Definition, Pathophysiology, and Prevalence

Dystonia is defined as a hyperkinetic movement disorder characterized by sustained or intermittent muscle contractions in one or more body parts causing abnormal, often repetitive, movements, abnormal posturing, or both. These movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and it is associated with an overflow of muscle activation [3]. Dystonia is a clinical diagnosis that can be caused by a wide range of genetic and acquired etiologies. The exact pathophysiology of dystonia is unknown. The basal ganglia are known to play an important role, as lesions within these nuclei may lead to dystonia. Recent imaging and neurobiological studies indicate a network disorder with involvement of the basal ganglia, thalamocortical connections, and the cerebellum. Dysfunction in any part of this network can give rise to dystonia [4].

Although the exact prevalence of dystonia is not known, it appears to be the most frequently diagnosed hyperkinetic movement disorder after tics and tremor. A meta-analysis of isolated forms of dystonia showed a prevalence of 16.4 in 100,000 [5]. This does not, however, include generalized and mixed forms of dystonia and probably it is an underestimate of the true prevalence. Among the extrapyramidal movement disorders associated with IEMs, dystonia is thought to be among the most prevalent [6].

Classification and Diagnosis

The heterogeneous nature of dystonic syndromes has led to the development of a classification system. In this system, dystonia is classified according to two axes: clinical manifestation and etiology (Table 8.1) [3].

Axis I, the clinical manifestation of dystonia, is based on five clinical characteristics: age at onset (from neonatal to late adulthood), body distribution (focal, segmental, multifocal, hemidystonia, or generalized), temporal pattern (diurnal variability, progression over time), coexistence of other movement disorders (isolated versus combined forms), and the presence of other neurological manifestations (e.g., spasticity or epilepsy). The classification of the clinical characteristics ultimately leads to the definition of a “dystonia syndrome.” This approach has been further developed by Fung and colleagues, who provided a list of 27 dystonic syndromes with potential etiologies to guide diagnostic testing [7].

Axis II of the dystonia classification focuses on etiology, as there are many possible acquired and genetic (including neurometabolic) causes. In addition to acquired and genetic causes, a third group consists of idiopathic forms. Young-onset dystonia is more likely to have an identifiable (acquired or genetic) cause, while many adult-onset focal dystonias are idiopathic.

Is It Dystonia?

The first essential question in the diagnostic process is whether the observed symptoms are either dystonia or “dystonia mimics.” For example, congenital muscular torticollis and Sandifer syndrome are conditions that may mimic dystonia in young children, whereas scoliosis or trochlear nerve palsy are known causes of pseudo-dystonia in both children and adults. Further, immaturity of the central nervous system can lead to “physiological” movement disorders, which are difficult to distinguish from “true” involuntary movements in young children [9].

Could the Dystonia Be Medication-Induced or Caused by Toxic Agents?

There are several drugs (dopamine-receptor blockers or stimulants, tricyclic antidepressants, antihistamines, serotonin reuptake inhibitors, cholinergic agonists, antiseizure drugs, antimalarial drugs, calcium channel blockers, disulfiram, lithium, and cocaine) and toxins (carbon monoxide, cyanide, manganese, methanol, and organophosphates) associated with the onset of dystonia. These agents should be ruled out before continuing the diagnostic process [8].

Childhood-Onset or Adult-Onset?

There is a clear relationship between the age at onset of dystonia and the clinical course and possible etiologies of the syndrome [3]. Therefore, the diagnostic approach depends on the age of onset. Patients with an onset before 21 years of age follow the diagnostic algorithm outlined in Figure 8.1. In patients with a typical focal dystonia manifesting above 21 years (usually above 40 years of age), additional investigations can be minimized, as these forms are mostly idiopathic, limiting the added value of further diagnostic investigations. These isolated focal dystonias include blepharospasm, oromandibular dystonia, Meige syndrome, cervical dystonia, task-specific dystonia, and isolated spasmodic dysphonia.

