What Causes Essential Tremor
Essential tremor is a complex and heterogeneous neurological disorder whose exact cause remains largely unknown, though it appears to involve a combination of genetic factors and possible environmental influences, with recent evidence increasingly pointing to cerebellar degeneration and dysfunction as the primary pathological mechanism. 1, 2
Genetic Factors
- Essential tremor demonstrates significant genetic heterogeneity, with autosomal dominant inheritance patterns observed in many families. 3
- Three distinct chromosomal loci have been linked to essential tremor: ETM1 on chromosome 3q13, ETM2 on chromosome 2p24.1, and a locus on chromosome 6p23, though specific causative genes have not yet been identified. 4
- A Ser9Gly variant in the dopamine D3 receptor gene on chromosome 3q13 has been suggested as a potential risk factor. 4
- The genetic complexity is underscored by multiple negative genetic studies, indicating that essential tremor likely involves multiple genetic pathways rather than a single gene defect. 1
Pathophysiological Mechanisms
- Recent research increasingly localizes the disease to the cerebellum and cerebellar system, with evidence of neurodegenerative changes within cerebellar structures. 2
- Two distinct neuropathological subtypes have been identified: one associated with cerebellar Purkinje cell pathology and another with brain stem Lewy bodies, suggesting essential tremor may actually represent a family of related diseases rather than a single entity. 3
- GABAergic mechanisms have been implicated based on animal model studies, though the exact receptor disturbances remain incompletely understood. 1
- There is ongoing debate about whether essential tremor represents true neurodegeneration versus a functional disturbance of neural circuits or receptors, with conflicting results from neuropathologic and imaging studies. 1
Environmental and Risk Factors
- While environmental agents have been proposed as potential contributors, specific toxic exposures have not been definitively established as causative factors. 4
- Essential tremor itself appears to be a risk factor for developing other degenerative diseases, including Alzheimer's disease and Parkinson's disease. 2
Clinical Heterogeneity and Diagnostic Challenges
- The traditional view of essential tremor as a single disease entity has been replaced by recognition that it represents a complex, heterogeneous syndrome with variable clinical presentations. 1
- This heterogeneity extends beyond tremor characteristics to include non-tremor manifestations such as cerebellar signs, neuropsychological features, distinct personality traits, and behavioral symptoms. 1
- The lack of objective diagnostic tests and standardized diagnostic criteria contributes to conflicting research findings, as patient selection varies significantly across studies. 1