The Semiology of Tics, Tourette's, and Their Associations

Abstract

Gilles de la Tourette syndrome (GTS) is a prototypical neuropsychiatric disorder breaking the boundary of disciplinary dualism between neurology and psychiatry. The diagnosis of GTS is clinical and, in most cases, straightforward. Tics as a hallmark of GTS are usually easy to recognize and distinguish from other movement disorders as fragmented, repetitive, exaggerated movements resembling normal motor behavior, but appearing out of context. In complex cases, knowledge on additional characteristics and signs as, for example, tic distribution, suggestibility, voluntary tic inhibition, and presence of echo‐ or paliphenomena might further aid clinical diagnosis. However, although defining GTS, tics are rarely the main issue. The presence of comorbidities and coexisting psychopathologies often hampers normal development and negatively affects quality of life. Their recognition and treatment is paramount. Here, we review existing literature and provide a comprehensive update on the multifarious aspects of the movement disorder and neuropsychiatry of GTS. We also provide a list of associated movement disorders known to occur in GTS patients and discuss differential diagnoses to be considered in atypical cases. We finally comment on available treatment options.

Gilles de la Tourette syndrome (GTS) is a spectrum disorder defined by the presence of tics. As with persistent (chronic) motor or vocal (phonic) tic disorder and provisional tic disorder, GTS is classified as a primary tic disorder.1 According to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5) criteria, the diagnosis of GTS can be made in the presence of multiple motor and vocal (or phonic) tics manifesting before the age of 18, lasting for more than 1 year, in the absence of secondary causes.1 It is encountered in nearly all cultures irrespective of ethnicity.2 Current overall prevalence of GTS in the population has been estimated to be up to 1%.2 It affects more males than females with a 3/4.3:1 ratio.2, 3, 4 GTS is a heterogeneous condition.5, 6, 7 Although the recognition of the classic presentations of GTS is straightforward, mis‐ and missed diagnoses are not uncommon. This is partly due to overlapping characteristics of tics and voluntary actions, but also other movement disorders, such as myoclonus or chorea. Also, the diagnosis of GTS does not preclude the concurrence of other movement disorders that may be “masked” by or mimic tics. A naturally fluctuating course, comorbidities, unusual behaviors, and psychosocial consequences often complicate clinical management and render prognosis uncertain.8, 9

Historically, medical opinions and knowledge on GTS have undulated a lot. Psychoanalytic approaches considered tics as the manifestation of conversions of suppressed instinctual impulses in an overprotective familial environment.10, 11, 12, 13 However, the therapeutic breakthrough after the introduction of haloperidol in the treatment of tics and the disappointing results of psychotherapy prompted a general shift in medical perception and understanding.5, 6, 14, 15, 16, 17, 18

Currently, the prevailing model of GTS pathophysiology encompasses an abundance of structural and functional changes in extended brain areas involving motor and nonmotor cortico‐striato‐thalamo‐cortical loops responsible for the generation of tics and associated symptoms.19

Here, we summarize clinical knowledge on the GTS complex by dissecting its core and comorbid fragments that may cause diagnostic difficulty and examine their interaction, evolution, and prognosis. We also consider the spectrum of different conditions that may be misdiagnosed as GTS or should be considered in the presence of atypical features. Finally, we comment on different treatment strategies.

The Movement Disorder

As with tremor, myoclonus, chorea, and dystonia, tics are considered a hyperkinetic movement disorder. Among those, tics are the only hyperkinesia that can be indistinguishable from voluntary actions with regard to phenomenology and neurophysiological characteristics.20, 21 Any single movement can be a tic. Hence, tics have a wide phenomenological variability reflecting the range of normal voluntary motor behavior. However, what separates tics from normal actions is their exaggerated character in intensity, frequency, and repetition. Also, voluntary actions are context bound, whereas tics are not. They thus represent fragments of normal motor behavior misplaced in context and time.22 Tics also lack the flexibility of voluntary actions, which typifies normal goal‐directed human behavior.

