Abstract
GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
Highlights
Parkinson’s disease is a common neurodegenerative disease mainly characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta and by the formation of -synuclein positive aggregates (Lees et al, 2009)
We subsequently explore the hypothesis that GCH1 variants might be associated with an increased risk for Parkinson’s disease, even without a family history for DOPA-responsive dystonia, through examination of wholeexome sequencing data from a large cohort of cases and controls
DOPA-responsive dystonia pedigrees were included in the study, where family members affected with adult-onset parkinsonism were available for clinical and genetic examination and in whom dopaminergic studies had been performed
Summary
Parkinson’s disease is a common neurodegenerative disease mainly characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta and by the formation of -synuclein positive aggregates (Lees et al, 2009). Nigral neuron degeneration and consequent decrease in dopaminergic striatal innervation result in classic Parkinson’s disease motor symptoms. Symptomatic treatment with levodopa or dopamine agonists is effective in alleviating these symptoms, along with disease progression, levodopa-induced motor complications (e.g. dyskinesias, wearingoff, on-off fluctuations) may appear. Mutations in GCH1 are the most common cause of DOPA-responsive dystonia (DYT5; OMIM#128230) (Clot et al, 2009), a rare movement disorder that presents typically in childhood with lower limb dystonia and subsequent generalization (Nygaard, 1993b). The hallmark of the disease is an excellent and sustained response to small doses of levodopa, generally without the occurrence of motor fluctuations (Trender-Gerhard et al, 2009). Dominant GCH1 mutations result in a significant reduction of GCH1 activity through a dominant negative effect of the mutant protein on the normal enzyme (Hwu et al, 2000)
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