Clinical Manifestations

Dystonia is a disorder of movement characterized by "involuntary, sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements, or abnormal postures" [Ad Hoc Committee 1984, Fahn et al 1987].

Individuals with dystonia have tightening, cramping, twisting, or abnormal postures in the affected body part. Impairment or loss of function of the affected body part may occur. Dystonic movements range from athetosis to rapid, shock-like myoclonic jerks. They are repetitive and sometimes rhythmic, and they may be accompanied by tremor. Dystonic movements tend to be aggravated by movement ("action dystonia") and the affected individual may initially note symptoms related to a specific movement. Such movement may be nonspecific or may be task specific (e.g., writing but not feeding, walking forward but not backward, playing the piano but not the organ, sewing but not knitting). Over time the dystonia occurs with less specific movements and eventually may occur at rest and cause sustained abnormal postures. Cervical dystonia (spasmodic torticollis), one of the most common types, includes twisting or jerking of the head, head tremor, neck pain, and considerable social and psychological disability [Dauer et al 1998]. Pain is not usually prominent in other types of dystonia.

Relieving factors. Dystonic muscle contractions are often relieved by tactile or proprioceptive sensory tricks known as "gestes antagonistiques." For example, touching the chin with the hand to bring the head back into the midline position or resting the head backwards on a wall may temporarily improve cervical dystonia.

Precipitating factors. Dystonia tends to worsen with stress or fatigue and to improve or disappear with relaxation, hypnosis, or sleep. Once they appear, dystonic movements usually persist through life. About 10% of affected individuals, particularly those with cervical dystonia, may experience one or more periods of remission that may last for many years. Controversy exists as to whether peripheral nerve injury can precipitate dystonia [Jankovic 2001, Weiner 2001].

Dystonia can be classified by affected body part or age of onset:

• Affected body part (Table 1). The more body parts that are affected, the more severe the dystonia is likely to be. Onset of dystonia in the limbs, particularly the legs, is more likely to be associated with spread to other body parts and is therefore also associated with a more severe prognosis.

• Age of onset. Those dystonias with an earlier age of onset are also more likely to generalize and have a more severe course. Those dystonias in which onset occurs in childhood tend to be generalized (or are likely to become generalized) whereas dystonias in which onset occurs in adulthood tend to be focal and remain so [Ad Hoc Committee 1984].

Establishing the Diagnosis

The diagnosis of dystonia is primarily clinical. If the diagnosis is in doubt, review of the individual (or a videotape of the individual) by a physician experienced in movement disorders is warranted. As a general rule, all children with dystonia and all adults with generalized dystonia require prompt investigation. Adults with stable focal dystonia do not always need such extensive investigations, but should be monitored by a movement disorder specialist and the diagnosis reviewed if the symptoms spread or other neurologic features develop.

Differential Diagnosis

Neurologic conditions from which dystonia must be distinguished:

