Objective: To describe the heterogeneity of parkinsonism in patients with GCH1 mutations.

Background: Dopa-responsive dystonia (DRD) is an inherited disorder that responds dramatically to levodopa (LD). The most common cause of DRD is an autosomal dominant deficiency of GTP Cyclohydrolase 1 enzyme secondary to a heterozygous mutation in the GCH1 gene. It presents in childhood with lower limb-onset dystonia and mild parkinsonism. Some patients present with adult-onset parkinsonism with a similar response to LD but without the late motor complications of Parkinson’s disease (PD). Recently, mutations in GCH1 have been implicated as a risk factor of PD. We present three cases with different parkinsonian phenotypes associated with GCH 1 mutations.

Method: Case Series

Results: Case 1: An 83-year-old lady with left foot equinovarus posture thought secondary to polio presented at the age of 56 with parkinsonism diagnosed as PD.  She responded very well to very low dose LD but developed mild LD-induced dyskinesia. She has a strong family history of DRD. She died at the age of 83 and autopsy showed loss of neuromelanin in substantia nigra neurons in the absence of neuronal loss. Case 2: A 69-year-old lady had a 13-year history of very slowly progressive adult-onset parkinsonism and left foot dystonia. She has a family history of PD. Her [11C] DTBZ PET scan showed reduced uptake in the right dorsal putamen. Case 3: A 73-year-old lady with childhood-onset right foot dystonia at the age of 7 developed adult-onset parkinsonism. She has a family history of DRD. On LD she developed dyskinesia and motor fluctuations requiring bilateral GPi DBS at the age of 65 with improvement.

Conclusion: Dose-dependent dyskinesia has been described in DRD and happens in the absence of striatonigral degeneration. This usually occurs on the initiation of LD therapy and striatal D2 receptor up-regulation is the postulated explanation. Case 1 also demonstrated reduced neuromelanin without loss of dopaminergic cells, as described previously in few cases. On the other hand, rarely, presynaptic nigrostriatal cell loss can be associated with GCH-1 mutations. In Case 2 this was associated with a very benign course while Case 3 experienced motor and non-motor fluctuations responding well to DBS. The underlying pathology of the presumed nigral cell loss in these cases remains to be elucidated.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/spectrum-of-parkinsonian-phenotypes-associated-with-gch1-mutation/