Objectives: To fully ascertain the familial aggregation of restless legs syndrome (RLS) and to characterize the clinical features of familial RLS (fRLS) cases.

Design: A case series survey with a high response rate.

Setting: Academic research center.

Participants: Consecutive RLS probands (n = 249) were followed up in a specialized sleep center for 15 years. A total of 671 cases of fRLS met the current standard diagnostic criteria, including 192 probands characterized using multidimensional clinical assessments and 479 affected family members assessed by their responses to a structured questionnaire telephone diagnostic interview.

Main outcome measures: Sibling and offspring relative risk ratio and clinical and genetic features of patients with fRLS and families.

Results: Our data showed that RLS aggregates in families with a familial rate of 77%, a sibling relative risk of 3.6 (95% confidence interval, 2.8-4.4), and an offspring relative risk of 1.8 (1.0-2.7). Familial RLS is a chronic disorder with a mean (SD) disease duration of 24 (16) years and a wide range of age of onset (mean [SD], 28 [15] years), with most family members having early-onset disease but mild to moderate RLS symptoms. Our clinical data also indicated that fRLS is more prominent among women who also had increased incidence of anemia/iron deficiency, arthritis, and number of pregnancies. Pregnancy-related RLS seems to be a characteristic feature of fRLS, and afflicted women tend to have a much younger age of onset.

Conclusions: Restless legs syndrome significantly aggregated in families with variable phenotypic expressivity, and the siblings of severely affected individuals have an increased risk of developing the disease.