Limits...
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.

Show MeSH

Related in: MedlinePlus

Representative histology from P102L patients showing appearances graded semi-quantitatively. (A, C and E) show progressively worsening degrees of spongiform change on haematoxylin and eosin stain of brain slices. (B, D and F) show increasing levels of plaque deposition, as demonstrated by immunohistochemistry with anti-PrP antibody ICSM 35. Views in the left-hand column do not necessarily correspond to the same region as the right column. A, C and D are from Patient 2.VII.2. B and E are from Patient VII.4, while panel F is from Patient 3.VIII.1. The scaling bar shown is 100 µM.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2570713&req=5

Figure 1: Representative histology from P102L patients showing appearances graded semi-quantitatively. (A, C and E) show progressively worsening degrees of spongiform change on haematoxylin and eosin stain of brain slices. (B, D and F) show increasing levels of plaque deposition, as demonstrated by immunohistochemistry with anti-PrP antibody ICSM 35. Views in the left-hand column do not necessarily correspond to the same region as the right column. A, C and D are from Patient 2.VII.2. B and E are from Patient VII.4, while panel F is from Patient 3.VIII.1. The scaling bar shown is 100 µM.

Mentions: Samples were examined by the same pathologist (S.B.), blinded to clinical details, and comparisons made between them. A semi-quantitative scale was used to grade spongiform change and PrP deposition (Fig. 1). Diffuse and plaque-related PrP deposition was documented and contrasted. Clinicopathological comparisons were made following this, with note being made of phenotype, PRNP codon 129 and apolipoprotein E (APOE) genotypes.Fig. 1


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)

Representative histology from P102L patients showing appearances graded semi-quantitatively. (A, C and E) show progressively worsening degrees of spongiform change on haematoxylin and eosin stain of brain slices. (B, D and F) show increasing levels of plaque deposition, as demonstrated by immunohistochemistry with anti-PrP antibody ICSM 35. Views in the left-hand column do not necessarily correspond to the same region as the right column. A, C and D are from Patient 2.VII.2. B and E are from Patient VII.4, while panel F is from Patient 3.VIII.1. The scaling bar shown is 100 µM.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 1: Representative histology from P102L patients showing appearances graded semi-quantitatively. (A, C and E) show progressively worsening degrees of spongiform change on haematoxylin and eosin stain of brain slices. (B, D and F) show increasing levels of plaque deposition, as demonstrated by immunohistochemistry with anti-PrP antibody ICSM 35. Views in the left-hand column do not necessarily correspond to the same region as the right column. A, C and D are from Patient 2.VII.2. B and E are from Patient VII.4, while panel F is from Patient 3.VIII.1. The scaling bar shown is 100 µM.
Mentions: Samples were examined by the same pathologist (S.B.), blinded to clinical details, and comparisons made between them. A semi-quantitative scale was used to grade spongiform change and PrP deposition (Fig. 1). Diffuse and plaque-related PrP deposition was documented and contrasted. Clinicopathological comparisons were made following this, with note being made of phenotype, PRNP codon 129 and apolipoprotein E (APOE) genotypes.Fig. 1

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