Isolated parkinsonism is an atypical presentation of GRN and C9orf72 gene mutations

TL;DR

This study explores how mutations in GRN and C9orf72 genes can cause atypical Parkinson's disease presentations, emphasizing clinical clues and neuropathological evidence linking these genetic mutations to parkinsonism.

Contribution

It provides detailed clinical and neuropathological characterization of IPD-like presentations in GRN and C9orf72 mutation carriers, highlighting features suggestive of genetic FTD etiology.

Findings

Family history of dementia or ALS suggests genetic cause.

C9orf72 carriers show longer disease duration and sustained dopa-responsiveness.

Neuropathology confirms TDP-43 pathology without alpha-synuclein, linking mutations to PD phenotype.

Abstract

Introduction: A phenotype of isolated parkinsonism mimicking Idiopathic Parkinson's Disease (IPD) is a rare clinical presentation of GRN and C9orf72 mutations, the major genetic causes of frontotemporal dementia (FTD). It still remains controversial if this association is fortuitous or not, and which clinical clues could reliably suggest a genetic FTD etiology in IPD patients. This study aims to describe the clinical characteristics of FTD mutation carriers presenting with IPD phenotype, provide neuropathological evidence of the mutation's causality, and specifically address their "red flags" according to current IPD criteria. Methods: Seven GRN and C9orf72 carriers with isolated parkinsonism at onset, and three patients from the literature were included in this study. To allow better delineation of their phenotype, the presence of supportive, exclusion and "red flag" features from MDS criteria were analyzed for each case. Results: Amongst the ten patients (5 GRN, 5 C9orf72), seven fulfilled probable IPD criteria during all the disease course, while behavioral/language or motoneuron dysfunctions occurred later in three. Disease duration was longer and dopa-responsiveness was more sustained in C9orf72 than in GRN carriers. Subtle motor features, cognitive/behavioral changes, family history of dementia/ALS were suggestive clues for a genetic diagnosis. Importantly, neuropathological examination in one patient revealed typical TDP-43-inclusions without alpha-synucleinopathy, thus demonstrating the causal link between FTD mutations, TDP-43-pathology and PD phenotype. Conclusion: We showed that, altogether, family history of early-onset dementia/ALS, the presence of cognitive/behavioral dysfunction and subtle motor characteristics are atypical features frequently present in the parkinsonian presentations of GRN and C9orf72 mutations .