Familial prion disease with a novel serine to isoleucine mutation at codon 132 of prion protein gene (PRNP)

Prion diseases are progressive, fatal neurodegenerative disorders that are characterized pathologically by spongiform change and/or abnormal prion protein accumulation in the brain. Most cases are sporadic, but some are acquired (e.g. in pituitary hormone and dura mater recipients) and others are inherited, associated with mutations or insertions in the prion protein gene (PRNP). Familial forms of human prion disease make up 10–15% of the total number cases, and follow a dominant pattern of inheritance with a high penetrance [1,2]. The clinical syndromes associated with pathogenic mutations in PRNP include Creutzfeldt– Jakob disease (CJD), Gerstman–Sträussler–Scheinker syndrome (GSS) and familial fatal insomnia (FFI), although there may be considerable clinical phenotypic heterogeneity within an affected family [3,4], and pure CJD and FFI phenotypes may represent the extremes of a spectrum [5]. Over 30 different mutations in PRNP have been described to date, although many of these are extremely uncommon [6,7]. We describe a patient who presented with progressive dementia, without ataxic features, and had a previously unreported mutation in the PRNP gene. A 62-year-old woman presented with a 12-month history of progressive cognitive decline. Her past medical history consisted of hypertension and tuberculosis. On examination, she was found to have impairment of visuospatial tasks, mild frontal signs and impairment of short-term memory. A mini-mental score was 14/30. Cerebrospinal fluid and electroencephalogram examinations were not performed. A computerised tomogram scan of the brain was normal. Her condition deteriorated and she developed emotional lability and loss of appetite, but did not attend follow-up in the months prior to death, and died of a pulmonary embolism 18 months after initial presentation. Cerebellar signs were not noted at any stage of the disease. The patient’s brother died at the age of 46 years, after a 7-year history of a progressive ataxic disorder with dementia. Her mother died at the age of 58 years, maternal grandfather at 60 years and great grandfather 66 years of age, all with dementia. None of these family members had an autopsy. The brain weighed 1049 g and showed a moderate degree of generalized cortical atrophy and mild atrophy of the superior cerebellar vermis. The brainstem and spinal cord appeared normal. A striking histological feature was the presence of numerous cortical plaques, which were a mixture of large diffuse (up to 310-mm diameter) and more compact unicentric and multicentric amyloid plaques, which showed strong PrP immunoreactivity (Figure 1A). Some of the diffuse plaques, particularly within the medial temporal lobe, were associated with tau-positive dystrophic neurites (Figure 1B) and showed argyrophilia with a modified Bielchowsky preparation. A minority of the non-neuritic plaques showed weak granular argyrophilia and the compact plaques showed fluorescence with thioflavin-S. In many areas, the plaques had a predominantly laminar distribution, particularly in the frontal cortex where there were numerous diffuse plaques in lamina 2 (Figure 1C) and, in the insula and medial temporal cortices, they were most numerous in lamina 6 (Figure 1D). Numerous diffuse, and scattered unicentric and multicentric PrP plaques were present in the thalamus, putamen, globus pallidus and caudate nucleus. There was a moderate degree of tau pathology within the medial temporal lobes, most marked in the entorhinal cortex, but also in the hippocampus and temporal neocortex, in the form of tangle and pretangle tau within neuronal perikarya, neuropil threads and dystrophic neurites in association with some PrP plaques. Mild tau deposition was noted in the frontal cortex. Occasional granular PrP deposits were seen in the substantia nigra and tectal regions of the midbrain. Within the cerebellum, there were numerous unicentric and multicentric plaques within the molecular layer, sometimes arranged in radial columns (Figure 1E), together with smaller granular PrP deposits. Purkinje cells were relatively well preserved. There was minimal spongiform change in the cerebral and cerebellar cortices. The remainder of the brainstem and spinal cord appeared normal without PrP deposition. PrP amyloid angiopathy and A4 deposition were not detected by immunohistochemistry.