UCL Queen Square Institute of Neurology


GCH1 gene and Parkinson’s risk

5 August 2014


A study published in Brain, led by researchers at UCL Institute of Neurology, has shown that genetic mutations which cause a decrease in dopamine production in the brain and lead to a form of childhood-onset Dystonia, also play a role in the development of Parkinson’s disease.

Investigators reported that adults carrying the GCH1 mutation are predisposed to the degeneration of nigral neurons – resulting in one of the four major dopamine pathways to the brain being defective. This GCH1 mutation is a novel risk factor of developing Parkinson's disease.

Mutations to the GCH1 gene result in a severe reduction of dopamine production in nigrostriatal cells and cause dopa-responsive dystonia (DRD), a treatable neurological condition that can be characterised by signs of parkinsonism including slowness of movement, balance difficulties and postural instability. DRD appears in childhood, often about the age of six, as dystonia of the lower limbs.

The dystonia then spreads, but has an excellent and sustained response to treatment by means of a drug called levodopa.

Those affected often have a relative with DRD, or one of the parents might have a GCH1 mutation but not show any symptoms. These individuals with GCH1 mutations but no dystonia in childhood might develop later on adult-onset parkinsonism.

The team initially studied four families in which GCH1 mutations were found in individuals with classic DRD and in older family members with no symptoms of DRD but who had adult-onset parkinsonism.

To understand the relationship between GCH1 mutations and parkinsonism the team used an imaging technology called ‘DaTscan’ where injections of small amounts of a radioactive drug help determine how many dopamine-producing cells are available in a person's brain.

The researchers observed that patients with DRD had normal DaTscans, indicating the absence of neurodegeneration, but their relatives with parkinsonism all had abnormal DaTscans, as observed in Parkinson's disease. This demonstrated that mutations in GCH1 can lead not only to DRD but also to neurodegeneration and Parkinson's disease.

The researchers also consulted the International Parkinson Disease Genomics Consortium database. They looked for mutations in GCH1 in 1,128 cases of Parkinson’s (without any family history for DRD) and compared results with 5,935 patients without the disease. They found a significant increased frequency of mutations in Parkinson’s disease.

Further information:

Mencacci et al. Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers Brain doi: 10.1093/brain/awu179 First published online: July 2, 2014.