosis was cerebellar atrophy and she died aged 59 years. The proband’s younger brother developed ataxia and depression aged 35 years and committed suicide four years later. The other five symptomatic family members died between the ages of 35 and 59, approximately 4-6 years from disease onset. The proband’s two sons are unaffected and did not consent to genetic analysis.
F 44 Alive at time of report which is four years into the clinical course Met/Met129 Ataxic onset with dysarthria. She was also diagnosed with cervical disk herniation at C5/6 and C6/7 that was operated on without improvement in speech and swallow. Her initial working diagnosis was that of hereditary cerebellar ataxia. Only following analysis of a gene panel that included 4800 genes related to common and rare hereditary diseases that the PRNP Pro102Leu mutation was identified, and her diagnosis revised to GSS. At time of reporting she did not report any cognitive deficiency.
Inoshita K 2017 [95] Japan 5 Five GSS Pro102Leu patients in four families seen in Yanagawa, Japan. Poster abstract – limited information. 2 F
3 M
28, 52-67 (mean 54.8 years) Within 8 years except one Not reported Not reported.
Wang J 2018 [96] China 2 There is no family history of neurological disease.
Unaffected mother and two adult children of index case also underwent genetic analysis. PRNP sequences of her mother and son were wild-type, but her asymptomatic daughter harboured the Pro102Leu mutant.
F 49 Alive with akinetic mutism at time of report which is 21 months from onset. Met/Met129
Glu/Glu219
Progressive unsteady gait and sleep disturbance. Myoclonus later developed. Initial clinical suspicion was that of Miller-Fisher syndrome.
Of note, this patient was also found to have three other mutations in the SYNE1 gene: V3643L, M3376V and T2860A.
Yoshimura M 2018 [97] Japan 5 Five patients from four Japanese families all born in Kagoshima Prefecture, in Southern Japan diagnosed with GSS Pro102Leu.
Patients 1 and 2 are sisters from the same pedigree.
3 F
2 M
57-72 All patients alive at time of reporting with clinical durations from nine months to over 2 years 4 Met/Met129
1 Met/Val129 (Met in cis)
5 Glu/Glu219
Initial symptom onset encompassed lower limb dysesthesia (patient 1), ataxic gait (patients 2 and 3), dysarthria (patient 4) and character change (patient 5). However, later all patients developed lower limb ataxia, dysesthesia and areflexia.
Patients 1 and 2 are sisters from the same pedigree (both Met/Met129). Although presenting differently, 3 and 6 months from onset, respectively, cognitive dysfunction appeared that rapidly progressed to rendering them bedbound within three months.
Decreased blood flow in the anterior cerebellar lobes, a projection field of the spinocerebellar tracts, was noted by SPECT analysis. No atrophy or decreased blood flow to the thalamus was seen, as has been reported by Sugiyama A 2017.
Areškevičiūtė A 2018 [98] Denmark 2 First case report of presumed sporadic CJD and GSS Pro102Leu occurring in the same family. The father and son have the Pro102Leu mutation, and the mother developed a rapidly progressive form of CJD. The extraordinary occurrence of GSS and sporadic CJD in one family led the authors to speculate whether transmission via acquired microchimerism may have occurred. The mother had no pathogenic PRNP mutation, but was found to have a silent Ala117Ala variant and was Val/Val homozygous at codon 129. 2 M 48 and 55 96 months for father, he died aged 63 years. Son is alive at time of report with > 4 years clinical duration Son Met/Val129 with Met in cis (also had a silent Ala117Ala mutation) Father’s genotype at codon 129 unavailable. Father presented with gait disturbance and tremor, he was suspected of having a Parkinsonian-plus syndrome. Son presented with cognitive impairment and personality changes.