• Essential tremor. Cervical dystonia is sometimes confused with essential tremor, particularly if the voice (laryngeal dystonia) or hand ("dystonic hand tremor") are also affected. The latter tends to be of low amplitude and is regarded by some as an exaggerated physiologic tremor [Deuschl et al 1997]. Both essential tremor and cervical dystonia are aggravated by movement and stressful conditions, and in both, there may be a family history. The age of onset (adult, usually over age 50 years) is also similar. However, dystonic tremor tends to be more irregular and jerky. Dystonic tremor is less frequently responsive to alcohol or beta-blockers (except in myoclonus-dystonia). In cervical dystonia, hypertrophy of the neck muscles (e.g., sterno-cleido-mastoid, spenius capitis) often occurs.
• Cerebellar ataxia. Dystonic tremor can also be misdiagnosed as cerebellar ataxia (see Hereditary Ataxia Overview). Some individuals with generalized dystonia have been misdiagnosed with "olivopontocerebellar atrophy" based on tremor and gait disturbance. Individuals with dystonia do not have other signs of cerebellar disease such as dysmetria, dysdiadochokinesis, dysarthria, or nystagmus. Individuals who do have these signs are unlikely to have a true primary dystonia, and are much more likely to have one of the heredo-degenerative conditions or a non-genetic cause of dystonia.
• Tics/Gilles de la Tourette syndrome. The differentiation between tics and dystonia may be difficult, particularly in myoclonic dystonia, in which the myoclonic jerks may outwardly resemble the tics of Tourette syndrome. However, individuals with tics usually report an urge to move just prior to the movement. Tics are usually suppressible albeit briefly and tics persist during all stages of sleep. In addition to having a variety of motor tics, individuals with Tourette syndrome often have vocal tics, which may include throat clearing, sniffing, coughing, barking, whistling, or coprolalia (the urge to utter obscene words). For a full description of tics and Tourette syndrome, see Jankovic [1987].
• Cerebral palsy and other causes of spastic paraparesis. Common misdiagnoses are "dystonic cerebral palsy," "atypical" cerebral palsy, "atypical" hereditary spastic paraparesis, and parkinsonism (see Hereditary Spastic Paraplegia Overview). Any individual with a condition resembling cerebral palsy who does not have a clear history compatible with this diagnosis should be considered for a trial of L-dopa because of the possibility of dopa-responsive dystonia (see also Dystonia-Plus Syndromes).
• Parkinson disease. The tremor of adult-onset focal dystonia is occasionally mistaken for an early Parkinsonian tremor. Parkinsonian features are present in dopa-responsive dystonia in which tardive dyskinesias do not develop and parkinsonian features are less common. Dystonia, especially foot dystonia with sleep benefit, may be present in early-onset Parkinson disease, which is characterized by onset usually before age 40 years, rigidity, bradykinesia, rest tremor, and a good response to L-dopa but early development of dyskinesias [Tassin et al 1998]. Mutations in PARK2 (see Parkin Type of Juvenile Parkinson Disease), DJ-1 (PARK7), or PINK1 may cause early-onset Parkinson disease [Kitada et al 1998, Bonifati et al 2003, Valente et al 2004]. The overlapping clinical features of dopa-responsive dystonia and early-onset Parkinson disease may cause diagnostic confusion [Tassin et al 2000].
• Psychiatric disorders or non-organic dystonia. Nonorganic ("functional") dystonia is a well-recognized but rare psychiatric disorder; it is incumbent on the physician to exclude an organic cause for dystonia before diagnosing a non-organic cause. Particular confusion may arise in individuals with a previous psychiatric history who have been exposed to neuroleptic medication. Dystonia may also result in psychiatric disorders, especially depressive illness caused by pain and disability.
• Heredo-degenerative syndromes in which dystonia may be a feature but is not usually the prominent or presenting feature:
  • Autosomal dominant
    • Huntington disease (rarely presents with dystonia)
    • Spinocerebellar ataxias, especially SCA3 (Machado-Joseph disease; occasionally presents as dystonia)
    • Huntington disease like-2
    • DRPLA
    • Prion diseases
  • Autosomal recessive
    • Aceruloplasminemia
    • Aicardi-Goutières syndrome
    • Ataxia-telangiectasia
    • Ataxia with oculomotor apraxia type 1 (AOA1) and ataxia with oculomotor apraxia type 2 (AOA2)
    • Biotinidase deficiency
    • Biotin-responsive basal ganglia disease
    • Congenital disorders of glycosylation and congenital disorders of glycosylation type 1a
    • Friedreich ataxia
    • Fucosidosis
    • Gaucher disease type 3 (subacute neurologic type)
    • Glucose transporter 1 deficiency
    • Glutaric aciduria type 1 (see Organic Acidemias Overview)
    • GM1 gangliosidosis
    • GM2 gangliosidosis
    • Guanidinoacetate methyltransferase deficiency
    • Hartnup disease
    • Infantile bilateral striatal necrosis
    • Juvenile neuronal ceroid-lipofuscinosis
    • Lipoid proteinosis
    • Metachromatic leukodystrophy
    • Methylmalonic and proprionic acidemia (see Organic Acidemias Overview)
    • Niemann-Pick type A (see Acid Sphingomyelinase Deficiency)
    • Niemann-Pick disease type C
    • Purine nucleoside phosphorylase deficiency
    • Short-chain acyl-CoA dehydrogenase deficiency
    • Succinylsemialdehyde dehydrogenase deficiency
    • Sulfite oxidase and molybdenum cofactor deficiency
    • Triosephosphate isomerase deficiency
    • Ataxia with vitamin E deficiency
    • Wilson disease
  • X-linked
    • ARX-related disorders (X-linked infantile spasms and intellectual disability, often associated with dystonia)
    • Creatine-transporter (SLC6A8) deficiency (see Creatine Deficiency Syndromes)
    • Lesch-Nyhan syndrome
    • Pelizaeus-Merzbacher disease
    • Rett syndrome

Prevalence of Dystonia

Estimates of the prevalence of dystonia range from approximately 1:10,000 (service-based estimates) to more than 1:200 (population-based estimates) [Nutt et al 1988, Nakashima et al 1995, ESDE Collaborative Group 2000, Muller et al 2002]. Overall, the most common type is adult-onset focal dystonia.

