Diagnostics & Imaging Week Correspondent

LONDON — The discovery of genetic variants that increase the risk of suffering from restless legs syndrome (RLS) has laid open the way to a better understanding of this mysterious condition with, eventually, the prospect of new therapies to treat it.

RLS is a common neurological disorder, affecting up to 10% of those over 65, although it can also affect much younger people, including children. People who have RLS experience an uncomfortable sensation in the legs when they try to go to sleep, and have an uncontrollable urge to move their legs or walk around, so that the condition prevents or delays sleep.

Juliane Winkelmannn, assistant professor at the Max Planck Institute of Psychiatry and the Institute of Human Genetics in Munich, Germany, told Diagnostics & Imaging Week’s sister publication BioWorld International, “This study provides us with a completely new perspective that will, we hope, allow us to gain an understanding of the cell biology involved in the development of RLS. It gives us insights into the possible genetic causes of RLS, which were completely unknown before.”

In what came as a complete surprise to the researchers, the three genetic variants identified turned out to be in genes that, during embryonic development, are involved in determining the pattern formation of the limbs and central nervous system.

Winkelmann said, “It will be interesting now to investigate the role of these genes in adults.”

In the long term, the finding could lead to new therapeutic strategies to treat RLS, Winkelmann added.

Winkelmann and her colleagues report their findings in a paper in the July 18 edition of Nature Genetics. Its title: “Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions”.

Researchers led by a team from DeCode Genetics in Reykjavik, Iceland, also report identifying one of the same variants in people with RLS. Their report appears in the July 18 edition of the New England Journal of Medicine, titled “A genetic risk factor for periodic limb movements in sleep.”

Winkelmann and her colleagues, including Thomas Meitinger, also of the Institute of Human Genetics at the GSF National Research Center of Environment and Health in Munich, Germany, knew that more than 50% of people with RLS also have a family history of the disease, suggesting that there is a genetic cause for it. Linkage analysis, however, had failed to identify any responsible genes.

The group, therefore, turned to the newly available technology known as a genome-wide association study, which makes it possible to identify genetic variants throughout the entire genome that associate with the disease of interest.

There are, for example, estimated to be more than 7 million common single nucleotide polymorphisms (SNPs) in the human genome, but because recombination generally takes place at particular “hotspots,” many of the SNPs commonly are inherited together. Researchers therefore can use a panel of SNPs (known as tags) to infer which groups of SNPs have been inherited by people with a disease and which by healthy controls.

Winkelmann, Meitinger and their colleagues compared the distribution of SNPs between 400 patients with RLS and 1,600 control subjects.

They found three genetic variants that were associated with RLS in a highly statistically significant way. The genes in which the variants were located were:

• The homeobox gene MEIS1 on chromosome 2p;

• The BTBD9 gene on chromosome 6p;

• A third locus on chromosome 15q, which included the genes encoding a protein kinase, and the transcription factor LBXCOR1.

Their findings were replicated in two independent cohorts from Germany and Canada.

Winkelmann said both MEIS1 and LBXCOR1 are known to be involved in early embryonic development in mammals, where they define the pattern formation of the limbs and central nervous system. BTBD9 is also involved in pattern formation and known to have a role in protein-protein interactions.

It is likely that there are further variants that increase the risk of RLS, Winkelmann added. “We will be working on identifying these additional risk factors, and we also want to produce an animal model for the disease,” she said.

Some treatments originally developed for use in Parkinson’s disease have been used successfully to treat RLS. Writing in Nature Genetics, the authors suggest that it will be interesting to investigate whether the genetic loci they have identified also have a role in dopaminergic disorders such as Parkinson’s disease, or in associated disorders such as attention deficit hyperactivity disorder, or sleep disorders.