Restless legs syndrome in DNAJC12 deficiency

Background: Restless legs syndrome (RLS) is characterized by an unpleasant or painful sensation generally localized to lower limbs and relieved by movement. Its pathogenesis is hypothesized to involve the dopaminergic system, also in the light of the response of RLS to ex adiuvantibus treatment with dopamine agonists. DNAJC12 deficiency is a recently identified inherited metabolic disease coupling hyperphenylalaninemia to deficient dopaminergic and serotoninergic neurotransmission, due to the combined impairment of the three aromatic amino acids' (i.e., phenylalanine, tyrosine, and tryptophan) hydroxylases. DNAJC12 deficiency was reported in 43 patients so far, presenting with wide spectrum of clinical symptoms.

Case presentation results: Here, we report RLS as a novel clinical manifestation of DNAJC12 deficiency, occurring in two adults while on treatment with L-dopa at longitudinal follow-up. The adjunct of low-dose pramipexole was effective in both patients to treat RLS. Besides, this treatment also allowed an improvement of dopaminergic homeostasis, as evidenced by clinical amelioration and stabilization of a peripheral short prolactin profile (a tool to indirectly evaluate dopaminergic homeostasis).

Discussion: Besides including RLS as a new treatable clinical manifestation of DNAJC12, these observations may suggest the opportunity of a selective screening for DNAJC12 deficiency in patients with idiopathic RLS.