Clinicopathological Correlates in a PRNP P102L Mutation Carrier with Rapidly Progressing Parkinsonism‐Dystonia

Abstract

Parkinsonism‐dystonia is rare in carriers of the prion protein (PrP) gene (PRNP) proline‐to‐leucine substitution at codon 102 (P102L mutation). The severity and distribution of PrP deposition may influence the clinical presentation. The authors present such clinicopathological correlation in a 56‐year‐old man who had a PRNP P102L mutation associated with a phenotype characterized by rapidly progressing parkinsonism‐dystonia. The patient was studied clinically (videotaped examinations, brain magnetic resonance images [MRIs]) and was analyzed using molecular genetics (gene sequence analysis) and neuropathology (histology, immunohistochemistry) during his 7‐month disease course. The patient had parkinsonism, apraxia, aphasia, and dystonia, which progressed rapidly. Molecular genetic analysis revealed his PRNP P102L mutation carrier status. Brain MRIs revealed progressive, global volume loss and T2‐weighted/fluid‐attenuated inversion recovery hyperintensity in the neocortex and basal ganglia. Postmortem examination showed neuronal loss, gliosis, spongiform changes, and PrP deposition in the striatum. PrP immunohistochemistry revealed widespread, severe PrP deposition in the thalamus and cerebellar cortex. Based on the neuropathological and molecular‐genetic analyses, the rapidly progressing parkinsonism‐dystonia was correlated with nigrostriatal, thalamic, and cerebellar pathology.

Gerstmann‐Sträussler‐Scheinker disease (GSS) is a rare, adult‐onset, autosomal‐dominant neurodegenerative prion disease. Genetically, GSS is associated with a variety of point mutations in the prion protein (PrP) gene (PRNP).1 The most common mutation identified among affected subjects is P102L, in which the pathogenic PRNP has a proline‐to‐leucine substitution at codon 102 (P102L).1, 2 The clinical phenotype of GSS associated with the P102L mutation shows a high degree of heterogeneity. However, it is predominantly characterized by progressive ataxia, pyramidal signs, and dementia over a course lasting several years. Pathologically, GSS is characterized by deposits of PrP in the form of diffuse and amyloid plaques in the central nervous system (CNS).2, 3, 4 Prominent parkinsonism and dystonia are not typical in individuals who carry the P102L mutation. Herein, we present a PRNP P102L mutation carrier who had a clinical presentation characterized by rapidly progressive parkinsonism‐dystonia. We describe the clinicopathological features in this case and discuss the possible mechanism of this unique clinical presentation.

Case Report

Clinical evaluations were carried out via detailed, videotaped, longitudinal movement disorder neurology examinations; electroencephalography; and serial brain magnetic resonance imaging (MRI). Videotaping was performed with the patient's informed consent. Molecular genetic assessments were accomplished using gene sequence analysis, and neuropathologic examination was performed using standard histologic and immunohistochemical techniques.

Results

A 56 year‐old‐man presented with initial symptoms of bradykinesia, right arm rigidity, intermittent resting tremor, and gait imbalance. Two months after the onset of symptoms, he developed memory impairment and expressive dysphasia with decreased verbal fluency. He had rapid functional decline and required assistance with his daily living activities. He was evaluated at the Johns Hopkins Movement Disorder Clinic 3 months after the onset of symptoms. On motor examination, he had bradykinesia, moderate right arm rigidity with dystonic forearm flexor posturing, and dystonic right thumb flexion. His gait examination showed evidence of decreased arm swing and postural instability (see Video 1). Furthermore, he had dysphasia, dysarthria, and apraxia.

Further investigation revealed that he had several family members that had been previously diagnosed with GSS (Fig. 1). Molecular genetic analysis revealed that he carried a PRNP P102L‐129M mutation and was heterozygous for M/V polymorphism at codon 129. Sequential high‐resolution brain MRI showed progressive cerebral and cerebellar volume loss and T2/fluid‐attenuated inversion recovery hyperintensity in the neocortex and basal ganglia (Fig. 2).5

Figure 1.

Family pedigree. The current case is indicated by the arrow. There were 7 family members who had symptoms consistent with Gerstmann–Sträussler–Scheinker (GSS) disease. Five family members were positive for the GSS mutation. One family member with a positive GSS mutation had no symptoms at the time of testing (at age 23 years). The mean age at symptom onset was 45 years. Clinical phenotypes of affected family members included ataxia, cognitive impairment, and dysarthria.

Figure 2.

Brain MRI shows increased signal in multiple cortical and basal ganglia regions on diffusion (E) and T2‐weighted/fluid‐attenuated inversion recovery sequences (F). E,F: Cerebral and (G) cerebellar atrophy is also present. Severe spongiform changes are observed with hematoxylin and eosin staining in the caudate (A) and frontal cortex (H), indicated by vacuoles in the neuropil (arrows). Note the eosinophilic amyloid cores (blue arrowheads). Widespread prion protein deposits are shown in the caudate (B), thalamus (K), and frontal (I)/parietal (J) cortices (3F4 antibodies) and in the substantia nigra (3F4 antibodies) and the cerebellum (12F10 antibodies) (C).

