Purkinje cell pathologies contribute to myoclonus development primarily by disrupting the cerebello-thalamo-cortical (CTC) projection, a circuit that regulates the excitability of the sensorimotor cortex (Latorre et al. 2020). When Purkinje cells are damaged or lost, the cerebellum's ability to provide inhibitory drive to the motor cortex is impaired, leading to the hyperexcitability that characterizes cortical myoclonus (Latorre et al. 2020).

Pathomechanisms in Purkinje cells

• RNA-mediated toxicity: In disorders like familial cortical myoclonic tremor and epilepsy (FCMTE), non-coding repeat expansions lead to the formation of RNA foci within Purkinje cells (Latorre et al. 2020). These foci are believed to drive the pathogenesis of the disease through RNA-mediated toxicity (Latorre et al. 2020).
• Structural degeneration: Neuropathological studies in FCMTE patients have revealed significant structural abnormalities, including mild to severe Purkinje cell loss and the development of dendritic sprouts (Latorre et al. 2020). In some cases, halo-like amorphous material is observed around the cytoplasm of these cells (Latorre et al. 2020).
• Genetic overlap: Similar Purkinje cell degeneration is observed in other pentanucleotide-repeat expansion disorders, such as spinocerebellar ataxia type 31 (SCA31), suggesting shared pathological mechanisms between some cerebellar ataxias and cortical myoclonus syndromes (Latorre et al. 2020).

Impact on motor control and myoclonus

• Loss of gain control: The cerebellum normally adjusts the gain of long-latency stretch reflexes (LLSR) (Latorre et al. 2020). Purkinje cell pathology increases the gain of sensorimotor connections, which transforms normal sensory input into the abnormal bursts of excitation seen in reflex myoclonus (Latorre et al. 2020).
• Reduced intracortical inhibition: A decrease in cerebellar drive (resulting from Purkinje cell loss) reduces intracortical inhibition within the primary motor cortex (M1) (Latorre et al. 2020). This lack of inhibition allows cortical discharges to manifest as rhythmic or arrhythmic jerks (Latorre et al. 2020).
• Rhythmicity and tremor: Pre-existing CTC loops are essential for the rhythmicity of cortical tremor (Latorre et al. 2020). It is proposed that these loops provide feedback following an initial cortical discharge, reactivating the focus in the motor cortex and sustaining a rhythmic tremulous movement (Latorre et al. 2020).

Involvement in specific disorders

• Creutzfeldt-Jakob Disease (CJD): In some subtypes of CJD (particularly MV2), compact amyloid plaques formed by PrPSc aggregates are located specifically between the granular and Purkinje cell layers of the cerebellar cortex (Jurcau 2024).
• Late-onset myoclonic epilepsy in down syndrome (LOMEDS): As this condition progresses, cerebellar signs and global decline become evident, often following the development of persistent myoclonic jerks (Riva et al. 2024).