Panencephalopathic Creutzfeldt‐Jakob Disease with Distinct Pattern of Prion Protein Deposition in a Patient with D178N Mutation and Homozygosity for Valine at Codon 129 of the Prion Protein Gene

Abstract

Prion diseases include sporadic, acquired and genetic forms linked to mutations of the prion protein (PrP) gene (PRNP). In subjects carrying the D178N PRNP mutation, distinct phenotypes can be observed, depending on the methionine/valine codon 129 polymorphism. We present here a 53-year-old woman with D178N mutation in the PRNP gene and homozygosity for valine at codon 129. The disease started at age 47 with memory deficits, progressive cognitive impairment and ataxia. The clinical picture slowly worsened to a state of akinetic mutism in about 2 years and the disease course was 6 years. The neuropathologic examination demonstrated severe diffuse cerebral atrophy with neuronal loss, spongiosis and marked myelin loss and tissue rarefaction in the hemispheric white matter, configuring panencephalopathic Creutzfeldt-Jakob disease. PrP deposition was present in the cerebral cortex, basal ganglia and cerebellum with diffuse synaptic-type pattern of immunoreactivity and clusters of countless, small PrP deposits, particularly evident in the lower cortical layers, in the striatum and in the molecular layer of the cerebellum. Western blot analysis showed the presence of type 1 PrP(Sc) (Parchi classification). These findings underline the clear-cut distinction between the neuropathological features of Creutzfeldt-Jakob disease associated with D178N PRNP mutation and those of fatal familial insomnia.

Differential astrocyte and oligodendrocyte vulnerability in murine Creutzfeldt-Jakob disease

“…Moreover, oligodendrocyte alterations described in CJD [ 11–13 ] and present experimental model may link transition between mild to moderate white matter involvement in common forms compared with severe white matter involvement in panencephalopathic forms of CJD [ 24–28 ]. Although alterations of the white matter parallel the intensity of lesions of the grey matter in cases with long duration of the disease [ 28 , 29 ], pioneering panencephalopathic cases, described principally in Japan, were in favour of a primary alteration of the white matter [ 24 , 30 , 31 ]. Myelin and nerve fibre loss accompanied by variable astrocyte proliferation and phagocytosis of myelin debris is usually described in panencepaholopathic CJD, but, curiously, any information about oligodendrocytes in the white matter is almost disregarded.…”

Familial fatal insomnia with atypical clinical features in a patient with D178N mutation and homozygosity for Met at codon 129 of the prion protein gene

“…D178N/Met129 haplotype causes FFI, while D178N/Val129 haplotype results on Creutzfeldt-Jakob disease (CJD). 5,6 At present, descriptions of patients with the D178N/Met129 PRNP phenotype are few. 7 We report a patient with the D178N/Met129 PRNP mutation, affected by FFI without typical refractory insomnia early in the disease course or MRI changes in the thalamus.…”

<p>Novel prion mutation (p.Tyr225Cys) in a Korean patient with atypical Creutzfeldt–Jakob disease</p>

“…More than 30 pathogenic mutations were reported within the PRNP gene (NC_000020.11), and the inheritance of prion mutations may follow a Mendelian autosomal dominant pattern. For example, p.Glu200Lys was a quite common causative mutation for familial CJD,7 but several additional mutations, such as p.Asp178Asn,8 p.Val180Ile,9 p.Val210Ile,10 p.Tyr226Ter,11 or p.Met232Arg,12 were also associated with familial form of the disease. Interestingly, the limited variants in PRNP were also reported without prior family history of the disease (de novo disease cases),5 such as p.Glu196Ala13 and p.Glu200Gly 14.…”