Rapidly Progressive Parkinsonism and Dementia with No Insomnia due to the PRNP D178N Mutation

Abstract

Dera Editor, Hereditary prion diseases are fatal progressive neurodegenerative disorders caused by mutation in the prion-related protein (PRNP) gene.1 There are three major clinical phenotypes: familial Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), and Gerstmann-Straussler-Scheinker disease.1 An aspartate-to-asparagine substitution due to mutation at codon 178 (D178N) of PRNP is known to cause either the FFI or CJD phenotype depending on the genotype of codon 129.2 However, recent studies suggest that the clinical manifestations of D178N mutants are highly variable independently of the genotype of codon 129.3 Here we report a family carrying the PRNP D178N mutation and having hereditary prion disease with an atypical presentation. A 68-year-old female presented with gait disturbance and frequent falls with a 2-month history (III-2) (Fig. 1A). A neurological examination revealed moderate bradykinesia, mild rigidity, mild dysphagia, and moderate postural instability. She had a score of 32 on the Unified Parkinson’s Disease Rating Scale (UPDRS) part III. She reported having experienced troublesome constipation and the sensation of residual urine for the past few years. Her sleeping partner reported to have witnessed her dream enactment behaviors, sleep apnea, and inspiratory stridor. However, the patient denied insomnia, and there was no myoclonus or ataxia. MRI including diffusion-weighted imaging (DWI) showed mild leukoaraiosis (Fig. 1B and C). Heterogeneous decrease in dopamine transporter binding were observed on 18F-N-(3fluoropropyl)-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane (CIT) positron-emission tomography (PET). 18F-fluorodeoxyglucose (FDG) PET showed subtle hypometabolism of the midbrain (Fig. 1D and E). There was no therapeutic response to levodopa at 600 mg/ day for 2 months, during which she developed visual hallucination, and overt dementia developed 1 month later. She had received 12 years of education, and had a score of 10 on the Mini Mental Status Examination (MMSE). She became bedridden 5 months after the initial visit, and was repeatedly admitted for dilated cardiomyopathy, fever, and stercoral colitis. She died at 15 months after her initial visit. Similar symptoms manifested in the proband’s mother and sister (II-2 and III-4) (Fig. 1A) prior to their deaths. Her sister presented cognitive decline and bradykinesia at the age of 62 years. She reported a urinary frequency, sensation of residual urine, constipation, inspiratory stridor, snoring, and dream enactment behaviors, but no insomnia. Her MMSE score was 17 and she had 12 years of education, and mild parkinsonism was documented by a UPDRS part III score of 16. There was no sign of myoclonus or ataxia. She became bedridden after 3 months and died 9 months later. Brain MRI revealed mild brain atrophy (Fig. 1F and G). No amyloid deposition was seen in florbetaben PET, and diffuse cortical hypometabolism was observed on FDG PET (Fig. 1H and I). Her cerebrospinal fluid (CSF) was negative for 14-3-3 protein. Sanger sequencing of the DNA of the proband and her sister for PRNP identified the c.532G>A (D178N) mutation (Fig. 1J) with the methionine-methionine genoKye Won Park Seung Hyun Lee Yun Soo Hwang Keon Woo Kim Kwan Young Park Mi-Jung Kim Yena Lee Yunha Choi Beom Hee Lee Sun Ju Chung