Restless Legs Syndrome Causes: Iron, Genetics & More

What is restless legs syndrome?

Restless legs syndrome — also called Willis-Ekbom disease — is a neurological sensorimotor condition defined by an irresistible urge to move the legs, usually accompanied by uncomfortable sensations. Symptoms typically begin or worsen during periods of rest, are worse in the evening and at night, and improve at least temporarily with movement. The International RLS Study Group's diagnostic criteria require all four of those features to be present 1Ref 1Allen RP, Picchietti DL, Garcia-Borreguero D, et al. (2014).Restless Legs Syndrome/Willis-Ekbom Disease Diagnostic Criteria: Updated International Restless Legs Syndrome Study Group (IRLSSG) Consensus Criteria.The four diagnostic criteria for RLS — urge to move, worsening at rest, evening/night predominance, and relief with movement.

RLS is more common than many people realize. It affects adults of all ages, is roughly twice as common in women as in men, and its frequency tends to increase with age.

What causes primary (idiopathic) RLS?

The most common form of RLS appears to run in families and involves no identifiable underlying medical condition. Research points to three interconnected mechanisms:

Genetics Familial RLS is well documented, and several gene variants have been linked to risk. If a first-degree relative has RLS, your risk is meaningfully higher. Early-onset RLS (before age 45) tends to have a stronger familial component.

Dopamine system dysfunction Dopamine is a brain chemical that helps regulate movement. In RLS, there appears to be a disruption in dopamine signaling in the parts of the brain that control sensory and motor activity during rest. This explains why medications that boost dopamine activity are effective for many people with RLS 2Ref 2Winkelman JW, Armstrong MJ, Allen RP, et al. (2016).Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.Dopamine system involvement in RLS; dopaminergic medications effective for RLS treatment.

Iron and dopamine — the connection Iron plays a critical role in producing and regulating dopamine. Low iron in the brain — even when blood iron levels look borderline-normal — reduces dopamine availability and appears to drive or worsen RLS symptoms. Studies have found reduced ferritin levels in the cerebrospinal fluid of people with RLS, even when serum ferritin is within normal range 3Ref 3Winkelman JW, Berkowski JA, DelRosso LM, et al. (2025).Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline.Iron deficiency (including low ferritin even with normal hemoglobin) is a key treatable cause of RLS; ferritin target in management. Serum ferritin below 75 micrograms per liter is often considered a treatment target for RLS, though your clinician will interpret your specific results in context.

What causes secondary (symptomatic) RLS?

Secondary RLS has an identifiable underlying cause. Treating that cause can significantly reduce or eliminate symptoms.

Iron deficiency (with or without anemia): Low iron stores are among the most treatable causes of RLS. A ferritin level is a more sensitive measure than hemoglobin alone.

Pregnancy: RLS affects a substantial proportion of pregnant people, typically in the third trimester, and usually resolves after delivery. Iron and folate levels drop during pregnancy, which likely contributes.

Chronic kidney disease: Dialysis patients have a notably high rate of RLS. The mechanism is thought to involve uremic toxins affecting dopamine and iron metabolism.

Certain medications: Several drug classes can trigger or worsen RLS — particularly dopamine-blocking antiemetics (such as metoclopramide or prochlorperazine), many antidepressants (SSRIs, SNRIs, tricyclics, and mirtazapine), antipsychotics, and some antihistamines. If symptoms started after a medication was added, that connection is worth discussing with a clinician.

Peripheral neuropathy: Nerve damage from diabetes or other causes can produce sensations that overlap with or trigger RLS.

Other associations: Rheumatoid arthritis, Parkinson's disease, and sleep disorders such as sleep apnea have been associated with higher rates of RLS.

Which tests help identify the cause?

A clinician evaluating RLS will typically check: - Serum ferritin (iron stores) — this is the most important initial test - Complete blood count - Kidney function (creatinine) - Fasting glucose or A1c - Thyroid-stimulating hormone

A review of all current medications is also essential. There is no specific blood test that diagnoses RLS itself; it remains a clinical diagnosis based on symptoms.

Can caffeine, alcohol, or sleep deprivation trigger RLS?

Yes. These are well-recognized aggravating factors rather than root causes. Caffeine and alcohol — particularly in the evening — can worsen RLS symptoms in people who already have the condition. Sleep deprivation also tends to amplify symptoms. Identifying and reducing these triggers is often part of initial management alongside addressing any correctable underlying cause.