Neuroimaging

After ruling out a medication or toxin-induced dystonia, neuroimaging is the next step. Brain MRI should always be obtained in young-onset dystonia. For adult-onset focal dystonia, an MRI is only indicated in patients with additional “red flags.” These red flags are an acute onset or progressive course of symptoms, hemidystonia, and atypical distributions (in one limb without task-specificity, generalized or isolated trunk dystonia). Basal ganglia abnormalities may be seen on brain MRI in neurometabolic disorders, such as Wilson disease, pyruvate dehydrogenase (PDH) deficiency, co-enzyme Q10 deficiency, cerebral folate deficiency, thiamine transporter deficiency (biotin–thiamine-responsive basal ganglia disease), organic acidurias, and forms of neurodegeneration with brain iron accumulation (NBIA; i.e. the “eye of the tiger” sign due to pantothenate kinase-associated neurodegeneration [PKAN]) [6]. This can help with distinguishing the type of IEM before additional targeted biochemical or genetic testing.

Obvious Clues for Acquired Dystonia?

Acquired forms of dystonia mainly involve dystonia due to structural brain lesions, cerebral palsy, or autoimmune-associated dystonia. In children, cerebral palsy is the most frequent cause of dystonia, defined as a group of permanent disorders causing impairment of movement and posture, attributed to non-progressive disturbances that occurred in the developing fetal or infant brain [10]. An abnormal birth or perinatal history is a positive clue for the diagnosis of cerebral palsy and brain MRI may reveal structural lesions [11]. Important clues for an autoimmune-associated dystonia are an acute or rapidly progressive course, unilateral symptoms (hemidystonia), and dystonia accompanied by psychiatric symptoms, seizures, or signs of a meningoencephalitis. In case the brain MRI does not show any structural lesions, additional investigations such as autoantibodies in the serum and cerebral spinal fluid (CSF) are recommended [8].

Clinical Clues That Might Suggest an IEM

In IEMs, dystonia is often part of a more complex, mixed movement disorder phenotype. Dystonia can present together with parkinsonism, ataxia, myoclonus, tremor, and, less common, chorea. Further, the dystonic symptoms are predominantly embedded in a complex clinical picture with other neurological and non-neurological symptoms, such as eye movement abnormalities, neuropathy, muscle weakness, dementia, psychiatric problems, organomegaly, ophthalmological or skin abnormalities, and deafness [12].

Dystonia as the presenting symptom of IEMs typically involves a generalized form of dystonia, with an early and acute or subacute onset and a progressive course. Other clues include diurnal variation, in which symptoms worsen toward the end of the day or with fasting [1].

Although the presence of these clues may lead in the right direction, the varieties of clinical presentations in IEM patients, and the importance of not missing a treatable condition, imply that all children presenting with dystonia of a non-acquired cause should undergo additional investigations to look for an IEM. Important IEMs for which the targeted treatment options exist include dopamine-responsive dystonia (DRD), the organic acidurias, glucose transporter type 1 (GLUT1) deficiency syndrome, and lysosomal storage disorders [13]. In these patients, early treatment may lead to stabilization or reduction of existing symptoms.

Because of the clinical complexity of dystonia in IEMs, often embedded in several other neurological and non-neurological symptoms, a multidisciplinary approach can have added value in the process of classification [14]. Neurometabolic disorders with dystonia are naturally at the interface of different specialists, including movement disorder experts, (pediatric) neurologists, metabolic specialists, and clinical geneticists.

Biochemical Investigations and a Levodopa Trial

Although the availability, turn-around time, and costs of next-generation sequencing (NGS) are improving, traditional biochemical tests in plasma, urine, and CSF often remain the fastest manner to obtain a diagnosis. Performing these tests is of critical value in treatable IEM, as a faster diagnosis means an earlier start of targeted treatment. It is therefore recommended to conduct the biochemical tests and NGS in parallel. An overview of the recommended biochemical tests can be found in Table 8.2 (adapted from van Egmond et al. [8]).

In addition to biochemical tests, a diagnostic trial of levodopa in all childhood-onset dystonia patients is important to reveal DRD. Recently, this diagnostic step was questioned based on the relatively low prevalence of DRD and in light of rapidly achievable results of NGS [15]. It is also important to realize that levodopa can also reduce dystonic symptoms in non-classic DRD dystonia (i.e. aromatic L-amino acid decarboxylase deficiency or GLUT1 deficiency) [15]. The recommended starting dose is 1 mg/kg per day with a gradual increase until the complete benefit or dose-limiting effects occur [16].

In adults, IEMs are relatively rare causes of dystonia and the usually slowly progressive course gives the clinician the possibility to wait for genetic test results and limits the advantages of biochemical tests.

