Dystonia

Sustained or intermittent involuntary muscle contractions producing abnormal, often repetitive movements or postures. Dystonia can be focal (cervical, blepharospasm, writer's cramp, oromandibular), segmental (contiguous body regions), multifocal, hemidystonia (one side; suggests structural lesion), or generalized. Onset can be acute (drug-induced reaction, dystonic crisis in glutaric aciduria type 1), subacute (autoimmune, toxic), or chronic and progressive (most genetic forms). Mixed phenomenology with myoclonus, parkinsonism, or chorea is common; the goal is to recognize the treatable entities before everything else.

A single rule structures the bedside approach: trial L-DOPA in any child or adolescent with otherwise unexplained dystonia. Dopa-responsive dystonia (Segawa syndrome) (GCH1, AD with female predominance and incomplete penetrance) presents as lower-limb dystonia with diurnal variation (worse in the evening) and dramatic, near-complete, sustained response to low-dose levodopa. Missing it commits a child to a lifetime of misdiagnosed cerebral palsy.

After the L-DOPA trial, organize by:

1. Age of onset. Childhood and adolescent onset is more often genetic and more often generalized. Adult onset is more often focal / segmental and more often acquired or idiopathic.
2. Body distribution and progression. Lower-limb start with caudal spread suggests DYT1 (TOR1A). Cervical or cranial start in adulthood suggests primary focal / segmental idiopathic dystonia or genetic adult-onset forms (THAP1, ANO3, GNAL).
3. Mixed phenotype. Dystonia + parkinsonism → DRD, Wilson, juvenile Parkinson, NBIA. Dystonia + chorea → Huntington, Lesch-Nyhan, neuroacanthocytosis. Dystonia + myoclonus → myoclonus-dystonia (SGCE, paternal-only expression). Dystonia + ataxia → mitochondrial, NPC, AOA2. Dystonia + cognitive decline → Wilson, NBIA, neurodegeneration.
4. Treatable causes always first. DRD (L-DOPA), Wilson disease (chelation), biotin-thiamine-responsive basal ganglia disease (SLC19A3, biotin + thiamine), GLUT1 deficiency (ketogenic diet), tardive / drug-induced (withdraw offender), psychogenic / functional.

Treatable / must-not-miss

• Dopa-responsive dystonia (GCH1, AR TH / SPR variants): lower-limb dystonia with diurnal variation; relentless misdiagnosis as cerebral palsy when L-DOPA trial is omitted. A single dose can be illuminating; full benefit takes days to weeks.
• Wilson disease (ATP7B): must rule out in any patient under 50 with new dystonia, tremor, dysarthria, or parkinsonism. KF rings on slit-lamp, low ceruloplasmin (< 20), elevated 24-h urine copper (> 100 μg), hepatic involvement common. Treatment: chelation (penicillamine, trientine) plus zinc; lifelong.
• Biotin-thiamine-responsive basal ganglia disease (SLC19A3): episodic encephalopathy with dystonia, dysphagia, dysarthria, often triggered by febrile illness. Responds dramatically to biotin and thiamine.
• GLUT1 deficiency (SLC2A1): paroxysmal exercise-induced dystonia or generalized dystonia; low CSF glucose. Ketogenic diet.
• Drug-induced (tardive) dystonia: dopamine receptor antagonists (antipsychotics, metoclopramide, prochlorperazine), antiemetics. Acute dystonic reaction: anticholinergics (diphenhydramine, benztropine).

Inherited isolated dystonia

• DYT1 / TOR1A dystonia (GAG deletion in TOR1A, AD, reduced penetrance ~30%): classic early-onset generalized dystonia, lower-limb onset (foot inversion in childhood), caudal-to-rostral spread. Ashkenazi Jewish founder mutation. Most childhood-onset generalized dystonia is DYT1.
• DYT6 (THAP1, AD): cranial / cervical onset, mixed adolescent / adult.
• DYT25 (GNAL, AD): adult-onset cervical / cranial.
• DYT24 (ANO3, AD): adult-onset cervical with tremor.

Inherited combined dystonia syndromes

• Myoclonus-dystonia (SGCE, paternal-only expression because of maternal imprinting): rapid jerky movements plus dystonia, alcohol-responsive, often psychiatric comorbidity. Inherits through fathers; can skip through unaffected obligate-carrier mothers.
• Rapid-onset dystonia-parkinsonism (DYT12, ATP1A3): sudden onset over hours to days, often triggered by stress / fever, with rostrocaudal gradient and parkinsonism.

