Scientists have pinpointed many gene variants that heighten a person’s risk for Parkinson's, but rarely have they happened upon deletions of whole chromosome fragments. Now, researchers led by Anne Bassett, Centre for Addiction and Mental Health, Toronto, Canada, report that loss of a snippet from chromosome 22 increases the risk of early onset Parkinson's disease (PD). They found a cluster of autopsy-confirmed PD in a cohort of people with a 22q11.2 deletion syndrome, suggesting there might be genes in that region of the chromosome that protect against PD. The results appeared in the September 9 JAMA Neurology online.
"If confirmed, this would be among the first discoveries that genomic microdeletions can contribute to PD susceptibility," wrote Joshua Shulman, Baylor College of Medicine, Houston, Texas, in an accompanying editorial. Some studies have implicated rare microdeletions encompassing the Parkin or tyrosine hydroxylase genes as possible susceptibility factors, Shulman pointed out (see Pankratz et al., 2009 and Bademci et al., 2010). Because current technologies tend to overlook deletions, the role of this chromosomal defect may be underestimated, Shulman added. Microdeletions usually crop one or more entire genes and can be more devastating than point mutations.
Deletions around chromosome 22q11.2 occur spontaneously in at least one in 4,000 people. Sometimes called velocardiofacial or DiGeorge syndrome, 22q11.2 deletion causes congenital and adult-onset disorders such as schizophrenia. Four people with the syndrome were previously diagnosed with PD (see Booij et al. 2010, and Booij et al. 2010), making researchers wonder if the two were linked.
To test this, first author Nancy Butcher and colleagues sorted through medical records of the relatively large and well-characterized 22q11.2 deletion cohort at the Centre for Addiction and Mental Health. Of the 159 people known to this center, four, ranging in age from 44 to 55, had been diagnosed with PD. They began showing motor symptoms between the ages of 39 and 48. Neither the sole 22q11.2 patient over 65, or patients younger than 34, showed any PD-like symptoms. Though the number of patients is small, Bassett estimated that people with the 22q11.2 deletion may have at least a 20-fold greater risk of PD than the general population. More accurate data could come from larger cohorts of 22q11.2 deletion patients, she said.
Brain tissue from the autopsies of three of the four patients with PD confirmed the diagnosis. Dopamine-producing cells of the substantia nigra and striatum had degenerated in all three. However, immunohistochemistry revealed classical Parkinson pathology in only two of them, including cortical and sub-cortical Lewy bodies—aggregates of misfolded protein made up principally of α-synuclein. Autopsy tissue from three PD-free 22q11.2 deletion patients showed no evidence of synuclein pathology or loss of dopamine neurons.
These results have implications both for patients with 22q11.2 deletions and those with PD, Bassett told Alzforum. Clinicians should look carefully for PD symptoms as people with a 22q11.2 deletion age. Complicating matters, PD symptoms can resemble side effects of the antipsychotic medications used to treat schizophrenia, which affects one in four people with 22q11.2 deletions. People with early onset PD should be checked for signs of 22q11.2 deletions, some of which can be managed, said Bassett.
The findings may also point to mechanisms underlying PD pathology, wrote the authors. As in patients with mutations in Parkin and LRRK2, Lewy bodies can be absent in PD linked to 22q11.2 deletion syndrome (for a review, see Poulopoulos et al., 2012). Determining what causes dopaminergic degeneration in the 22q11.2 patients might shed light on neurodegeneration in pathologically similar forms of familial PD, suggested the authors. While the genes for parkin and LRRK2 are on chromosomes 6 and 12, respectively, there are about 50 genes around chromosome 22q11.2 that might alter risk for PD. Candidates include catechol-O-methyltransferase, which is important for breaking down dopamine, DGCR8, which helps process microRNAs in the brain, and microRNA-185, which is predicted to target LRRK2 mRNA. "With the availability of various 22q11-related mouse models generated for previous schizophrenia studies, it would be interesting to interrogate these mice to identify the critical genes involved in the PD-related phenotypes," wrote Huaibin Cai, National Institute on Aging, Bethesda, Maryland, to Alzforum in an email (see full comment below).—Gwyneth Dickey Zakaib