High phenotypic variability in Gerstmann-Sträussler-Scheinker disease

Abstract

Gerstmann-Sträussler-Scheinker is a genetic prion disease and the most common mutation is p.Pro102Leu. We report clinical, molecular and neuropathological data of seven individuals, belonging to two unrelated Brazilian kindreds, carrying the p.Pro102Leu. Marked differences among patients were observed regarding age at onset, disease duration and clinical presentation. In the first kindred, two patients had rapidly progressive dementia and three exhibited predominantly ataxic phenotypes with variable ages of onset and disease duration. In this family, age at disease onset in the mother and daughter differed by 39 years. In the second kindred, different phenotypes were also reported and earlier ages of onset were associated with 129 heterozygosis. No differences were associated with apoE genotype. In these kindreds, the codon 129 polymorphism could not explain the clinical variability and 129 heterozygosis was associated with earlier disease onset. Neuropathological examination in two patients confirmed the presence of typical plaques and PrPsc immunopositivity.

Clinical Variability in P102L Gerstmann–Sträussler–Scheinker Syndrome

“…This estimation is difficult to apply directly to all published cases, because of (1) the long period of data acquisition (some patients died in the 1950s, others in 2017), (2) a retrospective diagnosis in many cases, and (3) inconsistencies in prion disease surveillance in different countries. There is, however, an important argument for our observation, which is the increase in new cases reported since 2017; we found a total of 26 patients, including 6 of our 7 Czech patients (1 of our cases was published and is therefore already counted in the literature) …”

“…We focused on gender, age at onset, disease duration, onset and duration of dementia (from the onset of cognitive deterioration impacting on activities of daily living and continuing until death), onset of ataxia, MRI abnormalities (in particular basal ganglia, cortex, and cerebellum), polymorphism in codon 129, changes in deep tendon reflexes and sensory symptoms, and 14‐3‐3 protein in the CSF …”

“…The first step was to retrospectively analyze the clinical manifestation and results from auxiliary diagnostic methods (ie, brain magnetic resonance imaging [MRI], electroencephalogram [EEG], and cerebrospinal fluid [CSF] analysis) in the 7 Czech cases with postmortem confirmation. The next step was to extend this analysis by combining the data from the 7 Czech patients with data from 87 previously published P102L GSS cases, and with the use of cluster analysis, to define typical GSS syndrome phenotypes.…”

Viral and Prion Infections Associated with Central Nervous System Syndromes in Brazil

“…In addition to the notified cases of sCJD, the following case reports have been published: One family with gCJD T183A mutation [ 239 ]; one patient with gCJD V210I mutation and 129M/M [ 240 ], one patient with gCJD E200K mutation and 129M/M [ 241 ], one patient with gCJD V180I mutation and 129M/M [ 242 ], and two probable cases of iCJD due to use of human growth hormone [ 243 , 244 ]. In the case of the very rare GSS disease, the study of two families with the P102L mutation in the PRNP gene was reported, representing seven cases in total: Four with 129M/V and two with 129M/M (molecular data was not obtained from one patient) [ 245 ].…”

Unveiling the mysteries of hereditary prion diseases in Brazil

“…This important report emphasizes the need to maintain a high level of suspicion for the diagnosis of GSS in cases of slow-onset cerebellar ataxia, associated or not with dementia, particularly in those cases who run in families. At the same time, this study emphasizes the need to support a network of nationally coordinated researchers with different areas of expertise that can serve as reference to other physicians to contribute, each one in their own capacity, to the diagnosis of cases of rare neurological diseases 4 .…”