A newly discovered gene sequence variant is strongly associated with periodic limb movements in sleep, a component of restless legs syndrome, reported Dr. Hreinn Stefansson of deCODE Genetics, Reykjavik, Iceland, and associates.
Even though the authenticity of restless legs syndrome (RLS) has been called into question, “our study provides evidence that periodic limb movements in sleep is a genuine syndrome with an ascertainable phenotype and a genetic basis,” the researchers said.
Restless legs syndrome is characterized by uncomfortable and distressing sensory urges to move the legs during rest or inactivity. The condition often but not always involves involuntary, highly stereotypical, regularly occurring foot and leg movements in sleep.
The pathogenesis of the disorder is unclear, but it has been linked to low iron levels and has “a substantial” genetic component, according to the researchers.
Dr. Stefansson and associates genotyped 306 case subjects who had periodic limb movements in sleep, most of whom also had restless legs syndrome, as well as 15,664 control subjects from the general Icelandic population.
Overall, the researchers were able to assess more than 300,000 single nucleotide polymorphism (SNP) markers distributed across the human genome.
The researchers found a strong link between the disorder and allele A of rs3923809 on chromosome 6p.
To validate these results, they then conducted replication studies in an additional Icelandic cohort that included 123 case subjects and 1,233 control subjects, and in a U.S. cohort of 188 case subjects recruited from a sleep disorders center and 662 control subjects.
The association was evident in each study population, and it was highly significant when all three of the samples were combined, the investigators said (N. Engl. J. Med. 2007;357:639–47).
Subjects who carried the gene sequence variant also had higher ferritin indexes, a measure inversely related to bodily iron stores, as well as decreased serum ferritin levels. This correlation “is consistent with the suspected involvement of iron depletion in the pathogenesis” of RLS, Dr. Stefansson and his associates added.
In an editorial accompanying the study, Dr. John W. Winkelman of, Brigham and Women's Hospital and Harvard Medical School, Boston, said the results offer “hope to patients with periodic limb movements in sleep and RLS that the syndrome's pathophysiology will be understood, and that such knowledge will lead to additional effective and durable treatments” (N. Engl. J. Med. 2007;357:703–5).