Variability of presynaptic nigrostriatal dopaminergic function and clinical heterogeneity in a dopa-responsive dystonia family with GCH-1 gene mutation

These families are very interesting. GCH-1 released dopa responsive dystonia (DRD) is an inherited problem with the metabolic pathways that involve dopamine and other neurotransmitters. Typical features include dystonia and tremor, which tend to respond dramatically to small doses of levodopa. Here the authors describe a family in which some members had the DRD phenotype and others have a degenerative form of parkinsonism akin to Parkinson's disease.

This is not the first time that this link has been noted, but many people are were skeptical. A good friend of mine, Niccolo Mencacci, described 4 or 5 similar families in his paper in Brain in 2014. Subsequently it was shown through a different method, genome wide association study (GWAS), that variation in the region of the GCH-1 gene is associated with Parkinson's disease also. The GWAS findings have been replicated.

To me this raises important questions about the role of dopamine in PD and suggests that depletion may not only be a consequence of PD but also a causative factor. Importantly not all of the cases that developed degenerative parkinsonism had been treated long term for DRD with replacement dopamine, otherwise we might be talking about a potentially toxic effect of levodopa replacement therapy. As it stands, we are not... but the link between endogenous depletion of dopamine due to a metabolic defect and the eventual emergence of symptoms and imaging features of degenerative parkinsonism requires further exploration...

Alastair Noyce


J Neurol. 2017 Dec 30. doi: 10.1007/s00415-017-8723-5. [Epub ahead of print]
Lin JJ, Lu CS, Tsai CH.

https://link.springer.com/article/10.1007%2Fs00415-017-8723-5

We studied the presynaptic nigrostriatal dopaminergic function using single photon emission computed tomography (SPECT) imaging of a 99mTc-TRODAT-1 (TRODAT) scan in a dopa-responsive dystonia (DRD) family with the guanosine triphosphate cyclohydrolase 1 (GCH-1) gene mutation. Clinically, there was presentation of intrafamilial variability in the DRD family. The index patient was a 10-year-old girl with classic DRD and normal presynaptic nigrostriatal dopaminergic function. However, her grandmother, a 79-year-old woman, presented with slowly progressive Parkinson's disease (PD) without dystonic symptoms and excellent response to dopaminergic therapy for 21 years. Her brain TRODAT SPECT imaging revealed a markedly and asymmetrically reduced uptake of dopamine transporter at the bilateral striatum. Her father, a 54-year-old man, was an asymptomatic gene carrier and his brain TRODAT SPECT imaging revealed asymmetrically reduced nigrostriatal dopaminergic transmission in the bilateral striatum. We conclude variability of presynaptic nigrostriatal dopaminergic function in patients with DRD is related to their clinical heterogeneity. Significantly, impairment of presynaptic dopamine function actually occurs in the asymptomatic gene carrier.