Elsevier

Sleep Medicine

Volume 75, November 2020, Pages 361-367
Sleep Medicine

Original Article
Contrasting painless and painful phenotypes of pediatric restless legs syndrome: a twin family study

https://doi.org/10.1016/j.sleep.2020.08.024Get rights and content

Highlights

  • Painless and painful pediatric restless legs syndrome were contrasting phenotypes.

  • Painless restless legs syndrome was associated with iron deficiency and female sex.

  • Painful restless legs syndrome was heritable.

  • Painless and painful phenotypes differed in pain associations.

Abstract

Objective

This study was designed 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.

Methods

In a twin family study, twins (3–18 years) and their oldest siblings, mothers and fathers completed questionnaires, assessing lifetime prevalence of RLS using current criteria, as well as history of iron deficiency and pediatric pain disorders. Subsets were categorized as RLS-Painless or RLS-Painful. Within twin pair analyses were conducted to assess familial and potential genetic effects for the defined subsets. Penalized maximum likelihood logistic regression was used to test familial associations. Random-effects logistic regression modeling was used in the total pediatric sample to investigate univariate and multivariate associations with the subsets.

Results

Data were available for 2033 twin individuals (1007 monozygous (MZ), 1026 dizygous (DZ); 51.7% female), 688 siblings, 1013 mothers and 921 fathers. Odds ratios, correlations and casewise concordance were significantly higher in MZ than in DZ twins only for RLS-Painful. RLS-Painless, though familial (co-twin and mother), was not genetically influenced, but was independently associated with female sex (OR 0.52, p = 0.003), iron deficiency (OR 4.20, p < 0.001) and with persistent pain disorders (OR 2.28, p = 0.02). RLS-Painful was familial and was probably genetically influenced; was independently associated with non-migraine headaches (OR 2.70, p = 0.02) and recurrent abdominal pain (OR 2.07, p = 0.04).

Conclusions

Pediatric RLS was heterogeneous and was categorized into contrasting painless and painful phenotypes. RLS-Painless was associated with iron deficiency while RLS-Painful accounted for the heritability of RLS.

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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