Original ArticleContrasting painless and painful phenotypes of pediatric restless legs syndrome: a twin family study
Introduction
Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a common sensorimotor disorder whose basic components include a sensory experience, akathisia, and a sleep-related motor sign, periodic leg movements during sleep, both associated with an enhancement of the individual's arousal state [1]. Recent findings on RLS genetics indicate that RLS has aspects of a genetically moderated neurodevelopmental disorder involving mainly the cortico-striatal-thalamic-cortical circuits. Brain iron deficiency is the key initial pathobiological factor and relates to alterations of iron acquisition by the brain, also moderated by genetic factors [1].
The current diagnostic criteria for restless legs syndrome (RLS) [2] mention unpleasant sensations but not pain, yet pain is included in the definition of RLS: “a chronic sensorimotor disorder characterized by unpleasant, sometimes painful, sensations in the legs coupled with an irresistible urge to move them particularly in the evenings, at rest, or during sleep” [3]. Boissier de Sauvages (1763) in an early description of restless legs [4] referred to pains (dolores) and vague pains, presumably paraesthesiae (dolores vagui). Pain as a typical symptom was identified by Ekbom in 1945 [5], who termed the condition RLS and separated it into asthenia crurum paresthetica and asthenia crurum dolorosa, the painless and painful forms respectively.
Subsequently, there have been 13 publications [[6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]] (see Supplementary Material, Table 1) in which the painful subtype of RLS, determined by diverse measures, ranged from 8.9%% to 72% of the RLS cases. Eleven of the 13 studies were case series, a design not conducive to phenotypic definition or differentiation. Generally, as reviewed by Karroum [19], painful RLS was more severe by several criteria including more sleep interference and more fatigue, leading to his conjecture that at least some cases of the painful form might be distinct from the painless form.
In considering what factors would potentially best discriminate between painful and painless forms of RLS and thus identify contrasting phenotypes, the first considerations were that genetic influence [20] and iron deficiency [21] are the two major causal influences, and those particularly apply in young people. We also considered sex and comorbidities or associations [22] and, influenced by our previous research [23], chose the primary pain disorders of childhood (migraine, non-migraine headaches, recurrent abdominal pain) and persistent or chronic pain disorders as having most potential to differentially associate with the painless and painful forms of RLS. Our hypothesis was that there would be contrasting familial and genetic influence and associations between the painless and painful forms of RLS which would enable phenotypic differentiation. Therefore, our primary objective was to investigate painless and painful subsets of pediatric restless legs syndrome (RLS) for genetic influence and for associations with iron deficiency and common pediatric pain disorders.
Section snippets
Design, recruitment and participants
This study is a subset analysis of a larger twin family study by questionnaire of primary pediatric pain disorders, with initial association analyses including RLS having been reported in Donnelly et al. [23].
In the subset analyses of RLS in this twin family study, we tested for probable genetic factors in twins with RLS-Painless (RLS cases who did not consistently report pain in the legs) and RLS-Painful (RLS cases who reported a history of bilateral leg pain, usually concurrent with the
Results
There were 3909 randomly selected twin families who met inclusion criteria for this survey who were sent questionnaires and the overall response rate was 26%, the relatively low response rate having been influenced by the extensive number and detail of the questionnaires. Data for RLS were available for 2033 twin individuals, 688 siblings, 1013 mothers and 921 fathers, with the highest percentage RLS occurring in mothers (Table 1). Table 1 also presents the numbers of cases and non-cases
Discussion
Prompted by the increasing recognition that there are painless and painful forms of RLS [[6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]], we hypothesised that these are separate phenotypes and the results support that hypothesis, at least in the context of this pediatric focused study.
The RLS-Painless subset was familial but probably not genetically influenced. The familial associations, particularly mother, suggest iron deficiency, notably including maternal
Conclusions
We have presented evidence that pediatric RLS is a hybrid condition, with contrasting painless and painful phenotypes. RLS-Painless, excluding individuals with bilateral pain in their legs, was probably not heritable, and was independently associated with female gender, a history of iron deficiency, and with persistent pain disorders. The phenotype with both urge to move the legs and bilateral leg pain (ie RLS-Painful) had RLS-Painful familial associations and evidence of genetic influence, and
Financial disclosure
The authors have no financial relationships relevant to this article to disclose.”
Funding source
This work was supported by the School of Women`s and Children`s Health, Medicine, University of New South Wales, Kensington 2052, NSW, Australia; Private donors.
CRediT authorship contribution statement
David Champion: Conceptualization, Methodology, Validation, Investigation, Writing - original draft, Writing - review & editing, Supervision, Project administration. Minh Bui: Data curation, Formal analysis, Writing - original draft, Writing - review & editing. Phillip Aouad: Validation, Investigation, Writing - original draft, Writing - review & editing, Supervision, Project administration. Sara Sarraf: Validation, Investigation, Writing - original draft, Project administration. Theresa
Acknowledgements
The authors would like to sincerely thank Twins Research Australia, UNSW School of Women`s and Children`s Health, University of New South Wales medical students undertaking their Independent Learning Projects (Penny Lee and Kate Findeisen), and private donors supporting pediatric pain research.
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