Wang J 2019 [99] China 12 (13) There have been 12 unrelated Pro102Leu cases diagnosed by the Chinese National Surveillance Network for CJD since 2006. They are detailed in this report. However, Case 9 has previously been reported by Wang J 2018 and is counted there. The other patients in this report could not be correlated with published Chinese cases.
Cases 3 and 10 had no family history of neurological disease.
Son of Case 6 was also found to harbour the Pro102Leu (Met/Met129 and Glu/Glu219) mutation but was unaffected at time of report.
7 F
4 M
34-67 11-44 11 Met/Met129
10 Glu/Glu219
Case 3 Glu/Lys219
Presenting symptoms included gait instability, psychiatric disturbance such as anxiety and emotional lability and rapid or slow progression of dementia.
Zhao M-M 2019 [100] China 1 Family from Northeast China. Proband born in Jilin province.
Proband’s mother and brother exhibited similar symptoms. Onset in mother was aged 51 years; she was diagnosed with cerebellar atrophy, had mild dementia and died five years from onset. Onset in his older brother was at 36 years and he died following a nine-year clinical course.
Alive relatives of proband declined genetic testing.
M 45 Alive but in decorticate state, at time of report 66 months from disease onset. Not reported. Onset marked by ataxia and bilateral foot drop. Later dysarthria and head tremors developed. He was unstable even when seated with intense muscle pain in lower limbs. Five years after symptom onset seizure activity began which were controlled with sodium valproate.
Jung S-H 2019 [101] Korea 1 No family history. F 48 Alive at time of report nine months from onset and in a state of akinetic mutism. Met/Met129
Stated that no gene polymorphism present.
Initial presentation with rapidly progressive dementia and later myoclonic spasms and ataxia, without cerebellar signs. Eight months from onset akinetic mutism set in.
Tesar A 2019 [102] Czech Republic 6 (7) Seven Czech cases reported, of which one (case 1) has previously been reported – See Rusina R 2013 – and is counted there. Cases 4 and 5 are mother and daughter. Cases 6 and 7 are mother and son. Case 3 had no family history of GSS or neurological disorder. 2 F
4 M
29-65 4-108 All cases in cis with Met129 Two cases (2 and 3) classified as CJD-GSS, three (4, 5 and 6) as typical GSS and case 7 as GSS with areflexia and paraesthesia. Dementia was present in four cases (2, 3, 6 and 7).
Kang MJ 2019 [103] Korea 1 Index case has no family history of neurological disease. His 71 year-old mother, 74 year-old father and five siblings were healthy and neurologically intact.
The Pro102Leu mutant was not found in either parent.
M 48 36 Not reported. Presented with progressive ataxia, dysarthria and clumsiness of hands. Examination one year from onset revealed mild-dementia. 17 months from symptom onset he was in state of akinetic mutism.
Moser C 2020 [104] US 1 Limited information. M 55 Unclear Met129 in cis (residue at non-mutant allele not reported) Slowly progressing amyotrophy with subsequent cognitive decline
Bhatia S 2020 [27] India 4 First Indian GSS kindred over four generations reported. There was a family history of a similar neurological syndrome in proband’s (III-12) sister (III-14). In addition, seven paternal cousins/nephews had died between the ages of 35-55 years following a similar progressive neurological illness of duration ranging from 5 to 10 years (III-1, III-2, III-3, III-6, III-7, IV-1 and IV-2). The father of the proband is a healthy 80-year-old gentleman (II-6).
DNA analysis was undertaken in proband (III-12), his affected sister (III-14), his unaffected father (II-6) and an affected deceased paternal cousin (III-6). All were found to harbour the Pro102Leu mutation. It is notable, that the proband, sister and cousin are heterozygous Met/Val at codon 129 (Val in cis), whereas the unaffected 80-year-old father is homozygous Met/Met129 and, surprisingly, displays no neurological symptoms.
2 F
2 M
35-43 Paternal cousin (III-6): 120
Proband (III-12) and sister (III-14) are alive at time of report at 12 and 60 months, respectively.
3 Met/Val129 with Val in cis

