Objective: To evaluate presynaptic nigrostriatal dopaminergic function in a Dopa-responsive dystonia (DRD) family with guanosine triphosphate cyclohydrolase 1 (GCH-1) mutation.

Background: Mutation of GCH-1 located on chromosome 14q22.1-22.2, is the most common and best characterized condition that manifests as DRD. Since the gene products of GCH-1 are related to tyrosine hydroxylation, impairment of dopamine production in the nigral cell seems to be responsible for DRD. However, results of the functional imaging using 18F-fluorodopa positron emission tomography or single photon emission computed tomography (SPECT) of the dopamine transporter (DAT) was still controversial.

Methods: Three of five members of the DRD family were found to have a heterozygous T241C mutation in exon 1 of GCH-1. We studied the presynaptic nigrostriatal dopaminergic function using 99mTc-TRODAT-1 (TRODAT) SPECT imaging in those three members. We further analyze the correlation between the phenotypic presentation of DRD and the nigrostriatal dopaminergic function.

Results: Clinically, there was presentation of clinical Heterogeneity in the DRD family; one was a classic DRD (proband), one presented with parkinsonism which was distinguishable from typical PD, and the other one was an asymptomatic gene carrier. 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) 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.

Conclusions: We conclude variability of presynaptic nigrostriatal dopaminergic function in patients with DRD is related to their clinical heterogeneity.

References: 1. Mencacci NE, Isaias IU, Reich MM, Ganos C, Plagnol V, Polke JM, et al (2014) Parkinson’s disease in GTP cyclohydolase 1 mutation carrier. Brain 137:2480-2492. 2. Wijemannes S, Jankovic J (2015) Dopa-responsive dystonia- clinical and genetic heterogeneity. Nat Rev Neurol 7:414-424.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/phenotypic-heterogeneity-and-variability-of-nigrostriatal-dopaminergic-function-in-a-dopa-responsive-dystonia/