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Source: Ondo WG, et al. Restless leg syndrome in monozygotic twins: Clinical correlates. Neurology 2000;55:1404-1406.
Restless leg syndrome (rls), one of the most common neurologic disorders, is a highly prevalent disorder, affecting as many as 5% of the population. RLS patients are best classified into two groups: primary and secondary RLS. Patients with primary RLS often have a family member similarly affected, while patients with secondary RLS develop the condition in the setting of reduced iron stores, peripheral neuropathy, renal failure, or pregnancy. Distinguishing primary from secondary RLS can be difficult, as the two conditions are clinically indistinguishable.
To date, little is known about the pathologic mechanisms responsible for the symptoms of RLS. Several researchers have shown that the dopaminergic innervation of the striatum is reduced in RLS patients. RLS symptoms also respond best to treatment with dopaminergic agonists or levodopa. These two pieces of evidence suggest that the dopamine system is critically involved in RLS. However, genetic linkage studies of large families with RLS have failed to identify a locus with adequate lod score. These studies have been hampered by the phenotypic variability of the disorder, and by the fact that the disorder is frequent enough that often, family members on both sides of a family tree are affected.
In this paper, Ondo and colleagues report their studies of 12 monozygotic twins where at least one twin was initially known to be affected with RLS. They identified three twin pairs from their clinic, and obtained the other nine by advertising in the RLS newsletter. Clinical phenotypes and details of family history were established for both members of each twin group.
The results of this study were striking. In 10 of 12 monozygotic twin pairs, RLS symptoms were present in both members of the twin pair. An affected parent was identified in all 10 of these cases. Although the twin pairs were highly concordant for the disease, the phenotypic expression varied markedly between the monozygotic pairs. Reported symptoms and severity of symptoms were not tightly correlated. More remarkable, the age of onset of symptoms was not concordant, varying by as much as 42 years between two monozygotic twins. The inheritance pattern was most consistent with an autosomal dominant disorder with high penetrance. Ondo et al also compared these 12 monozygotic twins to their clinic population, affected with sporadic RLS. The mean age of onset of symptoms in familial RLS was approximately 28, while the mean age of onset was 47 in sporadic RLS.
These observations are important for several reasons. The finding of near-complete concordance of monozygotic twins for RLS symptoms confirms prior studies suggesting that familial RLS is a genetic disorder. However, even among monozygotic twins, there is marked phenotypic variability in the disorder, both in age at symptom onset and in the clinical phenotype.
How do these results affect neurologists treating patients with RLS? Ondo et al’s work suggests that RLS is best viewed as an amalgam of two conditions: secondary RLS, occurring later in life in the setting of iron deficiency or peripheral neuropathy, and familial RLS, occurring earlier. While both conditions respond to treatment, establishing a patient’s age of symptom onset and determination of a family history of RLS should enable the neurologist to separate primary from secondary RLS. —Steven Frucht