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Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series.

Webb TE, Poulter M, Beck J, Uphill J, Adamson G, Campbell T, Linehan J, Powell C, Brandner S, Pal S, Siddique D, Wadsworth JD, Joiner S, Alner K, Petersen C, Hampson S, Rhymes C, Treacy C, Storey E, Geschwind MD, Nemeth AH, Wroe S, Collinge J, Mead S - Brain (2008)

Bottom Line: We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02).We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias.These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurodegenerative Disease and MRC Prion Unit, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.

ABSTRACT
The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.

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Deposition of abnormal prion protein in cortex and cerebellum. The upper panels show characteristic multicentric PrP plaques, stained with the anti-PrP monoclonal antibody, ICSM35 (A+B from Patient 2. VII. 2). The lower panel shows synaptic deposition of abnormal PrP (C+D from Patient 7. VIII. 1), demonstrating significant pathological heterogeneity. The scaling bar shown in 100 μM.
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Figure 8: Deposition of abnormal prion protein in cortex and cerebellum. The upper panels show characteristic multicentric PrP plaques, stained with the anti-PrP monoclonal antibody, ICSM35 (A+B from Patient 2. VII. 2). The lower panel shows synaptic deposition of abnormal PrP (C+D from Patient 7. VIII. 1), demonstrating significant pathological heterogeneity. The scaling bar shown in 100 μM.

Mentions: A total of 11 patients were available for neuropathological examination. Varying degrees of atrophy were observed macroscopically, with brain weights varying from 1200 to 1740 g. Histopathological examination demonstrated spongiform change, astroctyosis and PrP deposition. These three features, however, were very variable between individuals and brain regions. Spongiform change was present in some brain regions in the majority, but not all, of the patients examined (7 out of 10 patients) and varied from mild to severe. PrP deposition was most commonly found in the context of multicentric amyloid plaques. PrP antibodies ICSM 18 and ICSM 35 positively labelled these plaques. Multicentric plaques were commonly found in the molecular layer of the cerebellum but also less frequently in the granular layer. Similar plaques were found in the cortex in most patients examined (9 out of 10 patients) (Fig. 8). In a single patient (VI.12), the only definite abnormality seen was small numbers of plaques positively stained with ICSM 18 in the basal ganglia, although the tissue examined was 20 years old. More diffuse PrP deposition was demonstrated in the majority of patients available (7 out of 10). A single patient (VIII.1) showed very atypical diffuse staining that appeared to follow cortical tracts and was similar to other IPD patients but not to previously described P102L pathology.Fig. 8


Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series.

Webb TE, Poulter M, Beck J, Uphill J, Adamson G, Campbell T, Linehan J, Powell C, Brandner S, Pal S, Siddique D, Wadsworth JD, Joiner S, Alner K, Petersen C, Hampson S, Rhymes C, Treacy C, Storey E, Geschwind MD, Nemeth AH, Wroe S, Collinge J, Mead S - Brain (2008)

Deposition of abnormal prion protein in cortex and cerebellum. The upper panels show characteristic multicentric PrP plaques, stained with the anti-PrP monoclonal antibody, ICSM35 (A+B from Patient 2. VII. 2). The lower panel shows synaptic deposition of abnormal PrP (C+D from Patient 7. VIII. 1), demonstrating significant pathological heterogeneity. The scaling bar shown in 100 μM.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2570713&req=5

Figure 8: Deposition of abnormal prion protein in cortex and cerebellum. The upper panels show characteristic multicentric PrP plaques, stained with the anti-PrP monoclonal antibody, ICSM35 (A+B from Patient 2. VII. 2). The lower panel shows synaptic deposition of abnormal PrP (C+D from Patient 7. VIII. 1), demonstrating significant pathological heterogeneity. The scaling bar shown in 100 μM.
Mentions: A total of 11 patients were available for neuropathological examination. Varying degrees of atrophy were observed macroscopically, with brain weights varying from 1200 to 1740 g. Histopathological examination demonstrated spongiform change, astroctyosis and PrP deposition. These three features, however, were very variable between individuals and brain regions. Spongiform change was present in some brain regions in the majority, but not all, of the patients examined (7 out of 10 patients) and varied from mild to severe. PrP deposition was most commonly found in the context of multicentric amyloid plaques. PrP antibodies ICSM 18 and ICSM 35 positively labelled these plaques. Multicentric plaques were commonly found in the molecular layer of the cerebellum but also less frequently in the granular layer. Similar plaques were found in the cortex in most patients examined (9 out of 10 patients) (Fig. 8). In a single patient (VI.12), the only definite abnormality seen was small numbers of plaques positively stained with ICSM 18 in the basal ganglia, although the tissue examined was 20 years old. More diffuse PrP deposition was demonstrated in the majority of patients available (7 out of 10). A single patient (VIII.1) showed very atypical diffuse staining that appeared to follow cortical tracts and was similar to other IPD patients but not to previously described P102L pathology.Fig. 8

Bottom Line: We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02).We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias.These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurodegenerative Disease and MRC Prion Unit, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.

ABSTRACT
The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.

Show MeSH
Related in: MedlinePlus