Next-Generation Sequencing

The rapid developments in NGS now enable us to screen for a large number of genes at once, instead of sequencing genes individually. Currently used techniques include sequencing of the whole genome (whole-genome sequencing, WGS), the coding regions (or exomes) of each gene (whole-exome sequencing, WES), or sequencing of a panel of genes currently known to be associated with dystonia (multi-gene panel). A list of dystonia-associated genes is provided by van Egmond et al. [8].

After eliminating an acquired etiology, NGS is recommended in childhood-onset dystonia patients. In adult-onset dystonia, clues that might suggest a genetic cause are onset before the age of 40 years, a positive family history, a combined (not isolated) dystonia, and the presence of other neurological abnormalities. The application of NGS in movement disorders leads to a higher percentage of genetically defined dystonias [14]. A widespread use of NGS in patients with movement disorders is very likely to lead to more frequently detected and a broader phenotype of IEMs [17].

To obtain the highest possible yield of NGS techniques, close cooperation between clinical geneticists and the treating neurologist or metabolic specialist is essential. Results need to be carefully interpreted in order to decide whether a mutation is pathogenic or an incidental and unrelated finding [18]. In addition, some disorders might be missed with NGS, especially trinucleotide repeat disorders, but also deletions in genes are not always detected. In addition to routine NGS diagnostics for dystonia, mitochondrial DNA (mtDNA) can be tested as there are mitochondrial disorders with mutations in the mtDNA known to be associated with dystonia (i.e. mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes [MELAS] syndrome).

Neurotransmitter Disorders

In neurotransmitter disorders, movement disorders are directly related to the biochemical defect. Biochemical tests to identify neurotransmitter disorders include dopaminergic, serotonergic, and tetrahydrobiopterin markers in CSF [19]. DRD is a well-known neurotransmitter disorder presenting with dystonia as the main symptom. Autosomal-dominant GTP cyclohydrolase 1 (GTPCH1) deficiency (or Segawa disease) is the most prevalent form. In classic DRD, dystonia arises from a dopaminergic deficit and a good response to levodopa-substitution therapy is one of the hallmarks. The dystonia has an early onset, usually starts in one limb and gradually spreads over the body. There is diurnal fluctuation and symptoms tend to worsen over the day and are associated with fatigue. Besides dystonia, parkinsonian features are part of the clinical picture, particularly as adult-onset manifestations. Symptom severity is highly variable [20].

The rare recessive forms of DRD, sepiapterin reductase deficiency and tyrosine hydroxylase deficiency, usually have a more complex and severe phenotype with onset in infancy or early childhood. Besides the dystonic–hypokinetic picture, these patients also have an encephalopathic presentation and oculogyric crises. Other monoamine neurotransmitter disorders such as 6-pyruvoyltetrahydrobiopterin synthase (PTPS) deficiency, dihydropteridine dehydrogenase (DHPR) deficiency, and aromatic L-amino acid decarboxylase (AADC) deficiency can also cause dystonia and parkinsonism, frequently with a more complex phenotype and less obvious response to treatment with levodopa [19].

Metal Storage Disorders

The basal ganglia appear particularly vulnerable to the accumulation of different metal metabolites. The abnormal storage of copper in Wilson disease, iron accumulation in neurodegeneration with brain iron accumulation (NBIA), and manganese accumulation caused by SLC30A10 mutations (dystonia with brain manganese accumulation), all present with dystonia. An early diagnosis of Wilson disease and dystonia with brain manganese accumulation is of particular importance because symptoms can be prevented by timely treatment. Neurological symptoms usually occur in Wilson disease in the second decade. Beside the presence of dystonia, Wilson disease and dystonia with brain manganese accumulation are known for involvement of the liver (elevated serum transaminases) and the Kayser–Fleischer corneal ring. The biochemical abnormalities are a low serum copper and ceruloplasmin for Wilson disease and hypermanganesemia in plasma for dystonia with brain manganese accumulation [21, 22].

PKAN, caused by mutations in the PANK2 gene, is the most prevalent form of NBIA associated with dystonia. The disorder is characterized by generalized dystonia, often starting in childhood with dystonic gait abnormalities and prominent dystonia in the oromandibular region. Accumulation of iron in the globus pallidus results in a typical MRI pattern known as the “eye of the tiger” sign (pallidal hypointensity with central hyperintensity on T2 images). In addition to PKAN, other NBIA disorders such as PLA2G6-associated neurodegeneration can also present with dystonia [23].