Genetic Tremors: Causes and Mechanisms
Genetic tremors are primarily caused by inherited mutations in specific genes that affect neuronal function, with essential tremor (ET) being the most common genetic tremor disorder, inherited in an autosomal dominant pattern with high penetrance by age 65. 1
Primary Genetic Causes
Essential Tremor Gene Mutations
Autosomal dominant inheritance is the predominant pattern, with virtually complete penetrance by age 65 years and no generation-skipping observed in affected families 1
Multiple genetic loci have been identified, including FET1 mapped to chromosome 3q13, though significant genetic heterogeneity exists suggesting additional unmapped loci 2, 3
Candidate genes identified through whole-exome sequencing in early-onset ET families include:
Repeat expansion mutations may underlie some familial ET cases, with evidence of anticipation (earlier onset in successive generations) in certain families, though large CAG expansions have been excluded 5, 3
Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
FMR1 gene premutations (CGG repeat expansions) cause FXTAS, characterized by late-onset progressive intention tremor and ataxia 6
X-linked inheritance with higher penetrance in males carrying premutations compared to females, and penetrance increases with age and repeat length 6
Mechanism involves loss of FMRP (fragile X mental retardation protein), an RNA-binding protein that regulates translation in neuronal dendrites and synaptic function 6
Pathophysiological Mechanisms
Cerebellar Dysfunction
Purkinje cell degeneration and reduced GABA-ergic tone in the cerebellum represent the primary pathophysiological process in genetic essential tremor 4
Neurotransmitter dysregulation occurs through mutations affecting nitric oxide synthesis and GABA system function in cerebellar circuits 4
Ion Channel and Calcium Homeostasis
Ion channel gene mutations (including those causing long QT syndrome, Brugada syndrome) can manifest with tremor as part of genetic arrhythmia syndromes 6
Altered calcium handling in neurons may contribute to tremor generation through effects on spontaneous electrical activity 6
Clinical Genetic Patterns
Inheritance Characteristics
Equal sex distribution with men and women affected in equal proportions and equal severity 1
Bimodal age of onset with median around 15 years, though onset can occur throughout life 1
Normal biological fitness despite progressive disability, allowing transmission across multiple generations 1
Phenotypic Features
Postural tremor of upper limbs is the typical presentation, with possible involvement of head (predominantly "no-no" type), voice, jaw, and tongue, but never in isolation 1
Alcohol responsiveness occurs in approximately 50% of cases and tends to cluster within families, though 20% of kindreds show heterogeneity 1
Progressive disability beginning in the second decade, with severity increasing with age and tremor duration rather than age of onset 1
Genetic Testing Considerations
Fragile X testing should include FMR1 gene analysis for males with tremor/ataxia, particularly with family history of X-linked neurodevelopmental disorders or FXTAS 6
Cascade genetic testing is recommended for family members when a pathogenic variant is identified in the proband 6
Genetic heterogeneity means that exclusion of known loci (2p, 3q) does not rule out genetic etiology, as additional unmapped loci likely exist 3, 5