Neurodegeneration with brain iron accumulation (NBIA)

• PKAN (PANK2): dystonia, dysarthria, dysphagia, retinal degeneration. Eye-of-the-tiger sign on MRI (T2 hypointensity of the globus pallidus with central hyperintensity) is virtually pathognomonic.
• PLAN (PLA2G6): infantile neuroaxonal dystrophy or atypical NAD with regression, ataxia, dystonia.
• Beta-propeller-associated neurodegeneration (BPAN, WDR45): static encephalopathy in childhood followed by adolescent / adult dystonia-parkinsonism with dementia.
• MPAN, FAHN, Kufor-Rakeb, aceruloplasminemia: additional NBIA subtypes.

Metabolic / lysosomal

• Glutaric aciduria type 1 (GCDH): macrocephalic infant who develops dystonic crisis after a febrile illness, with bilateral striatal injury. Newborn screening prevents most cases. Lysine-restricted diet plus carnitine.
• Niemann-Pick disease type C: dystonia + vertical supranuclear gaze palsy + splenomegaly + gelastic cataplexy; treatable with miglustat.
• GM1 / GM2 gangliosidoses, late-onset: dystonia in adolescents and young adults, often with motor neuron findings.
• Lesch-Nyhan syndrome (HPRT1, X-linked): dystonia, choreoathetosis, self-injurious behavior, hyperuricemia.

Mitochondrial

• Leigh syndrome: dystonia + brainstem / basal ganglia T2 lesions + lactic acidosis.
• MELAS, POLG-related disorders, MERRF: dystonia as one component of multisystem mitochondrial disease.

Juvenile and early-onset parkinsonism with dystonia

Dystonia is often the presenting feature of juvenile-onset Parkinson disease, particularly in AR forms.

• PRKN (PARK2): AR, most common cause of juvenile Parkinson, dystonia + bradykinesia, excellent L-DOPA response.
• PINK1, DJ1, ATP13A2 (Kufor-Rakeb), FBXO7: other AR juvenile parkinsonism genes; some have dystonia, dementia, pyramidal signs.
• LRRK2, SNCA: AD adult-onset; dystonia uncommon at onset.
• See also Parkinson disease.

Acquired and structural

• Hemidystonia after stroke or perinatal injury: structural lesion in the contralateral basal ganglia.
• Tardive / drug-induced (see above).
• Autoimmune: anti-NMDA receptor encephalitis, anti-LGI1, post-streptococcal (Sydenham, PANDAS-spectrum).
• Functional / psychogenic dystonia: abrupt onset, fixed posture, distractibility, incongruence with organic patterns. A real diagnosis with real treatment, not a label of last resort.

1. L-DOPA trial at low dose with clinical follow-up over weeks. Many clinicians treat for 6-8 weeks before calling the trial negative.
2. Wilson workup: slit-lamp for KF rings, ceruloplasmin, 24-h urine copper, liver enzymes. If equivocal, hepatic copper on biopsy.
3. MRI brain. Eye-of-the-tiger (PKAN), bilateral striatal injury (GA1, post-illness), T2 lesions of basal ganglia / brainstem (Leigh), corpus callosum / cerebellar findings (mitochondrial), iron accumulation patterns (NBIA family).
4. Targeted metabolic: lactate, ammonia, plasma amino acids, urine organic acids, acylcarnitines, copper / ceruloplasmin, uric acid (Lesch-Nyhan), CSF studies (GLUT1 ratio, neurotransmitter metabolites).
5. Dystonia gene panel or exome: age, distribution, and family history target the genes. TOR1A for childhood-onset generalized. GCH1 and TH/SPR for DRD (even if L-DOPA trial response is good, confirms diagnosis). SGCE for myoclonus-dystonia (remember imprinting on the pedigree). NBIA gene panel if MRI suggests iron accumulation. Juvenile Parkinson panel for early-onset parkinsonism-dystonia.
6. EEG and overnight polysomnography if paroxysmal events or possible epileptic component.
7. CSF neurotransmitters and pterins if DRD or related disorders suspected and L-DOPA equivocal; biopterin metabolism testing.