Tics are divided into motor and phonic, depending on whether they occur as a visible movement or as a sound.23 However, such a distinction is arbitrary and nonbiological. For instance, sniffing is caused by simultaneous activation of breathing and facial muscles, ear clicks by palatal, and sounds by laryngeal muscle contractions. Tics are considered simple when they involve single muscles or muscle groups and complex if they resemble goal‐directed actions but appear purposeless.23 The majority of tics are clonic (i.e., brief and fast). Some tics are tonic (longer lasting) or dystonic, that is, produced by prolonged agonist/antagonist cocontractions leading to abnormal postures as in dystonia.20, 23, 24 When tics lead to the disruption of an ongoing action or interfere with communication, they are labeled “blocking.”23

In GTS, some, but not all, tics are consciously perceived. The conscious perception of tics is facilitated by a preceding and often unpleasant somatic sensation known as “premonitory urge.” Patients often attribute voluntariness to tic generation as responses to the urge.25 Tic execution usually relieves the urge for variable amounts of time, depending on symptom severity and attentional focus. The cognitive and neurophysiological underpinning of the premonitory urge is still elusive, because it appears to fall between different sensory modalities. The hypothesis of increased interoceptive awareness has been suggested,26 but conclusive evidence is lacking. The localization of urges and tic generation is not random in GTS. They are most frequent in the head, followed by the neck and shoulders.27 Eye tics and, in particular, blinking are extremely common and have been considered to appear at the first stages of tic emergence in GTS, sometimes constituting the very first tic.28, 29, 30

Tics naturally appear in bouts.31 They are also suggestible and can be inhibited. Hence, their emergence can be influenced. Of note, tic and habit formation have been considered to share common pathophysiological routes32 however, experimental data have yet to confirm this.33 Tic inhibition is a patient‐specific capacity34 and can be further improved by contextual motivation.35 Whether tic inhibition functions through tic cancellation or tic suppression (withholding) is not clear. However, it appears to be independent from the intensity of premonitory urges34 initially thought to fuel this process.36 Although periods of increased tic frequency or severity, known as tic rebound, have been thought to follow tic inhibition, this has not been confirmed experimentally.37

Pali‐, echo‐, and coprophenomena are additional typical features in GTS (then also termed “full‐blown GTS”7, 8, 38). Paliphenomena denote the repetition39 and echophenomena the imitation of actions and utterances.40 Coprophenomena, infamous features of GTS, present only in the minority of patients, are obscene and often insulting gestures or utterances depleted of intent.41 Although all three phenomena are, by convention, lumped under the term of complex tics, pali‐ and particularly echophenomena might also be viewed as additional motor features, because they have distinct phenomenology and different pathophysiology. For instance, echophenomena are normal elements of motor and social development present in younger children with or without tics.40 Also, echophenomena may pathologically persist in other neurodevelopmental or reemerge in neurological conditions without tics.40, 42 Finally, whereas tics are typified by their random appearance or without an external trigger, echophenomena are exactly the opposite; they are generated as responses to external stimulation.

Neuropsychiatric Features

GTS is usually associated with comorbidities (also termed “GTS‐plus”43) and often characterized by coexisting psychopathologies.8 These include attention‐deficit hyperactivity disorder (ADHD), obsessive‐compulsive disorder (OCD), and autism‐spectrum disorder (ASD).8 In fact, only a minority (≈10%) of GTS patients presenting in clinics will have subclinical comorbid symptoms or no comorbidities at all (so‐called pure or uncomplicated GTS).4, 7, 44 Although prevalence estimates of GTS comorbidities vary depending on the examined cohort, age, and the instruments used,4, 45, 46 ADHD, probably the most common comorbidity, particularly at young ages, affects approximately 60% of patients.4, 47 The first ADHD symptoms usually precede the onset of tics.48 Their presence in children and adolescents with GTS has been associated with male sex, earlier GTS diagnosis, and the presence of further comorbidities, other integral symptoms, and associated psychopathologies.4, 47

