LETTER TOTHE EDITOR Parkinsonism in GTP cyclohydrolase 1 mutation carriers

Sir, We read with great interest the article by Mencacci and colleagues (2014) reporting a significantly higher frequency of GTP cyclohydrolase 1 (GCH1) variants in patients with Parkinson’s disease compared to controls. Whole-exome sequencing of a large case-control cohort showed that rare GCH1 coding variants are associated with a 7-fold increased risk of Parkinson’s disease. Heterozygous loss-of-function mutations in GCH1, a crucial enzyme for dopamine production in nigrostriatal neurons (Kaufman, 1959; Nagatsu et al., 1964), are the most common cause of DOPA-responsive dystonia (DRD) (Ichinose et al., 1994). DRD is a rare hereditary disease characterized by childhood-onset, generalized dystonia and a dramatic long-lasting response to levodopa (Segawa et al., 1976). The disease may also manifest in adulthood with parkinsonism as the sole or dominant clinical feature (Hjermind et al., 2006; Momma et al., 2009). GCH1 mutations have been shown to segregate in pedigrees with multiple individuals affected by isolated parkinsonism, a phenotype that is likely due to nigrostriatal degeneration (Kikuchi et al., 2004; Hjermind et al., 2006; Eggers et al., 2012; Mencacci et al., 2014). Herein, we report GCH1 variability in patients with Parkinson’s disease (n = 361, 68.7% male, mean age 69.9 12.8 years; mean age at onset 58.3 12.9 years), atypical parkinsonism (n = 167, male 61.7%, mean age 77.5 12.2 years; mean age at onset 66.3 11.2 years, including diagnostic categories of dementia with Lewy bodies, progressive supranuclear palsy and multiple system atrophy) and control subjects (n = 290, 59% male; mean age 73.3 11.2 years). Sequencing of GCH1 coding regions, performed on the SOLiD 5500xl platform (Life Technologies), identified four rare heterozygous non-synonymous coding substitutions including: (i) a novel missense variation (p.A99D); (ii) the known DRD pathogenic mutation (p.K224R); and (iii) two benign variants (p.P23L and p.P69L) (Jarman et al., 1997; Mencacci et al., 2014). The p.A99D mutation was identified in a male patient with typical late-onset Parkinson’s disease (age at onset 61 years) with an extensive family history of dementia and parkinsonism. This amino acid position is highly conserved, and substitution of a hydrophobic non-polar (alanine) to a negatively charged (glutamic acid) amino acid is likely to perturb the amphipathic alpha-helical structure of this domain. The mutation has not been reported in the publically available Exome Variant Server data set (http://evs.gs.washington. edu/EVS/), which suggests it is unlikely to be a benign, albeit rare, variant. The p.K224R mutation, previously described in pedigrees with dominantly inherited DRD (Leuzzi et al., 2002), was detected in two unrelated Canadian patients. One had asymmetrical tremor onset parkinsonism (age at onset 82 years) and good levodopa response. She died at 90 years and brain pathology showed doi:10.1093/brain/awu341 BRAIN 2015: 138; 1–2 | e349