The cerebellum is increasingly recognised as a "common denominator" and critical node in the pathophysiology of both cortical and subcortical myoclonus disorders (Latorre et al. 2020; Riva et al. 2024). While the primary generator of jerks may reside in the cortex or brainstem, advanced neuroimaging and genetic studies suggest that cerebellar dysfunction often drives the hyperexcitability and rhythmicity observed in these movements (Latorre et al. 2020).

Pathophysiological mechanisms

• The cerebello-thalamo-cortical (CTC) projection: This pathway is considered a central circuit for myoclonus. It is proposed that abnormal activity in the CTC projection reduces intracortical inhibition, thereby facilitating the cortical discharges that produce jerks (Latorre et al. 2020).
• Gain control and reflex myoclonus: The cerebellum plays a prominent role in motor adaptation and adjusting the gain of long-latency stretch reflexes (LLSR) (Latorre et al. 2020). If cerebellar drive is impaired, the gain of sensorimotor connections increases, transforming a normal afferent volley into an abnormal burst of excitation (reflex myoclonus) (Latorre et al. 2020). Supporting this, patients with cerebellar cortex atrophy demonstrate significantly enhanced LLSRs (Latorre et al. 2020).
• Rhythmicity in cortical tremor: The cerebellum is essential for the rhythmicity that distinguishes cortical tremor from arrhythmic cortical myoclonus (Latorre et al. 2020). Pre-existing CTC loops likely provide feedback following a cortical discharge, reactivating the focus in the motor cortex and resulting in sustained rhythmic muscle jerking (Latorre et al. 2020).

Genetic and pathological evidence

Recent genetic breakthroughs in familial cortical myoclonic tremor and epilepsy (FCMTE) have placed the cerebellum at the epicentre of the disorder:

• Gene expression: Candidate genes for FCMTE (such as SAMD12, STARD7, MARCH6, and YEATS2) are highly expressed in the cerebellum (Latorre et al. 2020).
• Purkinje cell pathology: In various FCMTE pedigrees, neuropathological findings include RNA foci in Purkinje cells, severe Purkinje cell loss with dendritic sprouts, and neuronal loss in the dentate nucleus (Latorre et al. 2020). These changes suggest that RNA-mediated toxicity in the cerebellum is a primary driver of the cortical hyperexcitability seen in the disease (Latorre et al. 2020).
• Bi-brachial synchronisation: One study identified bi-brachially coherent 8–9 Hz cortical tremor EMG bursts, suggesting a cerebellar-integral node that synchronises descending activity from the motor cortices of both hemispheres (Latorre et al. 2020).

Cerebellar involvement in specific disorders

• Prion diseases (CJD): Cerebellar signs and ataxia are hallmark features of Creutzfeldt-Jakob Disease. Neuropathology shows diffuse PrPSc deposits in the molecular layer of the cerebellum (synaptic) and compact amyloid plaques between the granular and Purkinje cell layers, particularly in the MV2 subtype (Jurcau 2024). In the VV2 subtype, involvement of the cerebellum and basal ganglia often results in ataxia as the presenting symptom (Jurcau 2024).
• Autoimmune encephalitis: Antibodies targeting cerebellar receptors, such as mGLUR1, present almost exclusively with cerebellar ataxia and atrophy (Jurcau 2024). Similarly, GFAP-related encephalitis often shows hyperintensities in the posterior thalamus and results in tremor, myoclonus, and ataxia (Jurcau 2024).
• Dementia syndromes: In patients with Down Syndrome who develop myoclonic epilepsy over age 40 (LOMEDS), cerebellar signs typically emerge as the condition progresses toward severe dementia and global decline (Riva et al. 2024).
• Secondary atrophy: While myoclonus in Alzheimer's disease is primarily cortical, some studies have noted neuronal loss in the parietal cortex and para-hippocampal gyrus that may interact with subcortical structures like the cerebellum to modify the clinical presentation of jerks (Kalyvas et al. 2024).