 

1 Met/Met129

Proband, a doctor himself, presented with progressive difficulty in walking and slurred speech. A similar syndrome is seen in his sister and paternal cousin. The probands awareness of the family history led to genetic testing that revealed the diagnosis in this family.
The father, at 80 years of age and harbouring the Pro102Leu mutation, has not developed any symptoms.

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.

Neurological examination:

A clinical sign emphasised for its potential role in the early diagnosis of GSS Pro102Leu is lower limb areflexia, in the presence of normal nerve conduction studies and somatosensory evoked potentials67. Webb et al5, in the largest cohort of GSS Pro102Leu cases reported to date, found 79% of patients to be lower limb areflexic. Absence of lower limb reflexes is seen in different ataxic disorders; however, it appears that GSS pro102Leu is the only disorder in which areflexia is associated with normal central and peripheral conduction83. This unique finding may be explained by PrPSc deposition in the posterior horns of the lumbar spinal cord (with sparing of the dorsal root ganglia and peripheral nerves)20,55 and suggests that early GSS signs may be related to a myelopathic process, at least in a subgroup of GSS102 patients. Dorsolumbar MR imaging has also shown spinal cord atrophy in GSS Pro102Leu patients83. The sensitivity of areflexia, as an early diagnostic feature of GSS, is uncertain as cases of hyperreflexia have also been reported22,72,78,93. Takazawa and colleagues78 attribute hyperreflexia, in their report of a Japanese GSS Pro102Leu family, to damage to the cerebral cortex and corticospinal tract before deposition of PrP in the lumbar posterior horns. Nevertheless, lower limb areflexia with normal conduction, is thought to be suggestive of GSS83.

Also see individual cases outlined in Table of Cases.

Clinical investigations:

See individual cases outlined in Table of Cases.

Genetic analysis:

c.305C>T mutation, leading to the CCG-to-CTG change, corresponding to mutation Pro102Leu. Pro102Leu mutation, together with D178N, V180I and E200K, which account for the greater majority of inherited prion disease worldwide105 occur at cytosine-phosphate diester guanidine (CpG) dinucleotide sites, that are mutational hotspots in human DNA106 and may explain the high incidence of the mutation in different ethnic groups.

Neuropathological studies:

Neuropathologically, the common denominator in GSS P102L is multicentric PrPSc plaques in the cerebellum and cerebral cortex, coexisting with severe spongiform degeneration107-108. Immunoblotting of brain homogenate in patients with Pro102Leu mutation typically shows the presence of proteinase K-resistant PrP fragments of approximately 21-30 kDa and 8kDa35.

Of note, no spongiform degeneration is seen in the brains of cases where the Pro102Leu mutant was on a valine 129 allele20,23 and western blot analysis of brain homogenate showed proteinase K-resistant PrPSc bands of 29 kDa, 24 kDa, a strong band at 20 kDa, 15 kDa and weaker band at 7 kDa23.

Structure-based protein function annotation:

Proline 102 lies in the second charge cluster, CC2 (aa 101-110), containing four positively charged lysine residues, and this is a position of perfect conservation amongst mammalian species109-110. Biophysical evidence converges on the finding that that the partially structured N-terminus and the globular C-terminal domain directly interact in a functionally important manner111-112. This cis interaction is mediated by both Cu2+ 112-115 and Zn2+ 116 binding to the octapeptide repeat domain, as well as electrostatic interactions between the polybasic N-terminus clusters CC1 and CC2 and a negatively charged pocket on the globular C-terminal domain, contributed predominantly by α-helices 2 and 3 112,114,116-119. (see Architecture of PrP). Copper also binds residues His96 and His111, in the post-octapeptide region120-123.

It has been shown that the N-terminal domain, and in particular the first nine residues (aa 32-31, encompassing charged cluster CC1) acts as a latent, toxic effector, whose activity is under autoinhibitory control by the cis N-C interaction that sequesters the metal bound N-terminus – thus, PrPC is involved in a neuroprotective self-regulatory process113-114,124. Indeed, mutations causing familial CJD (Glu200Lys – the most common cause worldwide) and either familial CJD or FFI (Asp178Asn, dependent upon whether the PRNP cis codon 129 polymorphism is Met or Val11) have demonstrated weakened N-C cis interactions, likely through reduction of negative charge on the C-terminal docking surface112,114,116. Conversely, the Q219K polymorphism, associated with resistance to sporadic CJD in the Japanese population125 induces a moderate strengthening of the N-C interaction116. Therefore, it may be possible that increased stability of the PrPC quaternary N-C interaction creates a barrier to misfolding and is, in turn, protective against prion disease.

