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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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Clinical features reported during course of P102L IPD. The high percentage of patients where cognitive deficits were apparent, even if only in later stages, is notable as is the frequency of sensory signs and lower motor neuron signs. Chorea was not reported or observed in any of the patients presented.
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Figure 6: Clinical features reported during course of P102L IPD. The high percentage of patients where cognitive deficits were apparent, even if only in later stages, is notable as is the frequency of sensory signs and lower motor neuron signs. Chorea was not reported or observed in any of the patients presented.

Mentions: The commonest clinical syndrome was progressive cerebellar ataxia associated with leg weakness and areflexia, similar, but not identical to, the classical GSS phenotype. Indeed, cerebellar signs were present in nearly all of the patients where information could be obtained at some point in the illness (98%). Cognitive features were usually mild initially and developed later in the illness course. Cognitive features were eventually present, however, in the large majority of patients at some point during the disease where information was available (81%), although in many patients these were mild. Lower motor neuron pattern leg signs with areflexia, often associated with objective evidence of muscle weakness and myopathic gait, was present in the majority of patients (79%) (Fig. 6). In one patient (4.VII.1), frank lower limb fasiculations were observed. Sensory symptoms in the legs were also common, with dysaesthesiae and hyperaesthesiae being frequently described by affected patients (69%). Extrapyramidal features, especially parkinsonism and severe psychiatric symptoms such as personality change, delusions, paranoia and visual hallucinations, occurred in around half of patients (48 and 47% of patients, respectively). Apraxia, however, in contrast with patients with PRNP insertional mutations (Collinge et al., 1992, 2005; Mead et al., 2006), was recorded in only a single individual. Myoclonus and seizures occurred in a minority of patients, although still relatively common (36 and 7%, respectively). One patient (VII.2) presented with a prominent generalized dystonia in addition to a cerebellar ataxia. This has not been reported previously in association with IPD P102L and the unusual phenotype in this patient delayed diagnosis until post-mortem examination of brain tissue. No reports of choreic movement disorders or of the dyspraxia and premorbid personality changes commonly reported in some other forms of IPD were obtained (Collinge et al., 1992; Mead et al., 2006).Fig. 6


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)

Clinical features reported during course of P102L IPD. The high percentage of patients where cognitive deficits were apparent, even if only in later stages, is notable as is the frequency of sensory signs and lower motor neuron signs. Chorea was not reported or observed in any of the patients presented.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 6: Clinical features reported during course of P102L IPD. The high percentage of patients where cognitive deficits were apparent, even if only in later stages, is notable as is the frequency of sensory signs and lower motor neuron signs. Chorea was not reported or observed in any of the patients presented.
Mentions: The commonest clinical syndrome was progressive cerebellar ataxia associated with leg weakness and areflexia, similar, but not identical to, the classical GSS phenotype. Indeed, cerebellar signs were present in nearly all of the patients where information could be obtained at some point in the illness (98%). Cognitive features were usually mild initially and developed later in the illness course. Cognitive features were eventually present, however, in the large majority of patients at some point during the disease where information was available (81%), although in many patients these were mild. Lower motor neuron pattern leg signs with areflexia, often associated with objective evidence of muscle weakness and myopathic gait, was present in the majority of patients (79%) (Fig. 6). In one patient (4.VII.1), frank lower limb fasiculations were observed. Sensory symptoms in the legs were also common, with dysaesthesiae and hyperaesthesiae being frequently described by affected patients (69%). Extrapyramidal features, especially parkinsonism and severe psychiatric symptoms such as personality change, delusions, paranoia and visual hallucinations, occurred in around half of patients (48 and 47% of patients, respectively). Apraxia, however, in contrast with patients with PRNP insertional mutations (Collinge et al., 1992, 2005; Mead et al., 2006), was recorded in only a single individual. Myoclonus and seizures occurred in a minority of patients, although still relatively common (36 and 7%, respectively). One patient (VII.2) presented with a prominent generalized dystonia in addition to a cerebellar ataxia. This has not been reported previously in association with IPD P102L and the unusual phenotype in this patient delayed diagnosis until post-mortem examination of brain tissue. No reports of choreic movement disorders or of the dyspraxia and premorbid personality changes commonly reported in some other forms of IPD were obtained (Collinge et al., 1992; Mead et al., 2006).Fig. 6

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