Non-Genetic Dystonias

Symptomatic or secondary dystonias are those caused by an external insult. Non-genetic causes of dystonia include strokes or other ischemic events, demyelination, infections, tumors, drugs, and toxins. The most common type of secondary dystonia is drug induced (tardive dystonia). Drugs associated with tardive dystonia include antipsychotic medications, L-dopa, and some antiemetics. No underlying genetic basis for drug-induced dystonia is known.

Intraneuronal inclusion disease is a rare disorder of unknown cause that occurs in children.

Inherited Dystonias

Inherited dystonias can be classified as primary dystonia, dystonia-plus, heredo-degenerative dystonia, and paroxysmal dyskinesias with dystonia.

Primary Dystonias

The primary dystonias are those with no other neurologic abnormalities. Primary dystonias were originally described as "idiopathic" since no neurophysiologic, neurochemical, or pathologic findings provided clues to the underlying etiology; however, many are now known to have a genetic basis. The familial primary dystonias can be subdivided into predominantly generalized or predominantly focal groups. Sometimes, different individuals in the same family have different subtypes and in such cases the term "mixed" dystonia may be used, although there is no absolute distinction between the subtypes. The vast majority of primary dystonias are inherited in an autosomal dominant manner (see Table 2). The existence of an autosomal recessive type, dystonia 2 [OMIM 224500] is unproven. X-linked dystonia-parkinsonism, although formerly classified as a primary dystonia, is more appropriately classified as a heredo-degenerative disorder and is discussed in that subsection.

Early-onset primary dystonia (DYT1) typically presents before age 21 years with involuntary sustained muscle contractions that cause posturing of a foot, leg, or arm. The contractions frequently, but not invariably, generalize to other body regions. No other neurologic abnormalities are present, except for postural arm tremor. Disease severity varies considerably even within the same family. Isolated writer's cramp may be the only sign. DYT1 is the most common of the early-onset primary dystonias. DYT1 is diagnosed by molecular genetic testing of TOR1A, which reveals a three-base pair GAG deletion in all affected individuals.

Table 2. Clinical Features of Autosomal Dominant Primary Dystonia

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Type	Clinical Features	Epidemiology	Age of Onset	OMIM
Dystonia 1. Dystonia musculorum deformans; idiopathic torsion dystonia; Oppenheim's dystonia	Dystonia may present as focal dystonia, usually in the limbs; often generalizes especially if early-onset	50% of early-onset dystonia in non-Jews, 90% in Jews; prevalence of 1:10000-1:15000 in non-Jews, 1:3000-1:5000 in Jews	Usually childhood, may be later (most <26 years)	128100, 605204
Dystonia 4	Laryngeal and cervical dystonia	Single large Australian family	13-37 years	128101
Dystonia 6	Focal or generalized; cranial, cervical, or limb dystonia	Two Mennonite families	Average 19 years	602629
Dystonia 7	Focal dystonia (cervical and laryngeal dystonia) and postural tremor	Single German family	28-70 years	602124
Dystonia 13	Cranial or cervical dystonia; some focal, some generalized	Single Italian family	Five years to adulthood	607671

Table 3. Molecular Genetics of Autosomal Dominant Primary Dystonia

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Type	Locus Name	Gene Symbol	Chromosomal Locus	Protein Name	Test Availability
Dystonia 1	—	TOR1A	9q34	Torsin-1A	Clinical
Dystonia 4	DYT4	Unknown	Unknown	Unknown	Research only
Dystonia 6	—	THAP1	8p11.21	THAP domain-containing protein 1	Clinical
Dystonia 7	DYT7	Unknown	18p	Unknown	Research only
Dystonia 13	DYT13	Unknown	1p36.3-p36.1	Unknown

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

Dystonia-Plus Syndromes

Dopa-responsive dystonia (DRD, DYT5) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. This clinical syndrome typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and worsening of symptoms toward the evening and their alleviation in the morning after sleep (a phenomenon called diurnal fluctuation). The average age of onset of DRD is approximately six years. The female to male ratio is 3:1. Initial symptoms are gait difficulties attributable to dystonia in the leg, typically flexion-inversion (equinovarus posture) of the foot. Some individuals have onset with arm or neck dystonia, easy fatigability or muscle cramps without overt dystonia, postural tremor of the hand, or slowness of movements. Features suggestive of lower extremity spasticity (brisk deep-tendon reflexes, ankle clonus, and/or dystonic extension of the big toe (the striatal toe) are present in many affected individuals. Progression to generalized dystonia occurs in at least 76% of affected individuals. Cognitive function is normal. The clinical picture described above is typical for DRD caused by deficiency of GTP cyclohydrolase 1, which is inherited in an autosomal dominant manner; penetrance is incomplete [Ichinose et al 1994]. Deficiency of tyrosine hydroxylase (TH) with residual activity of the enzyme (the mild form of TH deficiency) is inherited in an autosomal recessive manner and may cause dystonia that is responsive to L-dopa [Blau et al 2001]. However, more often, TH deficiency causes a more severe progressive neurologic disorder in which dystonia is a minor feature, consisting of motor retardation, fluctuating extrapyramidal, ocular, and vegetative features, and intellectual disability that is only partially responsive to L-dopa.

