Objective: To report a case of possible comorbid tau and Lewy pathology in an individual with a GCH1 mutation.

Background: A 69-year-old man developed atypical parkinsonism with backwards falls, postural instability, eye movement abnormalities, limb asymmetrical rigidity, dream enacting behaviour and frontal release signs, with partial improvement on 400 mg/day of levodopa. He later developed cognitive impairment and personality changes.

Method: Magnetic resonance image (MRI) of the brain showed atrophy of the midbrain compatible with progressive supranuclear palsy (PSP) and reduction of neuromelanin signal in the pars compacta of the substantia nigra and loss of the swallow tail sign, suggesting striatonigral degeneration.
The presence of a pathogenic variant in the GCH1 gene (Lys224Arg), was identified as part of the Rostock International Parkinson’s Disease Study (ROPAD). In which the GBA gene as well as LRRK2 and 68 PD associated genes (which included GCH1 gene) were analyzed.

Results: GCH1 mutations are associated with dopa responsive dystonia (DRD), usually presenting in infancy with levodopa-responsive dystonia/parkinsonism. However, different phenotypes have been reported in association with the Lys224Arg mutation including DRD, cerebral palsy, Parkinson’s disease (PD), and myoclonus dystonia, both in homozygosity and compound heterozygosity.^1,2 More recently, variants of the GCH1 have been associated with a seven-fold increased risk of developing PD, suggesting that variants of this gene could be associated with striatonigral degeneration.³
The patient reported here never presented DRD, which could be a consequence of reduced penetrance of the mutation in males.⁴ Despite the signs of striatonigral dysfunction, the remarkable feature of this case is the predominant PSP phenotype. Although rare, it is possible that two neurodegenerative conditions are occurring in this patient. The co-occurrence of tau and Lewy body pathology in an individual with a pathogenic mutation in the GCH1 has already been reported.⁵

Conclusion: Although the hypothesis of comorbid tau and Lewy pathology are supported by the MRI findings, a postmortem analysis is needed to confirm this. This report adds important data to the literature, further studies are needed to assess whether the presence of a pathogenic variant of the GCH1 could be one factor contributing to tau neurodegeneration or if the co-occurrence of these diseases are sheer coincidence.

References: 1. Bandmann O., Daniel S., Marsden CD., Wood NW., Harding AE. The GTP-cyclohydrolase I gene in atypical Parkinsonian patients: a clinico-genetic study. J Neurol Sci. 1996;141(1):27–32. Doi: 10.1016/0022-510X(96)00098-6.
2. Camargos ST., Cardoso F., Momeni P., et al. Novel GCH1 mutation in a Brazilian family with dopa-responsive Dystonia. Mov Disord. 2008;23(2):299–302. Doi: 10.1002/mds.21842.
3. Mencacci NE., Isaias IU., Reich MM., et al. Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers. Brain. 2014;137(Pt 9):2480–92. Doi: 10.1093/brain/awu179.
4. Furukawa Y., Lang AE., Trugman JM., et al. Gender-related penetrance and de novo GTP-cyclohydrolase I gene mutations in dopa-responsive dystonia. Neurology. 1998;50(4):1015 LP – 1020. Doi: 10.1212/WNL.50.4.1015.
5. Guella I., Sherman HE., Appel-Cresswell S., Rajput A., Rajput AH., Farrer MJ. Parkinsonism in GTP cyclohydrolase 1 mutation carriers. Brain. 2015;138(Pt 5):e349–e349. Doi: 10.1093/brain/awu341.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/atypical-parkinsonism-presenting-in-late-60s-in-an-individual-with-gch1-mutation/