Single gene mutation as the cause of around one in 25 cases of Parkinson’s disease worldwide

Three studies published online by The Lancet today identify a single gene mutation as the cause of around one in 25 cases of Parkinson’s disease worldwide. The studies suggest that the mutation, in a recently discovered gene called LRRK2, causes around 5% of inherited Parkinson’s cases and around 2% of isolated cases. Screening for the new mutation is likely to become a component of genetic testing for Parkinson’s disease in the near future.

Parkinson’s is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting more than 1% of individuals after the age of 65 years. It is characterised by resting tremor, slowness of movement, muscle rigidity, postural instability and impaired balance and coordination.

Vincenzo Bonifati (Erasmus Medical Centre, Rotterdam, Netherlands) and colleagues analysed the LRRK2 gene in 61 families with Parkinson’s disease. The investigators found that individuals in 4 unrelated families had inherited one copy of the mutation. Their findings indicate that this mutation is associated with the hereditary form of the disease.

Dr Bonifati comments: “This is a significant step forward in our understanding of the causes and mechanisms of Parkinson’s disease, with implications for both the scientific and clinical communities. The main challenge is now to try and understand how this and the other PDassociated LRRK2 mutations lead to neurodegeneration and disease, in order to design novel therapeutic and preventive strategies.

“From the genetic standpoint, the presence of the same mutation associated with the disease in patients from several different populations is intriguing. This raises the question of whether the mutation originated independently in the different cases and families, or if it was transmitted from a single common ancestor. Future genetic studies will address this issue; however, if it comes from a common ancestor, this mutation must be very ancient.”

Nicholas Wood (National Hospital for Neurology and Neurosurgery, London, UK) and colleagues analysed the LRRK2 gene in 482 Parkinson’s patients without a family history of the disease. The investigators found that the mutation was present in 8 patients; implicating the mutation in sporadic as well as inherited forms of the disease.

William Nichols (Cincinnati Children’s Hospital Medical Centre, Cincinnati, USA) and colleagues measured the frequency of the LRRK2 mutation in familial Parkinson’s disease by screening the DNA of patients and controls. Of 767 affected individuals from 358 families, 35 patients from 20 different families had one or two copies of the mutation and had typical clinical features of Parkinson’s disease. Their results suggest that the single mutation in the LRRK2 gene causes Parkinson’s disease in 5% of individuals with the familial form of the disease.

Dr Nichols comments: “Screening for the new mutation will probably become a key component of genetic testing for Parkinson’s disease in the near future. Importantly although we have only screened for one mutation, additional mutation in the LRRK2 gene have already been identified. Therefore the actual number of LRRK2 mutations in familial disease in general, is probably substantially higher than 5%. Mutations in this gene could become the most important cause of disease susceptibility for Parkinson’s disease identified so far.”

In an accompanying commentary Alexis Brice states that a number of issues need to be resolved before the results of these studies can be put into clinical practice. These include establishing the complete clinical spectrum associated with this mutation and accurately evaluating the risks associated with the mutation. He writes that genetic testing for the new LRRK2 mutation will also raise ethical issues. Due to the absence of preventative treatment, testing offers no direct medical benefit for patients.