The enzyme cyclohydrolase 1 (GTPCH1) catalyzes the first step in the biosynthesis of tetrahydrobiopterin (BH₄), the essential cofactor for TH. Measurement of the concentration of total biopterin (BP, most of which exists as BH₄) and neopterin (NP, the by-product of the GTPCH1 reaction) in CSF is useful for the diagnosis of GTPCH1-deficient DRD. In GTPCH1-deficient DRD, the concentrations of BP and NP in CSF are low, whereas in TH-deficient DRD, the concentrations of both BP and NP in CSF are normal. Mutations in GCH1 coding for the enzyme GTPCH1 can cause autosomal dominant DRD [Ichinose et al 1994], and mutations in TH coding for the enzyme TH can cause autosomal recessive DRD [Bartholomé & Ludecke 1998].

Myoclonus-dystonia (M-D, DYT11) is a movement disorder characterized by a combination of rapid, brief muscle contractions (myoclonus) and/or sustained twisting and repetitive movements that result in abnormal postures (dystonia). The myoclonic jerks typical of M-D most often affect the neck, trunk, and upper limbs with less common involvement of the legs. In approximately half of affected individuals, additional focal or segmental dystonia is found, presenting as cervical dystonia and/or writer's cramp. The most prominent non-motor features are psychiatric problems including depression, anxiety, obsessive-compulsive disorder (OCD), personality disorders, addiction, and panic attacks. Symptom onset is usually in childhood or early adolescence but ranges from six months to 38 years. Although disabling, the condition is compatible with an active life and a normal lifespan. Most affected adults report a dramatic reduction in myoclonus in response to alcohol ingestion; however, the risk of alcohol addiction is significant. Mutations in SGCE are associated with familial M-D in many cases [Zimprich et al 2001]; a second locus has been identified on chromosome 18 [Grimes et al 2002, Schule et al 2004]. Inheritance is autosomal dominant.

Rapid-onset dystonia-parkinsonism (RDP, dystonia 12) is an extremely rare condition in which dystonic spasms, bradykinesia, postural instability, dysarthria, and dysphagia develop over a period of several hours to weeks [Dobyns et al 1993]. A less rapid clinical course has also been described with a gradual progression of dystonia and parkinsonism over six to 18 months [Brashear et al 1996]. Onset can occur during childhood, adolescence, or adulthood [Dobyns et al 1993, Brashear et al 1996]. Treatment with L-dopa is not effective. Low concentration of homovanillic acid is observed in the CSF. Neuroimaging studies are normal. Mutations in ATP1A3 are causative. Inheritance is autosomal dominant with reduced penetrance.

Table 4. Molecular Genetics of Dystonia-Plus Syndromes

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Type	Gene Symbol	Chromosomal Locus	Protein Name	Test Availability
Dystonia 5	GCH1	14q22.1-q22.2	GTP cyclohydrolase 1	Clinical
	TH	11p15.5	Tyrosine 3-monooxygenase	Clinical
Dystonia 11	SGCE	7q21	Epsilon-sarcoglycan	Clinical
Dystonia 12	ATP1A3	19q12-q13.2	Sodium/potassium-transporting ATPase subunit alpha-3	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

Heredo-Degenerative Dystonia

Heredo-degenerative dystonias are defined as those in which dystonia is a prominent or presenting feature but in which other neurologic features may occur. Other neurologic features may include dementia, dysarthria, ataxia, and other movement disorders such as choreoathetosis or parkinsonism. Other heredo-degenerative syndromes not typically classified as dystonias but in which dystonia may be a feature are included in the Differential Diagnosis.

The following section details those heredo-degenerative conditions in which dystonia is a presenting or prominent feature.

