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. 2015 Apr;21(4):394-7.
doi: 10.1016/j.parkreldis.2015.01.004. Epub 2015 Jan 14.

Novel GCH1 variant in Dopa-responsive dystonia and Parkinson's disease

A J Lewthwaite  1 , T D Lambert  2 , E B Rolfe  3 , S Olgiati  4 , M Quadri  4 , E J Simons  4 , K E Morrison  5 , V Bonifati  4 , D J Nicholl  6
Affiliations

Novel GCH1 variant in Dopa-responsive dystonia and Parkinson's disease

A J Lewthwaite et al. Parkinsonism Relat Disord. 2015 Apr.

Abstract

Background: GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family.

Methods: We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed.

Results: We have identified a novel missense variant, c.5A > G, p.(Glu2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype.

Conclusions: We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCH1 genetic testing should be considered in patients with PD and a family history of DRD.

Keywords: Dopa responsive dystonia; GCH1; Parkinson's disease; SPECT DAT imaging.

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Figures

Supplementary Fig. 1
Supplementary Fig. 1
Electropherograms from subjects who are wild-type and heterozygote for the novel GCH1 mutation c.5A > G. Bars indicate position of nucleotide variation.
Supplementary Fig. 2
Supplementary Fig. 2
Alignment of the GCH1 protein homologs. Arrow indicates position of the mutated amino acid.
Supplementary Fig. 3
Supplementary Fig. 3
DaTSCAN of subject II:1. An abnormal scan, which shows bilateral reduced striatal uptake of [123I]FP-CIT, worse on the left side, as demonstrated by the arrow. Images 1–7 represent transverse sections through the brain, where 1 is the most superior and 7 the most inferior section. A normal DaTSCAN shows symmetrical bilateral striatal uptake which confers a comma-shaped configuration. There should be only minor background activity. The head of comma represents caudate activity whilst tail is due to uptake within putamen. In this example there is loss of uptake within each putamen. Caudate activity especially that on the left is also diminished. Note increased background activity. An MRI excluded a possible structural cause for these findings.
Supplementary Fig. 4
Supplementary Fig. 4
DaTSCAN of subject III:1. A normal scan, showing normal striatal uptake of [123I]FP-CIT bilaterally. Images 1–7 represent transverse sections through the brain, where 1 is the most superior and 7 the most inferior section. In normal DaT image striatum shown as comma shaped region with caudate and putamen appearing as high intensity against a low background. With increasing age background may become slightly more apparent. Compensating for any patient rotation, activity should be evenly distributed within each striatum with symmetrical configuration of comma.
Fig. 1
Fig. 1
Pedigree of study family. Numbers refer to the age (in years) at clinical evaluation and blood sampling of the twelve family members studied.
See this image and copyright information in PMC

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