Dystonia

Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions occur involuntarily, resulting in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often intensified or exacerbated by physical activity, and symptoms may progress into adjacent muscles.
The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to pharmaceutical drugs, particularly neuroleptics, or stress. Treatment must be highly customized to the needs of the individual and may include oral medications, chemodenervation botulinum neurotoxin injections, physical therapy, or other supportive therapies, and surgical procedures such as deep brain stimulation.

Classification

There are multiple types of dystonia, and many diseases and conditions may cause dystonia. Dystonia is classified by clinical characteristics such as age of onset, body distribution, nature of the symptoms, and associated features such as additional movement disorders or neurological symptoms. It is also classified by cause, which includes changes or damage to the nervous system and inheritance. Types include generalized dystonia, [|focal dystonia], psychogenic dystonia, acute dystonic reaction, and vegetative-vascular dystonia.

Generalized dystonias

For example, in dystonia musculorum deformans, also known as torsion dystonia or idiopathic torsion dystonia,

Focal dystonias

These most common dystonias are typically classified as follows:

Name	Location	Description
Anismus	muscles of the rectum	Causes painful defecation, constipation; may be complicated by encopresis or fecal incontinence.
Cervical dystonia	muscles of the neck	Causes the head to rotate to one side, to pull down towards the chest, or back, or a combination of these postures.
Blepharospasm	muscles around the eyes	The patient experiences rapid blinking of the eyes or even their forced closure causing functional blindness.
Oculogyric crisis	muscles of eyes and head	An extreme and sustained upward deviation of the eyes often with convergence causing diplopia. It is frequently associated with backward and lateral flexion of the neck and either widely opened mouth or jaw clenching. Frequently a result of antiemetics such as the neuroleptics or metoclopramide. Can be caused by Chlorpromazine.
Oromandibular dystonia	muscles of the jaw and muscles of tongue	Causes distortions of the mouth and tongue.
Spasmodic dysphonia/Laryngeal dystonia	muscles of larynx	Causes the voice to sound broken, become hoarse, sometimes reducing it to a whisper.
Focal hand dystonia.	single muscle or small group of muscles in the hand	It interferes with activities such as writing or playing a musical instrument by causing involuntary muscular contractions. The condition is sometimes "task-specific", meaning that it is generally apparent during only certain activities. Focal hand dystonia is neurological in origin and is not due to normal fatigue. The loss of precise muscle control and continuous unintentional movement results in painful cramping and abnormal positioning that makes continued use of the affected body parts impossible.

The combination of blepharospasmodic contractions and oromandibular dystonia is called cranial dystonia or Meige's syndrome.

Genetic/primary

Symbol	OMIM	Gene	Locus	Alt Name
DYT1		TOR1A	9q34	Early-onset torsion dystonia
DYT2		HPCA	1p35-p34.2	Autosomal recessive primary isolated dystonia
DYT3		TAF1	Xq13	X-linked dystonia parkinsonism
DYT4		TUBB4	19p13.12-13	Autosomal dominant whispering dysphonia
DYT5a		GCH1	14q22.1-q22.2	Autosomal dominant dopamine-responsive dystonia
DYT5b		TH	11p15.5	Autosomal recessive dopamine-responsive dystonia
DYT6		THAP1	8p11.21	Autosomal dominant dystonia with cranio-cervical predilection
DYT7		unknown	18p	Autosomal dominant primary focal cervical dystonia
DYT8		MR1	2q35	Paroxysmal nonkinesigenic dyskinesia
DYT9		SLC2A1	1p35-p31.3	Episodic choreoathetosis/spasticity
DYT10		PRRT2	16p11.2-q12.1	Paroxysmal kinesigenic dyskinesia
DYT11		SGCE	7q21	Myoclonic dystonia
DYT12		ATP1A3	19q12-q13.2	Rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood
DYT13		unknown, near D1S2667	1p36.32-p36.13	Autosomal dominant cranio-cervical/upper limb dystonia in one Italian family
DYT14	See DYT5
DYT15		unknown	18p11	Myoclonic dystonia not linked to SGCE mutations
DYT16		PRKRA	2q31.3	Autosomal recessive young onset dystonia parkinsonism
DYT17		unknown, near D20S107	20p11.2-q13.12	Autosomal recessive dystonia in one family
DYT18		SLC2A1	1p35-p31.3	Paroxysmal exercise-induced dyskinesia
DYT19		probably PRRT2	16q13-q22.1	Episodic kinesigenic dyskinesia 2, probably synonymous with DYT10
DYT20		unknown	2q31	Paroxysmal nonkinesigenic dyskinesia 2
DYT21		unknown	2q14.3-q21.3	Late-onset torsion dystonia
DYT24		ANO3	11p14.2	Autosomal dominant cranio-cervical dystonia with prominent tremor