Familial idiopathic basal ganglia calcification (FIBGC, Fahr disease), also known as bilateral striatopallidodentate calcinosis, is a neurodegenerative disorder with characteristic calcium deposits in the basal ganglia and other brain areas most easily visualized on CT imaging. Most affected individuals are in good health during childhood and young adulthood and typically present in the third to fifth decades with a gradual progression of neuropsychiatric and movement disorders. The first manifestations often include clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping. Seizures of various types occur frequently. Neuropsychiatric symptoms, often the first or most prominent manifestations, range from mild difficulty with concentration and memory, to changes in personality or behavior, to psychosis and dementia. In one family, more than half of the family members suffered from dystonia — usually focal dystonia affecting the upper or lower limbs, jaw dystonia, or writer's cramp. Inheritance is autosomal dominant. Genetic anticipation has been suggested [Geschwind et al 1999].

Neuroferritinopathy is a rare adult-onset basal ganglia disorder characterized by dystonia, chorea, and bradykinesia first identified in a single large UK family [Curtis et al 2001, Crompton et al 2002]. It typically presents with progressive adult-onset chorea or dystonia and subtle cognitive deficits. The movement disorder involves additional limbs within five to ten years and becomes more generalized within 20 years. When present, asymmetry remains throughout the course of the disorder. The majority of individuals develop a characteristic orofacial action-specific dystonia related to speech that leads to dysarthrophonia. Frontalis overactivity and orolingual dyskinesia are common. Cognitive deficits, behavioral issues, and dysphagia become major problems with time. FTL is the only gene currently known to be associated with neuroferritinopathy. Inheritance is autosomal dominant with reduced penetrance.

Spinocerebellar ataxias are a heterogeneous group of neurodegenerative disorders characterized by ataxia and various other neurologic features. Dystonia is a well-recognized although uncommon feature of many spinocerebellar degenerations, including both autosomal dominant and autosomal recessive types (see Ataxia Overview). When present, it may suggest a diagnosis of SCA3 (Machado-Joseph disease) [Schols et al 2000].

Pantothenate kinase-associated neurodegeneration (PKAN) is a subset of neurodegeneration with brain iron accumulation (NBIA; formerly called Hallervorden-Spatz syndrome). PKAN is characterized by basal ganglia iron deposition with onset usually before age ten years. Dystonia is always present and usually an early feature. Commonly associated features include dysarthria, rigidity, choreoathetosis, and pigmentary retinopathy. About 25% of affected individuals have an "atypical" presentation with later onset (after age ten years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease.

HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) (OMIM 200150) is now considered to be part of the PKAN disease spectrum [Ching et al 2002, Houlden et al 2003]. Affected individuals also have dystonia. Mutations in PANK2 have been identified in the only two families reported with HARP syndrome.

The "eye of the tiger," a characteristic finding in PKAN, is defined on coronal or transverse T₂ weighted MRI as a central region of hyperintensity of the globus pallidus surrounded by a rim of hypointensity. This specific change is highly correlated with the presence of a PANK2 mutation in both classic and atypical disease. Approximately half of the individuals given a clinical diagnosis of NBIA have identifiable mutations in PANK2 [Zhou et al 2001, Hayflick et al 2003]. Inheritance is autosomal recessive.

Chorea-acanthocytosis (ChAc) is a progressive movement disorder associated with a myopathy that can be subclinical, and acanthocytosis of the red blood cells. The movement disorder is mostly chorea, but some individuals present with a parkinsonian syndrome. Dystonia is common and affects the oral region and the tongue in particular, causing dysarthria and serious dysphagia with resultant weight loss. Habitual tongue and lip biting are characteristic. Progressive cognitive and behavioral changes resemble a frontal lobe syndrome. Seizures are observed in almost half of affected individuals and can be the initial manifestation. Myopathy results in progressive distal muscle wasting and weakness. ChAc can develop as early as the first decade or as late as the seventh decade; mean age at onset is approximately 35 years. It runs a chronic progressive course and may lead to major disability within a few years. Life expectancy is reduced.

The diagnosis of ChAc depends on the presence of characteristic MRI findings and evidence of muscle disease. CT and MRI reveal atrophy of the caudate nuclei with dilatation of the anterior horns. MRI commonly shows T₂ signal increase in the caudate and putamen. Acanthocytes are present in 5%-50% of the red cell population. In some cases, acanthocytosis may be absent or may appear only late in the course of the disease. Increased serum concentration of muscle creatine phosphokinase is observed in the majority of affected individuals. Muscle biopsy reveals central nuclei and atrophic fibers. VPS13A is the only gene currently known to be associated with ChAc [Rampoldi et al 2001, Ueno et al 2001]. Inheritance is autosomal recessive.

