Exploring the Role of GCH1 in Parkinson’s Disease

The role of GCH1 mutations in Parkinson's disease is complicated by the mutation's seemingly exclusive role in dopa-responsive dystonia.

A genetic mutation known to cause the rare neurological disorder dopa-responsive dystonia (DRD) may also be a risk factor for Parkinson’s disease. A 2014 study published in Brain found that carriers of the GCH1 mutation who do not develop DRD may have a significant risk of developing adult-onset Parkinson’s disease compared to people without this gene.1,2

GCH1 encodes GTP cyclohydrolase, an enzyme that controls the first step in the biosynthesis of dopamine in nigrostriatal cells. In DRD, loss-of-function mutations of GCH1 cause tremors and dystonias that range from mild to severe and usually present by age 6.1,2

“People with DRD are unable to manufacture dopamine, but they can store it. They do not have neurodegeneration as in Parkinson’s, so they remain responsive to levodopa,” said C. Warren Olanow, MD, professor of neurology and neuroscience at the Mount Sinai School of Medicine in New York.

GCH1 and Parkinson’s Disease Risk

The study published in Brain looked at family members of people with DRD who were GCH1 carriers and developed adult-onset Parkinson’s disease. Inheritance of GCH1 in DRD is usually autosomal dominant, but penetrance varies.1

“These carriers developed parkinsonism that is indistinguishable from classic Parkinson’s disease. In the study, neuroimaging found neurodegeneration in the relatives with Parkinson’s disease, while there was no degeneration in the family members with DRD,” said Benjamin Walter, MD, assistant professor of neurology at Case Western Reserve University School of Medicine in Cleveland, Ohio.

The study used whole exome gene sequencing to search for GCH1 variants in more than 1,000 patients with Parkinson’s disease and close to 6,000 patients without the condition. The researchers found that carriers of GCH1 were over seven times more likely to have Parkinson’s than noncarriers.1

“That is an intriguing finding,” said Olanow. “It adds one more gene to the many genes that have been linked to increased risk for the disease.”

A Complex Relationship

A lot of questions remain unanswered. For example, why do people with GCH1 and DRD maintain nigrostriatal cell integrity while these cells show degeneration in people with GCH1 and adult-onset Parkinson’s disease? One theory is that degenerative and nondegenerative GCH1-associated phenotypes are mutually exclusive. Carriers with dystonia during childhood may be protected from neurodegeneration in later life.3

Another grey area is GCH1’s link to adult-onset Parkinson’s disease, and its less probable relationship with early-onset Parkinson’s disease, which frequently presents with dystonia. A 2009 study published in the journal Movement Disorders did not find any GCH1 abnormalities in 53 patients with early-onset Parkinson’s disease.4

“It could be that some variants of GCH1 cause an asymptomatic but low-functioning state in dopamine neurons which gradually increases a person’s risk for Parkinson’s disease. But Parkinson’s disease is not a single disease, and it is not caused by a single gene. It is a complicated story,” said Walter.

Future Implications

It’s possible that children with DRD may be protected from developing Parkinson’s disease as adults because they are routinely treated with levodopa. If dopamine is preventing neurodegeneration in these patients, could a case be made to treat asymptomatic GCH1 carriers to prevent onset of Parkinson’s disease?3

“That is way too speculative at this point,” said Olanow. “Let’s just say that GCH1 is another potential risk factor for Parkinson’s disease and see where future research leads us.”

Gene therapy is an active area of research in Parkinson’s disease. One trial using monkeys attempted to introduce GCH1 to the brain along with two other genes needed to produce GTP cyclohydrolase through a viral vector. Results were encouraging, but human clinical trials are still a ways away.5

“We have discovered another piece of the puzzle. Each piece helps us create a story that starts to explain the complex puzzle that is Parkinson’s disease,” said Walter.

Chris Iliades, MD, is a full-time freelance writer based in Cape Cod, Massachusetts. This article was medically reviewed by Pat F. Bass III, MD, MS, MPH.    


  1. Mencacci NE, Isaias IU, Reich MM, et al. Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers. Brain. 2014;137(Pt 9):2480-92.
  2. Genetic Home Reference, Dopa-responsive dystonia. http://ghr.nlm.nih.gov/condition/dopa-responsive-dystonia.
  3. Terbeek J, Hermans S, Van laere K, Vandenberghe W. Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers. Brain. 2014;
  4. Cobb SA, Wider C, Ross OA, et al. GCH1 in early-onset Parkinson’s disease. Mov Disord. 2009;24(14):2070-5.
  5. Medscape, Another Player in Gene Therapy for Parkinson’s Disease. http://www.medscape.com/viewarticle/715617.