Subsequently, he had a rapid decline with progressive aphasia, bradykinesia, rigidity, and dystonia, leading to a bed‐bound state and death within 7 months of the onset of symptoms. Neuropathologic evaluation revealed moderate nigral neuronal loss and severe neuronal loss, gliosis, spongiform changes, and PrP deposition in the dentate and striatum (Fig. 2). In the cerebral cortex, neuronal loss, gliosis, spongiform changes, and PrP deposition involved the parietal cortex more severely than the frontal cortex. PrP immunohistochemistry revealed widespread, severe PrP deposition in the thalamus and cerebellar cortex. Alpha‐synuclein and tau immunostaining of the substantia nigra were carried out to rule out incidental synucleinopathy or tauopathy contributing to the parkinsonism. Both alpha‐synuclein and tau immunostaining were negative (data not shown). Western blot characterization of the protease‐resistant prion protein (PrP^res) showed 3 major bands of 21, 27, and 30 kDa together with an 8‐kDa fragment, which is typically present in GSS‐P102L (Fig. 3).

Figure 3.

Detection and characterization of protease‐resistant prion protein (PrP^res). An immunoblot of total homogenates (TH) treated with proteinase K that was obtained from the frontal cortex of the present case reveals the most common, sporadic Creutzfeldt–Jakob disease (sCJD) subtypes, sCJD‐MM1 and sCJD‐VV2 (representing PrP^res types 1 and 2, respectively). Membranes were probed with the monoclonal antibodies (Abs) 3F4 (amino acids 109–112) and 12B2 (amino acids 89–93). Pr^Pres of the present case includes an 8‐kDa fragment, typically present in the Gerstmann–Sträussler–Scheinker disease (GSS) P102L mutation (the prion protein gene [PRNP] proline‐to‐leucine substitution at codon 102). This fragment is much more visible when probed with 12B2, a type 1‐specific antibody.

Discussion

To expand upon the clinicopathological phenotype observed in GSS associated with PRNP P102L mutation, we describe a case with rapid clinical progression and a severe movement disorder. In fact, the severe PrP deposition and spongiform changes in the substantia nigra, striatum, thalamus, and cerebellum may well correlate with this patient's clinical presentation, which was characterized by impairment of motor control, parkinsonism, and dystonia.

Clinical and pathological heterogeneity is known to occur in GSS. Even in subjects with P102L mutations, phenotypic variations can be seen. PRNP P102L mutation carriers may present with cerebellar ataxia, dementia, pyramidal signs, and rarely parkinsonism.6 In P102L carriers, disease duration ranges from 1 to 10 years, with the age of onset variable from the 40s to the 70s.6 In a recent report of atypical parkinsonism in GSS, clinical heterogeneity in a family pedigree with the same tyrosine‐to‐asparagine (Y218N) mutation in the PRNP gene was described, suggesting that various factors influence the clinical phenotype.7 Although the authors describe a GSS case with a Y218N mutation in the PRNP gene who had atypical parkinsonism mimicking progressive supranuclear palsy,7 our case had a more rapidly progressing parkinsonism‐dystonia in a PRNP P102L mutation carrier. In GSS, PrP deposits resulting from degradation products found in the cerebral/cerebellar cortices and basal ganglia are characteristic pathological findings; however, spongiform changes and neuronal loss also are frequently seen.3, 6 The severity and extent of pathological changes may not easily explain the rapid clinical course, which, in turn, might be better explained by distribution and toxicity of the PrP^Sc.

The basis for the variable clinicopathological phenotypes observed in GSS is not fully understood, but several mechanisms have been postulated. Polymorphisms in PrP, including either methionine or valine at residue 129, are proposed to influence the clinical and pathological phenotype.3 In addition, variations in the anatomic distribution of pathologic PrP may account for the phenotypic differences seen among individuals carrying the same mutation.8 Finally, in GSS P102L carriers, the presence of proteinase K‐resistant PrP isoforms with a molecular weight from 21 to 30 kDa have been associated with pathologic phenotypes characterized by significant spongiform degeneration.9

In the initial evaluation of patients with suspected GSS, a broad differential diagnosis should be considered, including corticobasal syndrome (CBS), which can present with similar clinical signs. Features of CBS include parkinsonian rigidity, dystonia, apraxia, and cognitive impairment,10, 11 similar to the presenting features of our case. Further investigations that include brain MRI and genetic testing can aid in narrowing the diagnosis between these neurodegenerative conditions.

We present a GSS phenotype characterized by rapid disease progression and by a movement disorder with symptoms of parkinsonism‐dystonia. Based on clinical, imaging, and neuropathologic data obtained from the study of this patient, we hypothesize that the clinical manifestations, dominated by rapid progression and prominent movement disorder, may result from an early seeding and spread of a very toxic form of PrP^Sc within the basal ganglia, substantia nigra, and cerebellum.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

C.C.U.: 1A, 1B, 1C, 3A, 3B

P.K.: 1B, 3B

M.K.G.: 1A, 3B

S.N.: 1B, 1C, 3B

Y.C.: 1B, 1C, 3B

P.G.: 1B, 1C, 3B

A.L.O.: 1C, 2B

B.G.: 1B, 1C, 3A, 3B

Z.M.: 1A, 1B, 1C, 3A, 3B

Disclosures

Funding Sources and Conflicts of Interest: Part of this work was done with support by grants from the National Institutes of Health (P01 AG14359 and P30 AG 010133) and the Centers for Disease Control and Prevention (1U51CK000100).

Financial Disclosures for the previous 12 months: Dr. Mari has received consultancy fees from Navidea Biopharmaceuticals. Dr. Umeh reports receiving research grant from the BWH Parkinson's Research Fund. Dr. Gambetti reports receiving grant from Ferring Pharmaceuticals, Netherlands. The remaining authors report no sources of funding and no conflicts of interest.

Supporting information

A video accompanying this article is available in the supporting information here.

Video 1. Three months after the onset of symptoms, this patient has expressive dysphasia, apraxia, limb dystonia, and bradykinesia.