McLeod neuroacanthocytosis syndrome (MLS) findings significantly overlap with those of ChAc [Danek et al 2001]; in older reports, MLS has been mistaken for ChAc. MLS is a multisystem disorder with central nervous system (CNS), neuromuscular, and hematologic manifestations in males. CNS manifestations are a neurodegenerative basal ganglia disease including (1) movement disorder, (2) cognitive impairment, and (3) psychiatric symptoms. Neuromuscular manifestations include a mostly subclinical sensorimotor axonopathy and clinically relevant muscle weakness or atrophy.

The hematologic manifestations of MLS are red blood cell acanthocytosis, compensated hemolysis, and the McLeod blood group phenotype resulting from absent expression of the Kx erythrocyte antigen and reduced expression of the Kell blood group antigens. Immunohematologic studies using specific Kell antibodies are necessary to differentiate between ChAc and MLS. Individuals with ChAc show normal antigen expression, whereas the weak expression of Kell antigens is diagnostic for the McLeod erythrocyte phenotype. Heterozygous females have mosaicism for the Kell system blood group antigens and RBC acanthocytosis but lack CNS and neuromuscular manifestations. Mutations in XK are causative. Inheritance is X-linked.

X-linked dystonia-parkinsonism syndrome (XDP, "Lubag") is a neurodegenerative syndrome in which the initial presenting sign is almost universally parkinsonism. Some individuals may have pure parkinsonism and no dystonia for many years [Evidente et al 2002]. The dystonia develops focally, most commonly in the jaw, neck, trunk, and eyes, and less commonly in the limbs, tongue, pharynx, and larynx. The mean age of onset in men is 39 years, with a range of 12 to 64 years [Evidente et al 2004]. The time from onset of focal dystonia to generalization ranges from age one to 23 years, with a mean age of 3.8 years. Other neurologic findings may include pure tremor, chorea, athetosis, and myoclonus. Those who develop a combination of parkinsonism and orobuccolingual dystonia and cervical dystonia in the first year or two of the disease have the worst prognosis; developing multifocal or generalized symptoms from the second to fifth year after onset, they rapidly become bedridden and die prematurely. Female XDP carriers are mostly asymptomatic, although a small percentage may manifest symptoms.

XDP is believed to have originated ancestrally in the Philippines, particularly in the Panay Islands. The prevalence is 5.24:100,000 in the Panay Islands, with the highest rate of 18.9:100,000 in the province of Capiz where it is endemic [Lee et al 2002]. Inheritance is X-linked.

Deafness-dystonia-optic neuronopathy syndrome is characterized by prelingual or postlingual sensorineural hearing impairment in early childhood, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning about age 20 years, and dementia beginning about age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. The hearing impairment seems constant in age of onset and progression, whereas the neurologic, visual, and neuropsychiatric signs vary in degree of severity and rate of progression. Females may have mild hearing impairment and focal dystonia. The deafness-dystonia-optic neuronopathy syndrome occurs as either a single-gene disorder resulting from a mutation in TIMM8A or a contiguous gene deletion syndrome at Xq22, which also includes X-linked agammaglobulinemia secondary to disruption of BTK located telomeric to TIMM8A. Inherited is X-linked recessive.

Leigh syndrome (subacute necrotizing encephalomyopathy) is a progressive neurodegenerative disorder with characteristic neuropathologic features of symmetric necrotic lesions in the basal ganglia, cerebellum, thalamus, brain stem, and optic nerves [Sudarsky et al 1999]. The most frequently encountered clinical features of Leigh syndrome are developmental regression and signs of brainstem dysfunction such as respiratory abnormalities and nystagmus. Other common manifestations include optic atrophy, ophthalmoparesis, failure to thrive, hypotonia, weakness, spasticity, ataxia, seizures, bulbar problems, involuntary movements, and dystonia. The disorder is caused by altered oxidative phosphorylation secondary to mitochondrial dysfunction. Mutations in both mitochondrial and nuclear genes have been reported [Dahl 1998, Schapira 2002]. (See Mitochondrial DNA-Associated Leigh Syndrome and NARP.)

Leber hereditary optic neuropathy (LHON) typically presents in young adults as painless subacute bilateral visual failure. Males are more commonly affected than females. Women tend to develop the disorder slightly later in life and may be more severely affected. The acute phase begins with blurring of central vision and color desaturation that affect both eyes simultaneously in up to 50% of cases. After the initial symptoms, both eyes are usually affected within six months. The central visual acuity deteriorates to the level of counting fingers in up to 80% of cases. Neurologic abnormalities (such as dystonia, a postural tremor, or the loss of ankle reflexes) are said to be common in individuals with LHON. Some individuals with LHON, usually women, also have a multiple sclerosis (MS)-like illness. Ninety-five percent of individuals with LHON have one of three point mutations of mitochondrial DNA (mtDNA): m.11778G>A, m.14484T>C, or m.3460G>A.

