Beyond RSWA in prodromal α-synuclein disease: Do periodic limb movements signal potential early dopaminergic dysfunction?

Isolated REM sleep behavior disorder (RBD) is an established prodromal biomarker of α-synucleinopathies. However, nearly half of Parkinson's disease patients will not exhibit iRBD or abnormal REM sleep without atonia (RSWA) at disease onset. The SYNONE skin biopsy, which detects phosphorylated α-synuclein in cutaneous nerves, provides objective evidence of pathology even in prodromal or asymptomatic stages. We describe two SYNONE-positive individuals without RSWA and markedly elevated periodic limb movement indices (PLMI >100) and mild restless legs syndrome (RLS). However, another patient with PLMI of 84 tested negative on SYN-One Test. RSWA was assessed using both conventional and automated REM atonia index scoring. To our knowledge, SYNONE-positive and RSWA-negative presentations have not been previously reported. The markedly elevated PLMI may reflect an early sign of dopaminergic dysfunction in the amygdala or spinal cord predominant disease. Longitudinal follow up and further investigation are needed to delineate spatiotemporal progression and clinical evolution.