What are the causes of dystonia?

Causes of Dystonia

Dystonia can be caused by genetic mutations, medication side effects, neurological disorders, or acquired brain injuries, with primary genetic forms being the most common cause of isolated dystonia. 1, 2

Primary Causes of Dystonia

Genetic Causes

• Mutations in several genes have been identified as causes of dystonia, including:
  • PRRT2 - the major causative gene for paroxysmal kinesigenic dyskinesia (PKD), a form of dystonia 1
  • TOR1A, THAP1, GCH1, and KMT2B - common genetic causes of isolated dystonia 2
  • Other genes including ANO3, HPCA, GNAL, EIF2AK2, PRKRA, and VPS16 3
• Genetic dystonias can be inherited in autosomal dominant patterns with incomplete penetrance (60-90%) 1
• Molecular mechanisms of genetic dystonias involve abnormalities in:
  • Transcriptional regulation during neurodevelopment 3
  • Striatal dopaminergic signaling 2, 3
  • Synaptic plasticity 2
  • Calcium homeostasis 3
  • Endoplasmic reticulum stress response 3
  • Autophagy 3

Clinical Classification

• Pure/isolated dystonia - presents only with dystonic movements without other neurological symptoms 1, 4
• Complicated/combined dystonia - presents with dystonia plus additional neurological symptoms such as:
  • Benign familial infantile epilepsy
  • Febrile convulsion
  • Migraine or hemiplegic migraine
  • Episodic ataxia
  • Developmental delay
  • Intellectual deficit
  • Language dysfunction
  • Autism 1, 4

Secondary Causes of Dystonia

Medication-Induced Dystonia

• Antipsychotic medications - particularly first-generation/typical antipsychotics 1
  • Acute dystonia occurs in the first few doses or after dose increases 1
  • Risk factors include young age, male gender, and use of high-potency agents 1
  • Can manifest as involuntary motor tics or spasms involving face, extraocular muscles (oculogyric crisis), neck, back, and limb muscles 1
  • Laryngeal dystonia is a rare but potentially life-threatening adverse event 1
• Tardive dystonia/dyskinesia - associated with long-term use of neuroleptics 1
  • Occurs in approximately 5% of young patients per year 1
  • More common with older "typical" antipsychotics 1
  • Characterized by involuntary facial movements and extremity/truncal movements 1

Neurological Disorders

• Wilson's disease - characterized by copper accumulation that can cause dystonia 1
  • Dystonia can be an early neurological manifestation
  • Can present as akinetic-rigid syndrome, pseudosclerosis with tremor, ataxia, or dystonic syndrome 1
  • Focal, segmental, or severe dystonia involving all body parts 1
• Parkinson's disease and parkinsonism 1
• Spasmodic dysphonia - a form of laryngeal dystonia 1
• Essential tremor 1
• Amyotrophic lateral sclerosis 1
• Multiple sclerosis 1

Other Medical Conditions

• Cerebrovascular disease/stroke 1
• Metabolic disorders:
  • Hyperthyroidism
  • Calcium-phosphate metabolism disorders (hypoparathyroidism, pseudoparathyroidism)
  • Glucose metabolism disorders
  • Kernicterus 1
• Brain trauma 1
• Gastroesophageal reflux (Sandifer syndrome) - causes paroxysms of head tilt in young children 1
• Rheumatologic/autoimmune conditions:
  • Rheumatoid arthritis
  • Sjögren's syndrome
  • Sarcoidosis
  • Amyloidosis
  • Granulomatosis with polyangiitis 1

Age-Related Forms

• Transient dystonia of infancy - paroxysmal episodes of abnormal upper limb posture with trunk/lower limb involvement 1
  • Onset between 5-10 months, resolves between 3 months and 5 years 1
• Benign paroxysmal torticollis - recurrent episodes of abnormal head postures in infants 1
  • Onset before 3 months of age 1

Pathophysiology

• Dystonia results from dysfunctional networks involving:
  • Basal ganglia
  • Cerebellum
  • Thalamus
  • Cortex 3
• Loss of inhibition at neuronal circuits is a key mechanism 2
• Abnormalities in brain motor networks occur in the context of genetic factors 4
• Musculoskeletal tension with excessive recruitment in affected muscles (as in muscle tension dysphonia) 1

Clinical Presentations

• Dystonia can manifest as:
  • Dystonic movements - sustained or intermittent muscle contractions causing abnormal postures 2
  • Chorea - irregular, flowing movements 1
  • Ballism - large amplitude, flinging movements 1
  • Mixed forms 1
• Distribution can be:
  • Focal - affecting one body region
  • Segmental - affecting adjacent body regions
  • Multifocal - affecting non-adjacent body regions
  • Generalized - affecting multiple body regions 4
• Some forms only occur during specific tasks (task-specific dystonia) 4

Understanding the diverse causes of dystonia is crucial for proper diagnosis and treatment planning, as management approaches differ significantly depending on the underlying etiology 4, 5.