Table 5. Clinical Features of Heredo-Degenerative Dystonias

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Designation	Locus Name	Gene Symbol	Chromosomal Locus	Protein Name	Test Availability	OMIM
Familial idiopathic basal ganglia calcification	IBGC1	Unknown	14q		Research only	213600, 606656
Neuroferritinopathy	—	FTL	19q13.3-q13.4	Ferritin light chain	Clinical	606159, 134790
Pantothenate kinase-associated neurodegeneration (PKAN) (Hallervorden-Spatz syndrome)	—	PANK2	20p13-p12.3	Pantothenate kinase 2, mitochondrial	Clinical	234200, 606157
Early-onset Parkinson disease, including parkin type	—	PARK2	6q25.2-q27	Parkin	Clinical	602544, 600116
Chorea-acanthocytosis (ChAc)	—	VPS13A	9q21	Vacuolar protein sorting 13A	Research only	200150, 605978
McLeod neuroacanthocytosis syndrome	—	XK	Xp21.2-p21.1	Membrane transport protein XK		314850
X-linked dystonia-parkinsonism ("Lubag")	—	TAF1	Xq13.1	Transcription initiation factor TFIID subunit 1	Clinical	314250
Deafness-dystonia-optic neuronopathy syndrome	—	TIMM8A	Xq22	Mitochondrial import inner membrane translocase subunit TIM8 A	Clinical	304700, 300356,

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

Paroxysmal Dyskinesias with Dystonia

Paroxysmal dyskinesias with dystonia are clinically different from other dystonias because the symptoms and signs are intermittent [Bhatia 1999]. Affected individuals are clinically well between episodes. Individuals may have other features such as epilepsy or chorea. Most are inherited in an autosomal dominant manner.

Familial paroxysmal nonkinesigenic dyskinesia (familial PNKD, dystonia 8) is also known as paroxysmal dystonic choreoathetosis (PDC) or Mount-Reback syndrome. Familial PNKD is characterized by unilateral or bilateral involuntary movements; attacks are spontaneous or precipitated by alcohol, coffee, tea, chocolate, excitement, or stress fatigue. Attacks involve dystonic posturing with choreic and ballistic movements, are sometimes accompanied by a preceding aura, occur while the individual is awake, and are not associated with seizures. Attacks last minutes to hours and rarely occur more than once per day; attack frequency, duration, severity, and combinations of symptoms vary within and among families. Age of onset is typically in childhood or early teens, but can be as late as age 50 years. PNKD, encoding probable hydrolase PNKD, is the only gene known to be associated with familial PNKD.

Paroxysmal choreoathetosis and episodic ataxia and spasticity (dystonia 9) involves episodes of involuntary movements, dystonic postures of toes, legs, and arms, dysarthria, paresthesias, and double vision lasting approximately 20 minutes. Frequency of episodes ranges from twice a day to twice a year. Episodes can be induced by alcohol, fatigue, and emotional stress. However, unlike PNKD, physical exercise can precipitate the episodes. Five of 18 affected individuals reported that they had spastic paraplegia both during and between episodes of dyskinesia. Onset ranges from age two to 15 years. CSE is the only gene known to be associated with this disorder.

Familial paroxysmal kinesigenic dyskinesia (familial PKD, dystonia 10) is characterized by unilateral or bilateral involuntary movements precipitated by other sudden movements such as standing up from a sitting position, being startled, or changes in velocity; attacks include combinations of dystonia, choreoathetosis, and ballism, are sometimes preceded by an aura, and do not involve loss of consciousness. Attacks can be as frequent as 100 per day to as few as one per month. Duration of attacks is generally a few seconds to five minutes, but attacks can last several hours. Familial PKD has been associated with infantile, but not adult-onset, seizures. Varying severity and combinations of symptoms occur. Age of onset is typically in childhood and adolescence, but ranges from four months to 57 years. Familial PKD is predominantly seen in males. The gene(s) associated with paroxysmal kinesigenic dyskinesia have not been identified. Linkage of familial PKD to chromosome 16q has been established in at least ten individuals.

