Brain, Vol. 122, No. 10, 1823-1837,
October 1999
© 1999 Oxford University Press
Inherited prion disease with an alanine to valine mutation at codon 117 in the prion protein gene
1 MRC Prion Unit and Department of Neurogenetics, Imperial College School of Medicine at St Mary's, 2 Department of Neurology, St Mary's Hospital, 3 National Hospital for Neurology and Neurosurgery, 4 Department of Neuropathology, Institute of Psychiatry, London, 5 Department of Psychiatry, St James' University Hospital, 6 Department of Neuropathology, the General Infirmary, Leeds, 7 Department of Rheumatology, Rotherham District General Hospital, Rotherham, 8 Department of Neurology, the Yorkshire Clinic, Bingley, 9 Department of Neurology, Hull Royal Infirmary, Hull, Departments of 10 Neurology and 11 Neuropathology, Royal Hallamshire Hospital, Sheffield, 12 MRC Neurochemical Pathology Unit, Newcastle General Hospital, Newcastle, 13 National CJD Surveillance Unit, Western General Hospital, Edinburgh, the 14 Health Centre, Hatfield and the 15 Department of Neurology, Leicester Royal Infirmary, Leicester, UK
Correspondence to:
Professor John Collinge, Department of Neurogenetics, Imperial College School of Medicine at St Mary's, Norfolk Place, London W2 1PG, UK
A large English family with autosomal dominant segregation of presenile dementia, ataxia and other neuropsychiatric features is described. Diagnoses of demyelinating disease, Alzheimer's disease, Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker syndrome have been attributed to particular individuals at different times. An Irish family, likely to be part of the same kindred, is also described, in which diagnoses of multiple sclerosis, dementia, corticobasal degeneration and new variant CJD have been considered in affected individuals. Molecular genetic studies have enabled the classification of this disease at the molecular level as one of the group of inherited prion diseases, with the substitution of valine for alanine at codon 117 of the prion protein gene (PRNP). Only three other kindreds have been described world-wide with this mutation and only limited phenotypic information has been reported. Here we describe the phenotypic spectrum of inherited prion disease (PrPA117V). The diversity of phenotypic expression seen in this kindred emphasizes the logic of molecular classification of the inherited prion diseases rather than classification by specific clinicopathological syndrome. Indeed, inherited prion disease should be excluded by PRNP analysis in any individual presenting with atypical presenile dementia or neuropsychiatric features and ataxia, including suspected cases of new variant CJD.
inherited prion diseases; prion protein; mutation; molecular genetics
APOE = apolipoprotein E gene; CJD = Creutzfeldt–Jakob disease; FFI = fatal familial insomnia; GSS = Gerstmann–Sträussler–Scheinker syndrome; PRNP = prion protein gene; PrP = prion protein
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