The role of iron in restless legs syndrome
Abstract
The impressive relief from restless legs syndrome (RLS) symptoms provided by levodopa treatment indicates RLS is caused by a dopaminergic abnormality. But similar and more lasting relief also occurs for iron treatment in some patients. Thus there are two major putative causes for RLS: CNS dopaminergic abnormality and CNS iron insufficiency. This article presents the data documenting that both peripheral and CNS iron insufficiency occur with RLS symptoms. Brain iron insufficiency is supported by independently replicated cerebrospinal fluid and brain imaging studies for patients without iron deficiency (ID) anemia. Autopsy studies and intravenous iron treatment further link brain iron insufficiency to RLS. The brain iron insufficiency in patients with RLS is now well established. In this article the data are reviewed that support the following postulates combining dopaminergic and iron causes of RLS: (1) All conditions that compromise iron availability will increase the risk of RLS leading to a higher than expected prevalence of RLS in these conditions. (2) Some patients with RLS have marginal CNS iron status that can become insufficient when deprived of normal access to adequate peripheral iron or may be insufficient even with normal access to adequate peripheral iron. (3) The change or reduced CNS iron status produces RLS symptoms largely through its effects on the dopaminergic system and the corollary to 3. (4) Dopaminergic system abnormalities producing RLS symptoms will be included in those produced by brain ID. Study of the iron model of RLS offers hope for developing new treatment approaches and perhaps methods to prevent or cure the disorder.
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Autopsy and MRI investigations show decreased iron concentrations in the substantia nigra of patients with restless leg syndrome that are associated with disease severity.
“Autopsy and MRI investigations show decreased iron concentrations in the substantia nigra of patients with restless leg syndrome that are associated with disease severity.197,198”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [198]
Iron deficit conditions worsen symptomatology of restless legs syndrome, whereas iron replacement therapy improves symptoms.
“Iron deficit conditions worsen symptomatology, whereas iron replacement therapy improves symptoms.198,201”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [198]
Iron misregulation is implicated in the pathology of restless leg syndrome, so that concentrations of TFR, IRP1, DMT1, ferroportin, and heavy-chain ferritin are decreased in dopaminergic neurons of the substantia nigra.
“Iron misregulation is implicated in the pathology of restless leg syndrome, so that concentrations of TFR, IRP1, DMT1, ferroportin, and heavy-chain ferritin are decreased in dopaminergic neurons of the substantia nigra.198–200”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [198]
Iron deficiency has been implicated in the etiology of both RLS and ADHD, with potential links to alteration of dopamine transporter expression and the synthesis and catabolism of monoaminergic neurotransmitters.
“Iron deficiency has been implicated in the etiology of both RLS and ADHD, with potential links to alteration of dopamine transporter expression and the synthesis and catabolism of monoaminergic neurotransmitters (Allen and Earley 2007; Cortese et al. 2005, 2012).”
From Associations of sleep disturbance with ADHD: implications for treatment (2015) · cites this paper as Allen and Earley 2007
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Self-citation
- Authors
- Allen, R. P., & Earley, C. J.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Allen, Richard P.
- Venue
- Movement Disorders
- Publisher
- Wiley
- Published
- 2007
- Volume
- 22
- Issue
- S18
- Pages
- S440-S448
- ISSN
- 0885-3185 (ISSN-L)
- 1531-8257
- OpenAlex
- W1987570141
- Cited by
- 280
- References
- 54
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 4 · 2023: 8 · 2022: 19 · 2021: 13 · 2020: 10 · 2019: 16 · 2018: 19 · 2017: 15 · 2016: 11 · 2015: 14 · 2014: 23 · 2013: 22 · 2012: 20
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Movement Disorders (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Restless Legs Syndrome Research
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- restless legs syndrome, dopaminergic dysfunction, levodopa, intravenous iron, iron deficiency anemia
- MeSH terms
- Iron Deficiencies, Central Nervous System, Dopamine, Humans, Iron, Receptors, Dopamine, Restless Legs Syndrome
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