New findings from an ongoing genetic study of early-onset Parkinson’s disease indicate that relatives of individuals carrying parkin mutations are at increased risk for PD themselves. In addition, juvenile-onset PD can be due to any one of several known PD genes, and likely other genes yet to be discovered.
The goal of the Consortium on Risk for Early-onset Parkinson’s Disease (CORE-PD) study is to determine what genetic and environmental risk factors influence development of early-onset PD (EOPD), defined as disease onset before age 50. Over the past several years, investigators led by Karen Marder, MD, of Columbia University, have enrolled over 1100 individuals with EOPD, who give a blood specimen, receive a medical exam, and give a detailed medical and family history.
In the most recent work, investigators asked about the penetrance of PD in first-degree relatives with parkin mutations. Forty-two EOPD patients with parkin mutations were asked about the occurrence in PD in family members, using a validated family history interview. Of 1205 parents or siblings considered, 10 percent had PD. The investigators then used Mendelian inheritance principles to determine the probability that each relative carried the parkin mutation. Combining this with the information on disease status and relatedness, they calculated cumulative risk for PD to age 70 of those carrying mutations (penetrance). The risk was 40 percent for those carrying any mutation, versus 11 percent for those carrying none. The risk rose to 45 percent when only homozygotes or compound heterozygotes were included.
Investigators also explored the genetics of the earliest form of PD, juvenile-onset, defined as PD before the age of 20. Of 1103 individuals with early-onset PD from 16 centers across the United States, only 20 (1.8 percent) reported onset before age 20, with the earliest at age 7. Among this group, there were 11 females and 9 males. Tremor was the presenting symptom in 60 percent. Mean duration of disease at the time of enrollment in the study was 23 years, and ranged up to 47 years, suggesting a slow progression of disease in this very young group of PD patients.
Genetic testing indicated that 12 carried mutations in known genes: 7 parkin compound heterozygotes, 2 parkin heterozygotes, 2 glucocerebrosidase mutations, and 1 LRRK2 mutation. Only 4 of the 20 patients reported a family history of PD.
Gene testing in PD: Who and When
Comment from Dr. Higgins
The cardinal clinical features of PD are tremor, rigidity, and bradykinesia. A response to levodopa and asymmetric onset of limb involvement are supporting features. The genetic causes of PD include autosomal dominant forms caused by mutations in three genes, SNCA (PARK1), UCHL1 (PARK5), and LRRK2 (PARK8). Mutations in three known genes, PARK2 (PARK2), PARK7 (PARK7), and PINK1 (PARK6), result in autosomal recessive Parkinson disease. Molecular genetic testing is clinically available at Athena for PARK2 (the gene encoding parkin), PINK1, PARK7, SNCA, and LRRK2.
Further information about this ongoing trial can be found at clinicaltrials.gov.