Study identifies the most common genetic cause of Parkinson’s disease

Researchers have found that a single mutation in a recently discovered Parkinson’s disease gene is responsible for 5 percent of inherited Parkinson’s disease cases. The finding opens the door to the possibility of genetic screening for the LRRK2 gene mutation, which is believed to be the most common genetic cause of inherited Parkinson’s disease identified to date.

The study, conducted by William C. Nichols, PhD, a geneticist at Cincinnati Children’s Hospital Medical Center, is one of three Parkinson’s studies published in the Tuesday, January 18 online edition of The Lancet. The study will appear in the January 29 edition of the journal. The second study is by Nicholas W. Wood, MD, of the Institute of Neurology in London. The third study is by Vincenzo Bonifati, MD, PhD, of Erasmus MC in Rotterdam, Netherlands.

Parkinson’s disease, a disorder of the nervous system that causes tremors and muscular rigidity, affects more than one million people in the United States and is the second most common neurodegenerative disorder – second only to Alzheimer’s disease in frequency.

The Cincinnati Children’s study focused on a group of 767 Parkinson’s disease patients from 358 different families. The patients were recruited by specialists from 59 medical centers associated with the Parkinson Study Group, a non-profit, cooperative group of Parkinson’s disease experts from the United States, Canada and Puerto Rico. The study found that 5 percent of the patients carried the same LRRK2 mutation. The Wood report focused on Parkinson’s disease patients without a known family history of the disease. Dr. Wood found the same LRRK2 gene mutation in eight of 482 individuals in the study. The Bonifati study identified the same LRRK2 gene mutation as the Cincinnati Children’s study. Bonifati found the mutation in four of 61 families with a history of Parkinson’s disease.

“When we began, we really didn’t know how frequent the mutation in the LRRK2 gene would be, but to find the same single mutation in the genome in Parkinson’s patients is pretty dramatic. No other mutation in any other known Parkinson’s gene has been found in such high frequency,” said Dr. Nichols, who is the lead author of the Cincinnati Children’s study.

LRRK2 is one of five Parkinson’s disease genes in which mutations have been identified. The gene was identified in October 2004 by Andrew Singleton, PhD, of the National Institute on Aging at the National Institutes of Health, who is a co-author of the Nichols and Wood studies in The Lancet. The LRRK2 gene was isolated on a region of chromosome 12 called PARK8 by Dr. Singleton and colleagues who studied five families with a history of Parkinson’s disease.

Individual genes can have many mutations, which is also true of the LRRK2 gene. Dr. Singleton has identified other mutations in the LRRK2 gene, but those mutations were not manifested to the same degree as the mutation described in the Nichols’ study, which was found to occur in about one of every 22 patients with inherited Parkinson’s disease.

“It looks like mutations in this gene are going to account for far more than mutations in other Parkinson’s disease genes identified to date. Finding the same mutation in a single gene accounting for such a large percentage of patients is quite remarkable, and this mutation should be included in any future genetic testing for the disease,” Dr. Nichols said.

The patients in the Cincinnati Children’s study who had the mutation did have longer disease duration at the time of their clinical evaluation for the study, but their symptoms were less severe, suggesting that the mutation in LRRK2 is associated with slower disease progression, Dr. Nichols said.

Parkinson’s disease is a progressive disorder that is caused by the degeneration of nerve cells in the portion of the brain that controls movement. The disease occurs when certain nerve cells die or become impaired and can no longer produce dopamine. Without dopamine, individuals can develop tremor or trembling in hands, arms, legs, jaw, and face along with rigidity or stiffness of the limbs, slowness of movement; and impaired balance or coordination. Patients may also have difficulty walking, talking, or completing other simple tasks. The incidence of Parkinson’s disease increases with age.

Until recently, it was thought that environmental factors were the primary cause of Parkinson’s disease. A genetic link was thought to exist in the rare early onset form of the disease in people diagnosed before age 40 (children as young as 14 have been diagnosed with the juvenile form of Parkinson’s disease), but not in the more common form of the disease in which people, on average, are diagnosed at about 60 years. The first Parkinson’s disease gene was identified in 1997.

Dr. Nichols is a geneticist who specializes in the identification of novel disease genes. In addition to Parkinson’s disease, he conducts research on primary pulmonary hypertension and juvenile rheumatoid arthritis.

The Cincinnati Children’s study was funded by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health.

Cincinnati Children’s conducted this research in conjunction with Dr. Singleton of the National Institute on Aging, and Tatiana Foroud, PhD, of Indiana University Medical Center, who is also a co-author and principal investigator of an $8 million grant from the National Institute of Neurological Disorders and Stroke (NINDS).