Reply: Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers

Sir,Thank you for the opportunity to reply to the correspondence concerning our recent publication in Brain , ‘Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers’ (Mencacci et al. , 2014). We read with great interest these letters and we thank the authors for their insights.Guella et al. (2014) report the screening of GCH1 in 528 Canadian cases with Parkinson’s disease and atypical parkinsonism and 290 matched controls. They identified two variants, the known pathogenic p.K224R (×2) and the novel variant p.A99D (likely pathogenic according to in silico prediction tools and interspecies conservation) in three unrelated cases with Parkinsons’s disease and the two benign variants p.P23L and p.P69L in one single control individual. The mutational frequency, excluding the aforementioned benign variants, was 0.56% (3/528) in cases versus 0% (0/290) in controls, consistent with the frequency we observed in our study (0.75% in cases versus 0.1% in controls).This result is relevant as it represents the first independent confirmation that rare deleterious GCH1 variants are enriched in patients with Parkinson’s disease compared to control subjects. Furthermore, they describe the post-mortem findings of one of the mutated patients, who presented at the age of 82 with DOPA-responsive asymmetric rest tremor. This showed a combination of brainstem Lewy body pathology together with the presence of tau-immunoreactive neurofibrillary tangles. To date, the only available brain pathology analysis of a GCH1 -associated neurodegenerative parkinsonism case showed severe nigral neurodegeneration and Lewy bodies in surviving nigral cells and in the locus coeruleus (Gibb et al. , 1991; Segawa et al. , 2004). Further studies are needed to establish if the tauopathy described by Guella et al. …