Table 6. Molecular Genetics of Paroxysmal Dyskinesias with Dystonia

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Type	Locus Name	Gene Symbol	Chromosomal Locus	Protein Name	Test Availability
Dystonia 8	—	PNKD	2q35	Probable hydrolase PNKD	Clinical
Dystonia 9	—	CSE	1p	Unknown	Research only
Dystonia 10	PKC		16p11.2-q12.1	Unknown

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

Mode of Inheritance

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

• Individuals having an autosomal dominant dystonia may have an affected parent or have the disorder as the result of a de novo mutation.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation may include clinical evaluation and molecular genetic testing when available.
• An apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although some individuals diagnosed with autosomal dominant dystonia have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent or reduced penetrance of the mutant allele in an asymptomatic parent.

Sibs of a proband

• The risk to sibs depends on the genetic status of the proband's parents.
• If one of the proband's parents has a mutant allele, the risk to the sibs of inheriting the mutant allele is 50%.

Offspring of a proband

• Each child of an individual with autosomal dominant dystonia has a 50% chance of inheriting the mutation.
• Because many of the inherited dystonias demonstrate incomplete penetrance, not all individuals who inherit the mutation will develop dystonia.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

• The parents are obligate heterozygotes and, therefore, carry a single copy of a disease-causing mutation.
• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
• Heterozygotes are asymptomatic.

Offspring of a proband. All offspring are obligate carriers.

Risk to Family Members — X-Linked Inheritance

Parents of a proband

• Women who have an affected son and another affected male relative are obligate heterozygotes.
• If pedigree analysis reveals that an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
  • He has a de novo disease-causing mutation, in which case his mother is not a carrier.
  • His mother has a de novo disease-causing mutation either (a) as a "germline mutation" (i.e., occurring at the time of her conception and thus present in every cell of her body); or (b) as "germline mosaicism" (i.e., occurring in some of her germ cells only).
  • His mother has a disease-causing mutation that she inherited from a maternal female ancestor.

Sibs of a proband

• The risk to sibs depends on the genetic status of the proband's mother.
• A female who is a carrier has a 50% chance of transmitting the disease-causing mutation with each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation are carriers and will not be affected.
• If the mother is not a carrier, the risk to sibs is low but may be greater than that of the general population because the risk of germline mosaicism in mothers is not known.

Offspring of a proband. Affected males will pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for some forms of dystonia is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation(s) have been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Treatment of Manifestations

All individuals with dystonia require assessment and management by a neurologic or neurosurgical specialist.

If no specific treatable cause (such as a tumor, demyelination, or one of the dopa-responsive dystonias) is found, treatment is symptomatic and usually consists of the following:

• Pharmacologic intervention
  • Anticholinergic drugs or, less commonly, dopamine depletors (e.g., reserpine), which may be effective in a minority of individuals with idiopathic dystonia. Individuals with dopa-responsive dystonia occasionally respond to anticholinergic drugs.
  • Symptomatic oral medications, which include baclofen (a muscle relaxant), benzodiazepines (minor tranquilizers), and standard analgesics. All medications require supervision to avoid side effects and tolerance or addiction.
• Botulinum toxin injections to affected muscles. Botulinum toxins, neurotoxins produced by the bacterium Clostridium botulinum, are lethal human neurotoxins that block neuromuscular transmission by inhibiting the release of acetylcholine at the neuromuscular junction. Injection of commercial preparations of botulinum toxin causes a local flaccid paralysis of the injected muscles that lasts for weeks to months. It has become the "gold standard" against which other treatments of dystonia are measured, as the success rate is high and the complication rate low. Injections should only be performed by those experienced in its use [Dauer et al 1998, Adler 2000, Adler & Kumar 2000].

Occasionally, peripheral or stereotactic central surgery is considered for individuals with incapacitating dystonia.

• Peripheral surgery involves selective denervation or myomectomy [Cohen-Gadol et al 2003].
• Deep-brain stimulation (DBS) originally evolved in the 1950s from ablative neurosurgery for Parkinson disease, which had mixed success probably as a result of technical limitations. Over the past few years, DBS has been re-introduced for the treatment of dystonia and there are increasing reports of its success. It is still an experimental technique [Coubes et al 2000, Krauss 2002, Castelnau et al 2005, Marks 2005, Vidailhet et al 2005].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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Revision History

• 23 January 2006 (me) Comprehensive update posted to live Web site
• 27 May 2005 (cd) Revision: information on neuroferritinopathy
• 21 December 2004 (cd) Revision: information on Mcleod neuroacanthocytosis syndrome
• 3 June 2004 (cd) Revision: change in test availability
• 5 February 2004 (cd) Revision: change in test availability
• 28 October 2003 (me) Review posted to live Web site
• 8 April 2003 (an) Original submission