Creutzfeldt-Jakob disease associated with a V203I homozygous mutation in the prion protein gene

Abstract

We report a Japanese patient with Creutzfeldt-Jakob disease (CJD) with a V203I homozygous mutation of the prion protein gene (PRNP). A 73-year-old woman developed rapidly progressive gait disturbance and cognitive dysfunction. Four months after the onset, she entered a state of an akinetic mutism. Gene analysis revealed a homozygous V203I mutation in the PRNP. Familial CJD with a V203I mutation is rare, and all previously reported cases had a heterozygous mutation showing manifestations similar to those of typical sporadic CJD. Although genetic prion diseases with homozygous PRNP mutations often present with an earlier onset and more rapid clinical course than those with heterozygous mutations, no difference was found in clinical phenotype between our homozygous case and reported heterozygous cases. IntroductionCreutzfeldt-Jakob disease (CJD) is a disease of fatal neurodegenerative conditions pathologically characterized by accumulation of the abnormal prion protein (PrP Sc ) in the central nervous system. Approximately 85-90 % of CJD cases are sporadic (sCJD) lacking any mutations in the prion protein gene (PRNP), while about 10-15% of the disorders are inherited.1 Familial CJD (fCJD) is associated with at least 20 distinct genetic mutations that are all transmitted as autosomal dominant traits, including point, deletion and insertion mutations.2 Most of the mutations that cause fCJD, are heterozygous. Pathomechanisms of homozygous mutations in the PRNP remain unclear due to the extreme rarity of the disorder. We describe a Japanese fCJD patient with a V203I homozygous point mutation in the PRNP. Case PresentationA 73-year-old Japanese woman developed gait disturbance and rapidly progressive cognitive dysfunction. She had no family history of the prion diseases or other neurological disorders; however, her parents were first cousins. Three months after the onset, she became bedridden state. On admission to our hospital, neurological examinations revealed severe cognitive impairment and left-sided hemiparesis. Hyperreflexia with positive plantar reflex was evident in the left extremities.No myoclonus or extrapyramidal signs were obvious. No visual disturbance or cerebellar signs were apparent. Routine hematological examinations and blood chemistry were unremarkable. Cerebrospinal fluid (CSF) study revealed an elevation of tau protein (22,528 pg/ml; normal range, <202 pg/ ml) and 14-3-3 protein (5,428 mg/ml; normal range, <500 mg/ml); however, there was neither pleocytosis nor an elevation of protein levels. There was no evidence of infectious diseases in the culture from the CSF. Electroencephalography (EEG) revealed diffuse slowing of the waves without apparent periodic synchronous activities. Diffusion weighted brain magnetic resonance imaging (MRI) showed hyperintensity in the right basal ganglia and the right frontal, parietal, and occipital lobes (Fig. 1). Single photon emission computed tomography images using 99m Tc-Ethylcysteinate dimer showed mild hypoperfusion in the right frontal lobe and right pariet...

Homozygous R136S mutation in PRNP gene causes recessive inherited early onset prion disease

“…Neuropathological examination revealed the presence of abundant multicentric PrP amyloid plaques with mild neuritic component, along with severe neuronal loss, gliosis and microglial proliferation with only mild spongiform change, which is consistent with a GSS neuropathological phenotype. In contrast to previous description of homozygous mutations in PRNP [10][11][12][13]27] (Table 1), the disease in R136S families presented with an autosomal recessive pattern of inheritance, keeping the heterozygous family members protected from developing the disease, at least, at early ages. In vitro propagation and in vivo transmissibility studies suggest that the PrP Sc variant resulting from the R136S mutation failed to propagate both in vivo and in vitro in the conditions analyzed, suggesting that this variant is biologically less active than other mutations causing genetic prion diseases.…”

“…Up to date, all described pathogenic variants cause the disease in heterozygous carriers, being the disease inherited with an autosomal dominant pattern. Very few individuals have been reported to be homozygous for PRNP variants [10][11][12][13]. Most of them are homozygous carriers of well-known pathogenic mutations which cause also the disease in heterozygous carriers from areas of high prevalence of the mutation.…”

Characterization of mutations in <em>PRNP</em> (prion) gene and their possible roles in neurodegenerative diseases

“…The patient developed progressive gait disturbances and cognitive dysfunctions, followed by akinetic mutism. 49 The clinical phenotypes were similar to the previously described heterozygous cases, but the disease progression was more rapid. 49 This mutation is located in the hydrophobic core of PrP.…”

“… 49 The clinical phenotypes were similar to the previously described heterozygous cases, but the disease progression was more rapid. 49 This mutation is located in the hydrophobic core of PrP. In silico modeling suggested that it could result in minor effects on prion conformation.…”

Tau pathology in Creutzfeldt‐Jakob disease revisited

“…Genetic CJD associated with the V203I mutation and homozygosity for Met at codon 129 was first described only with clinical data . Further cases were reported from China and Japan, including a homozygous case for the mutation and neuropathological description of a case . Here we describe three new cases of V203I‐129M, showing classical neuropathological features of CJD.…”