OCD affects approximately one third of GTS patients,4 although estimates at different ages vary largely.8 Some of these patients may not fulfill diagnostic criteria for OCD, but do have obsessive‐compulsive symptoms/behavior (OCS/OCB).8 OCS/OCB/OCD in GTS usually appear a few years after tics onset.48, 49 It can be difficult to distinguish between tics and obsessions/compulsions because some phenomenological characteristics are similar. The terms “tic‐like obsessions/compulsions” or “cognitive tics” have been applied to describe these intermediate phenomena.8, 39, 50 In pure OCD, obsessions are sources of major anxiety and discomfort, intrusive and disruptive (or “ego‐dystonic”), and lead to the ritualistic and excessively repetitive execution of compulsions, which alleviate aforementioned distress. In contrast, in GTS, most obsessions are not associated with marked anxiety and compulsions are rather the result of an urge or impulse.8 With regard to phenomenology, in pure OCD, fears of contamination and washing or checking rituals are characteristic.8, 39, 50 In GTS with OCS, repetitive touching, “just right” experiences, or symmetry behaviors predominate clinical symptoms.8, 39, 50 Also, if echophenomena are conceptualized as impulsions within a spectrum of OCS, their presence has been found to be GTS specific.39, 40, 51 However, it is important to consider GTS plus OCS/OCB/OCD as a spectrum disorder, with some OCS being typical for GTS and others for OCD, but all potentially occurring in GTS patients.8, 50, 52 Genetic and imaging studies further support this notion.53, 54, 55, 56, 57 Of note, the presentation of different OCS in GTS may change over time and is age related.8, 58 Also, children and adolescents with GTS+OCD have significantly more comorbidities and coexisting psychopathologies at a younger age than age‐matched GTS without OCD.49

Of late, ASD has also been associated with tics and GTS. Previously, tics in ASD were considered coincidental or caused by neuroleptic medication.59, 60, 61, 62 However, an increasing number of clinical reports63, 64, 65, 66 and systematic studies67, 68, 69, 70 established that tics (or GTS) in ASD were common. Likewise, a significant proportion of GTS patients have ASD (currently 4.5%–12.9%).4, 71, 72

Not much is known on tic phenomenology, tic awareness, and associated sensory phenomena in these patients. Their tic severity is usually mild.69, 72, 73 The presence of ASD in GTS, though, is associated with higher comorbidity rates for ADHD, rage attacks, and OCD.72 Implicated genetic factors behind both ASD and GTS,74, 75, 76, 77 and similarities in neuroimaging findings,78, 79, 80 further place these different neurodevelopmental disorders in a common, yet complex, pathophysiological and clinical frame.

GTS can be complicated by self‐injurious behavior (SIB), including skin picking/scratching, poking into the body with sharp objects, head banging, hitting oneself, or hitting objects.8, 81 Depending on its operational definition (from mild to severe SIB), its prevalence has been estimated to be as high as 60%.81 Severe SIB in GTS, albeit rare, can lead to life‐threatening body mutilation and is associated with increased tic severity and the presence of OCS/OCB/OCD, but also impulsivity (rages and risk‐taking behavior).81, 82 Explosive outbursts/rage attacks are also commonly observed in GTS.83, 84, 85 Their presence has been associated with a greater tic severity and additional comorbidities, in particular impulsivity (ADHD), but also OCD, and are a major cause of distress.83, 84, 85

Other associated GTS symptoms include anxiety disorder, depression, and other mood disorders, personality disorders, conduct disorder/oppositional defiant disorder, and nonobscene socially inappropriate (NOSI) behaviors.8, 86

Analytical Approaches to the GTS Spectrum

Although the defining clinical characteristic of GTS are tics, the multitude of other symptoms and associated psychopathologies in different intensities, depending on the stage of brain development (or age) against the often complex familial (i.e., genetic) background, makes it difficult to delineate the central GTS phenotype. Hierarchical cluster, principal component factor, latent class, and cluster analyses have revealed different clusters/factors/classes of GTS subgroups and phenotypes.87, 88, 89, 90, 91, 92, 93, 94, 95 Although these vary depending on methodology and patient populations, most studies reiterated and thus confirmed the presence of a pure GTS phenotype. However, as already highlighted, a direct translation of the results of the aforementioned analytical approaches to clinical work with a view to symptom evolution, prognosis, and response to treatment is not yet possible.96 Knowledge from clinical observations, though, has been helpful in this regard.

Evolution and Prognosis

Tics typically appear around the age of 6 and often involve cranial (eye tics; i.e., tics of eyelids, eyebrows, and oculomotor tics) and typically also cervical and shoulder regions. Phonic tics usually appear a few years later. Worst‐ever tic severity is commonly reported around the first years of the second life decade, after which tics improve in most cases.48 Of note, the subjective experience of tic presence and severity and their objective assessments differ. Pappert et al. demonstrated that half of adult GTS patients who considered themselves to be tic free had tics on video recordings.97 Hence, although tics do “quiet down” in most cases, they may not completely remit. In some patients, tic severity may even increase with age.48, 97