There is a group called myoclonic dystonia where some cases are hereditary and have been associated with a missense mutation in the dopamine-D2 receptor. Some of these cases have responded well to alcohol.
Other genes that have been associated with dystonia include CIZ1, GNAL, ATP1A3, and PRRT2. Another report has linked THAP1 and SLC20A2 to dystonia.

Signs and symptoms

Symptoms vary according to the kind of dystonia involved. In most cases, dystonia tends to lead to abnormal posturing, in particular on movement. Many individuals with the condition have continuous pain, cramping, and relentless muscle spasms due to involuntary muscle movements. Other motor symptoms are possible including lip smacking.
An accurate diagnosis may be difficult because of the way the disorder manifests itself. Affected individuals may be diagnosed as having similar and perhaps related disorders including Parkinson's disease, essential tremor, carpal tunnel syndrome, temporomandibular joint disorder, Tourette's syndrome, conversion disorder or other neuromuscular movement disorders. It has been found that the prevalence of dystonia is high in individuals with Huntington's disease, where the most common clinical presentations are internal shoulder rotation, sustained fist clenching, knee flexion, and foot inversion. Risk factors for increased dystonia in patients with Huntington's disease include long disease duration and use of antidopaminergic medication.

Causes

Primary dystonia is suspected when the dystonia is the only sign and there is no identifiable cause or structural abnormality in the central nervous system. Researchers suspect it is caused by a pathology of the central nervous system, likely originating in those parts of the brain concerned with motor function—such as the basal ganglia and the GABA producing Purkinje neurons. The precise cause of primary dystonia is unknown. In many cases it may involve some genetic predisposition towards the disorder combined with environmental conditions.
Meningitis and encephalitis caused by viral, bacterial, and fungal infections of the brain have been associated with dystonia. The main mechanism is inflammation of the blood vessels, causing restriction of blood flow to the basal ganglia. Other mechanisms include direct nerve injury by the organism or a toxin, or autoimmune mechanisms.
Malfunction of the sodium-potassium pump may be a factor in some dystonias. The - pump has been shown to control and set the intrinsic activity mode of cerebellar Purkinje neurons. This suggests that the pump might not simply be a homeostatic, "housekeeping" molecule for ionic gradients; but could be a computational element in the cerebellum and the brain. Indeed, an ouabain block of - pumps in the cerebellum of a live mouse results in it displaying ataxia and dystonia. Ataxia is observed for lower ouabain concentrations, dystonia is observed at higher ouabain concentrations. A mutation in the - pump can cause rapid onset dystonia parkinsonism. The parkinsonism aspect of this disease may be attributable to malfunctioning - pumps in the basal ganglia; the dystonia aspect may be attributable to malfunctioning - pumps in the cerebellum possibly in Purkinje neurons.
Cerebellum issues causing dystonia is described by Filip et al. 2013: "Although dystonia has traditionally been regarded as a basal ganglia dysfunction, recent provocative evidence has emerged of cerebellar involvement in the pathophysiology of this enigmatic disease. It has been suggested that the cerebellum plays an important role in dystonia etiology, from neuroanatomical research of complex networks showing that the cerebellum is connected to a wide range of other central nervous system structures involved in movement control to animal models indicating that signs of dystonia are due to cerebellum dysfunction and completely disappear after cerebellectomy, and finally to clinical observations in secondary dystonia patients with various types of cerebellar lesions. It is proposed that dystonia is a large-scale dysfunction, involving not only cortico-basal ganglia-thalamo-cortical pathways, but the cortico-ponto-cerebello-thalamo-cortical loop as well. Even in the absence of traditional "cerebellar signs" in most dystonia patients, there are more subtle indications of cerebellar dysfunction. It is clear that as long as the cerebellum's role in dystonia genesis remains unexamined, it will be difficult to significantly improve the current standards of dystonia treatment or to provide curative treatment."