Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers

Extract

Sir,

We read with great interest the study titled ‘Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers’ in the September edition of Brain (Mencacci et al., 2014). The study demonstrates loss-of-function variants in the GCH1 gene are not only a major cause of DOPA-responsive dystonia but are also enriched in relatives with adult-onset parkinsonism. Furthermore, the authors identify, through exome re-sequencing, a number of GCH1 variants that are enriched in patients with Parkinson’s disease compared to control subjects. This elegant study demonstrates the power of exome re-sequencing and highlights the potential role for rare variants in genes such as GCH1 as susceptibility factors in Parkinson’s disease. A genetic role for the GCH1 locus is reinforced by the recent discovery that a SNP at the GCH1 locus is associated with Parkinson’s disease in a large-scale genome-wide association study (GWAS) meta-analysis (Nalls et al., 2014).

The coding variants identified in the exome re-sequencing study increased the risk of Parkinson’s disease by 7.5-fold (2.4–25.3, 95% confidence intervals) and the authors note that this is likely to be an underestimation of the true odds ratio, because of the method of implementing prediction scores. Therefore, these variants seem to significantly impact Parkinson’s disease aetiology. The authors propose a number of mechanisms by which loss-of-function GCH1 variants may lead to increased nigral degeneration and Parkinson’s disease including that dopamine exerts a protective, anti-apoptotic role through dopamine receptors, that variants in GCH1 result in compensatory mechanisms that stave off DOPA-responsive dystonia, but increase the vulnerability of the neurons to ageing, and finally, that the lower striatal dopamine levels observed in GCH1 mutation carriers mean a lower threshold of nigral cell loss is sufficient to induce clinical symptoms. In addition to these logical hypotheses put forward in the manuscript, it may be significant to note that tetrahydrobiopterin (BH4) has a number of other cellular roles, which may contribute to nigral cell loss in individuals carrying GCH1 variants. These mechanisms may include the role of BH4 as a cofactor for nitric oxide synthases (NOS), alkylglycerol monooxygenase (AGMO) or other amino acid hydroxylases, in addition to the role of BH4 as an antioxidant.