The near-UV CD spectra of Pro102Leu are indistinguishable from wild-type, and therefore, this mutant does not result in significant perturbation of the secondary or tertiary protein structure126. This has been confirmed by solution NMR analysis of Pro102Leu, which reveals that chemical shift perturbations caused at pH 5.5 are small and strictly localised to the mutation site and immediate neighbour residues, without leading to any significant conformational or dynamical changes relative to wild-type PrPC 127. Furthermore, mutant Pro102Leu does not have a measurable effect on PrPC thermodynamic stability126,128. Whereas pathogenic C-terminal mutants (Phe198Ser/Gln217Arg/Arg208His/Asp178Asn/Val180Ile/Val201Ile) stabilise a folding intermediate (in a three-state transition model) that may serve as a direct precursor to the pathogenic PrPSc isoform, mutant Pro102Leu populates this partially folded species to a similar degree as wild-type PrPC 128. MD simulations of 4 and 8 ns at 320 K of the Pro102Leu mutant in combination with Val129 and Met129 of Syrian hamster PrP (aa 90-231) revealed no significant differences with the wild-type structure (either between the globular domain or the flexible N-terminus)129. These data are consistent with the position of Pro102 in the solvent-exposed, largely unstructured, N-terminus and therefore, would not be expected to significantly change the energy landscape – a similar result is likely for mutant Pro105Leu. As such, the pathogenicity of Pro102Leu cannot be rationalised using the concept of mutation-induced thermodynamic destabilisation of PrPC 126, but rather, mutation-dependent changes in the amyloidogenic propensity of the N-terminus likely facilitates the spontaneous conversion of PrPC to PrPSc 128.

Several lines of evidence support the notion that Pro102Leu increases PrPSc-conversion potential through disruption of the N-C interaction. First, evidence for disrupted copper binding; using X-ray absorption spectroscopy, it has been shown that mutant P102L alters copper coordination at the non-octapeptide region130. Pro102Leu makes His96 unavailable for copper interaction at both neutral and acidic pH, and the experimental His96Tyr mutant causes spontaneous PrPSc-like formation in cultured neuronal cells, with accumulation in acidic endosomal compartments. The authors130 propose a model in which a PrP molecule that coordinates copper with both His96 and His111 in the post-octapeptide repeat region is more resistant to prion conversion compared to a molecule that coordinates copper with only one histidine131. This group went on to show that alteration of copper binding-sites caused a modest structural perturbation (30% α-helix/22% β-sheet in wild-type mouse PrP and 21% α-helical/26% β-sheet in mouse Pro101Leu mutant), which in-turn, failed to induce neurite outgrowth through NCAM-Fyn-ERK signalling132. Second, evidence for disrupted inter-domain interaction; mutant Pro102Leu was observed by NMR to weaken the cis N-C fold116. The N-terminus is thought to form an extended poly(L-proline) II helix structure133 and substitution of Pro102 may interfere with the conformational adaptability imparted by such a structure, which may be required to correctly orientate the N- and C-termini (see Pro39Leu analysis). It is possible that loss of proline in mutant 102Leu alters local conformational dynamics required to mediate effective docking of the N-terminus onto the C-terminal pocket. Support for this is provided by studies showing that substitution of CC2 proline 102 to leucine in recombinant hamster PrP, under physiologically compatible conditions, promoted scrapie-templated formation of synthetic recombinant prion amyloids, and the combination of Pro102Leu with charge-neutralising mutagenesis of the four cationic lysines in CC2 resulted in spontaneous prion formation134. Therefore, Pro102Leu appears to diminish the energy-barrier to amyloid conversion, an effect that is enhanced by CC2 charge neutralisation134-135. This is in keeping with the model of N-C interaction being stabilised by charge complementarity between the N- and C-terminal domains. Lastly, Jones et al136, compared the fibril formation of a wild-type PrP fragment (aa 23-144) with Pro102Leu, Pro105Leu and Ala117Val fragments, and found 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. Furthermore, Pro102Leu replaces a β-sheet incompatible residue, which may further compound the amyloidogenic potential of this mutant.

Therefore, it appears that mutant Pro102Leu mediates its pathogenicity through local cumulative effects on factors influencing conformational transition of PrPC to PrPSc, rather than through gross structural perturbations and protein instability. A simple and plausible mechanism would be that alteration in PrPC copper binding and perturbations in regional conformational adaptability conspire to weaken the neuroprotective N-C PrPC arrangement culminating in prion pathogenesis and GSS. It is likely that mutants Pro84Ser and Pro105Leu/Thr/Ser operate by a similar pathogenic mechanism.

In silico Pathogenicity predictions:

Pon-P2 (independent)137:

  • Probability of pathogenicity: 0.762
  • Standard error: 0.132
  • Prediction: Unknown

Revel (ensemble)138:

  • Score: 0.93
  • Prediction: Pathogenic

A stringent REVEL score threshold of 0.75 is applied, above which the variant is classified as pathogenic.

References:

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