In spite of very limited longitudinal data, prediction models of tic persistence into adulthood imply behavioral and anatomical biomarkers. Bloch et al. could show that tic severity and poor fine motor skills in childhood predicted tic persistence and severity into adulthood (mean follow‐up: 7.5 years).98, 99 Interestingly, the volumes of the caudate nuclei in childhood also inversely correlated with tic severity at follow‐up.100 Also, levels of psychosocial stress and depression were demonstrated to predict future levels of tic severity during a 2‐year observation period in children and adolescents.101

On clinical grounds, evidence increases that patients with ADHD and/or OCS/OCB/OCD fall within the more severe ends of the GTS spectrum102, 103, 104 (Fig. 1). Also, their presence, as pointed out above, increases the likelihood of additional GTS‐related psychopathologies, the need for medication, leads to poorer symptom control, and negatively affects different aspects of patients' quality of life.105, 106, 107, 108, 109, 110 However, the complexities of the overlapping GTS phenotypes and their variable presentation throughout the clinical course, particularly in the transition phase from childhood to early adulthood, do not yet allow to reliable predicting future tic severity. Systematic longitudinal assessment of large patient populations is needed. In this regard, Rizzo et al. conducted the only available longitudinal study that carefully assessed the 10‐year clinical course of 100 GTS patients (86 males; mean age at initial assessment: 5.3 years).45 They demonstrated that although the overall prognosis of the majority of patients as regards tics and quality of life was favorable, none of the patients was tic free at the time of follow‐up. They also showed that more complex inter‐relationships than previously thought define the spectrum of GTS comorbidities and most likely also integral symptoms and coexisting psychopathologies throughout adolescence.45 Of note, satisfactory symptom control was more difficult in GTS subjects with comorbidities.45

Figure 1.

Simplified scheme of the relation between tic severity and associated psychopathology. Although echo‐ and paliphenomena may appear in the entire spectrum of chronic tic disorders (CTD), coprophenomena are associated with more severe phenotypes and the presence of multiple psychopathologies. ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; GTS, Gilles de la Tourette syndrome; NOSI, non‐obscene socially inappropriate behavior; OCB/OCD, obsessive‐compulsive behavior/disorder; SIB, self‐injurious behavior.

Pitfalls of Differential Diagnosis

The diagnosis of GTS is clinical and clear cut in most cases. A normal developing child under the age of 10 will present with some hyperactivity and/or inattentiveness, a 3‐ to 4‐year history of multiple motor and several phonic tics, and perhaps a few obsessions and compulsions, but an otherwise unremarkable medical history. Typically, family history is positive, with some family members having tics and others ADHD, OCS/OCB/OCD, or a combination of these. Often, mother or father will have tics sometimes without being aware of it. Neurological examination will be unrevealing. This is the common scenario. However, sometimes discerning tics from other movement disorders or diagnosing GTS can be more difficult for the following reasons: (1) Tics are overlooked or misinterpreted as a psychological phenomenon; (2) nontic abnormal movements that may coexist in GTS are mislabeled as tics; (3) tics are part of the clinical presentation of another condition; and (4) other movement disorders are mistaken as tics.

In spite of a typical history, a diagnosis of tics is sometimes not made because only few, if any, tics are present during the examination. Alternatively, tics are sometimes considered to result from anxiety, psychological stress, or restlessness and the diagnosis of “nervous habits,” rather than GTS, is given. This produces extra burden and feelings of guilt in patients and relatives. It will also cause avoidable secondary morbidity, stigma, and will have a negative effect on patients' development.

Not every abnormal movement encountered in patients with GTS is a tic. For instance, it was shown that 18 of 373 GTS cases (≈5%) had additional abnormal movements mislabeled as tics.111 Two thirds of these movements were drug related (neuroleptic induced) and included acute akathisia, acute dystonic reaction, tardive dystonia or chorea, and withdrawal emergent chorea,111 although it has to be commented that there is no good evidence for tardive phenomena in GTS.112 The distinction between dystonia and (dystonic) tics can rarely be difficult. Historically, there was some overlap in terminology (“tonic tics,” “attitude tic,” and “rotatory tic” for cervical dystonia),113 and co‐occurrence of tics and dystonia has been reported.114, 115 In clinical practice thought, this rarely causes confusion.

