Significant Step Forward

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 analyzed the LRRK2 gene in 61 families with Parkinson's disease. The investigators found that individuals in four unrelated families had inherited one copy of the mutation. Their findings indicate that this mutation is associated with the hereditary form of the disease.

"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," comments Dr. Bonifati in email correspondence regarding the study. "The main challenge is now to try and understand how this and the other PD-associated LRRK2 mutations lead to neurodegeneration and disease, in order to design novel therapeutic and preventive strategies," he notes.

Mutation May Be 'Very Ancient'

"From the genetic standpoint, the presence of the same mutation associated with the disease in patients from several different populations is intriguing," Dr. Bonifati continues in his email message. "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," he says.

"Future genetic studies will address this issue; however, if it comes from a common ancestor, this mutation must be very ancient," Dr. Bonifati suggests.

Nicholas Wood of the National Hospital for Neurology and Neurosurgery, London, UK, and colleagues analyzed 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, which implicated the mutation in sporadic, as well as inherited, forms of the disease.

Probably More Than 5% Affected

William Nichols of Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 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.

"Screening for the new mutation will probably become a key component of genetic testing for Parkinson's disease in the near future," comments Dr. Nichols. "Importantly, although we have only screened for one mutation, additional mutation[s] 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."

Ethical Issues

A number of issues need to be resolved before the results of these studies can be put into clinical practice, says Alexis Brice in an accompanying commentary. These include establishing the complete clinical spectrum associated with this mutation and accurately evaluating the risks associated with it.

Genetic testing for the new LRRK2 mutation will also raise ethical issues, Brice writes. Due to the absence of preventative treatment, testing offers no direct medical benefit for patients.