An autopsied case of V180I Creutzfeldt‐Jakob disease presenting with panencephalopathic‐type pathology and a characteristic prion protein type

Abstract

A 73-year-old Japanese woman showed slowly progressive aphasia, apraxia and dementia. She had no family history of prion disease or dementia. One year later she showed parkinsonism and corticobasal degeneration was initially suspected. On MRI, the left temporal neocortex seemed swollen on T2-weighted images in the initial stage, and a later high-signal intensity region was observed in the cerebral cortex in diffusion-weighted images. The patient developed myoclonus and an akinetic mutism state 15 months and 22 months after onset, respectively. Consecutive electroencephalography revealed no periodic sharp-wave complexes. Prion protein (PrP) gene analysis revealed a valine to isoleucine point mutation at codon 180, and methionine homozygosity at codon 129. This patient's clinical symptoms and disease course were atypical for Creutzfeldt-Jakob disease (CJD), and a stable state with nasal tube-feeding lasted several years. She died of respiratory failure at the age of 81, 102 months after the onset. Autopsy revealed widespread spongiform degeneration with weak synaptic-type PrP deposition, confirming the diagnosis of genetic CJD. Neurons in the cerebral cortex were relatively preserved in number and hypertrophic astrocytosis was generally moderate for such long-term disease, but cerebral white matter showed diffuse severe myelin pallor with tissue rarefaction suggestive of panencephalopatic-type pathology. The cerebellar cortex was relatively well preserved with observation of mild spongiform change in the molecular layer, moderate neuron loss in the Purkinje neuron layer, and scattered small plaque-like PrP deposition. Western blot analysis of protease-resistant PrP showed a characteristic pattern without a diglycoform band. V180I CJD is an interesting form of genetic CJD with regards to the clinicopathologic, molecular and genetic findings.

Three cases of Creutzfeldt–Jakob disease with prion protein gene codon180 mutation presenting with pathological laughing and crying

“…Previous investigators have reported that neuroradiological findings in V180I CJD cases show a characteristic swollen cerebral cortex on T2-weighted MRI [3,9,10] and widespread cortical hyperintensity on DWI except in the medial occipital and cerebellar cortices [10]. An MRI finding of a disproportionately prominent cerebral cortical lesion in V180I CJD may also be related to pathological laughing and crying.…”

“…According to autopsy case reports of V180I CJD, diffuse spongiform change in the cerebral cortex and basal ganglia was observed, but cerebellar and brainstem lesions were absent or mild despite the prolonged disease duration [3,9]. The neurons of the cerebral neocortex showed a tendency towards preservation in spite of the severe spongiform change and long disease duration [3,9].…”

“…V180I CJD is extremely rare in European and North American CJD patients [7], but it is the most frequent type of genetic CJD in Japan [8]. According to some reports [3,9,10], the clinical features of V180I CJD are relatively uniform but considerably different from those of sporadic CJD as follows: 1) older age of onset; 2) prolonged disease duration with a slower progression course; 3) unique clinical symptoms such as frequent higher cortical dysfunction; 4) lower positive rate of brain-specific proteins such as neuron-specific enolase, total tau protein, and 14-3-3 protein in the cerebrospinal fluid; 5) no PSWCs on the EEG throughout the disease course; 6) a lack of affected family members and appearance as a sporadic neurodegenerative disorder. These clinical features make a premortem diagnosis of CJD difficult without PrP gene analysis, and cases may be misdiagnosed as neurodegenerative disorders with dementia such as corticobasal degeneration or Alzheimer's disease [9,10].…”

“…The neurons of the cerebral neocortex showed a tendency towards preservation in spite of the severe spongiform change and long disease duration [3,9]. It has been hypothesized on the basis of these neuropathological findings that an unknown protective factor associated with V180I CJD against rapid progression of the clinical course and development of pathological involvement is suggested [3,9]. This widespread cerebral cortical pathology, which was similar to that of the MRI findings, would appear to be strongly related to the pathogenesis of pathological laughing and crying observed in the present series of V180I CJD cases.…”

Sporadic Jakob-Creutzfeldt Disease Presenting as Primary Progressive Aphasia

“…12,13 In a prior study, 14 we found that 6% of patients with sporadic CJD had a language problem as their first symptom. A few cases of aphasia in genetic prion disease are reported in the Japanese literature, 15 but none met Mesulam's criteria. 10 Our patient's condition also met new international PPA criteria for logopenic variant PPA.…”