Other paroxysmal events, in particular, attacks of paroxysmal kinesigenic dyskinesia (PKD), can be mistaken as tics.116 This leads to great problems because PKD is exquisitely sensitive to low doses of anticonvulsants, but causes major distress if not adequately treated because PKD attacks are misinterpreted as complex tics. Tics (and GTS) have been reported to co‐occur in patients with PKD.116, 117, 118, 119 Currently, it is unclear whether shared pathophysiological aspects might exist between the two disorders or whether their co‐occurrence is merely coincidental.

Periodic patterned limb movements occurring during sleep, which are commonly associated with dopaminergic dysfunction120 and negatively affect sleep quality, have also been reported in GTS.121 In our experience, they are often missed because neither patients nor clinicians consider their presence or mislabel them as tics, given that the latter are known to persist during sleep in some cases.

Tics can occur in other diseases. They are sometimes part of the clinical presentation of Huntington's disease and are very typical in neuroacanthocytosis. However, these diseases usually do not manifest in childhood and, if so, present with additional symptoms and signs. Complex tics have been described in neurodegeneration with brain iron accumulation (e.g., pantothenate kinase‐associated neurodegeneration) and a number of (X‐)chromosomal disorders.122, 123 Again, tics are not the leading symptom in these disorders. Tics can be also induced or exacerbated by certain drugs (e.g., amphetamine/cocaine).122, 123

Other movement disorders need to be distinguished. Tics can resemble stereotypies. However, the former are less complex and are usually not repeated consecutively as is the case for stereotypies. On the other hand, stereotypies are not preceded by an inner urge to move.

In the setting of rapid‐onset stereotypic movements consisting of sudden unilateral dystonic posturing, usually of the arm with ipsilateral facial involvement, the condition of faciobrachial dystonic seizures resulting from LGI1 antibodies should be considered.124

Some brief tics can be difficult to distinguish from myoclonus, but the latter is not preceded by an urge. Sometimes it can be challenging to distinguish between rapid tics and chorea, particularly with outstretched arms or raised legs. Chorea, though, is unpredictable, floating, and chaotic. Tonic ocular tics can be mistaken as oculogyric crises or paroxysmal tonic upgaze of childhood.125

Functional (or “psychogenic”) tics, although rare, should also be considered in cases with atypical features.126 Tic awareness and the common attribution of tics as voluntary responses to preceding urges,25 as well as the capacity of tic inhibition, are features that argue against functional tics.111 These features, though, are often not present in small children who may not be aware of their tics. Helpful diagnostic clues are rostro‐caudal tic distribution in primary tic disorders, tic suggestibility, the presence of echo‐ and paliphenomena, as well as the spectrum of aforementioned comorbidities, integral symptoms, and coexisting psychopathologies characteristic of GTS.

Figure 2 provides a summary of differential diagnostic considerations of tics from a phenomenological point of view. Other movement disorders that may occur in patients with GTS are listed in Table 1.

Figure 2.

List of differential diagnoses of tics on grounds of phenomenology. FBDS, faciobrachial dystonic seizures; PKD, paroxysmal kinesigenic dyskinesia; PTU, paroxysmal tonic upgaze; RLS, restless legs syndrome.

Table 1.

Movement disorders other than tics co‐occurring in GTS

Primary	Dystonia
	PLM
	Stereotypies
Secondary	Dystonia
	Akathisia
	Chorea
	PKDa

List of associated movement disorders in GTS.

^aThe pathophysiological relation between PKD and GTS is currently unclear.

PKD, paroxysmal kinesigenic dyskinesia; PLM, periodic limb movements.

Treatment

Explaining the neurological background and the natural course of tics and GTS to patients and their families is the mainstay of management. Children with tics are often told to stop their tics and “behave.” Therefore, communicating that tics are automatic and represent neurobiological phenomena helps to decrease tension in families or at school. Similarly, counseling of teachers is important. A long‐time relationship with a GTS expert is helpful to support patients and families through the years.

If general measures do not suffice, medical treatment may be necessary. Often, it is more important to treat ADHD, OCS/OCB/OCD, or depression first because successful treatment then often reduces tic severity.

Medical antitic treatment can be difficult. Recently, European guidelines for the pharmacological management of GTS have been published.127 Given the natural waxing and waning course of tics and GTS it is often not easy to assess the effectiveness of a particular drug. The most widely used class of drugs are α2‐ adrenergic agonists (guanfacine and clonidine) and antidopaminergic drugs (i.e., neuroleptics).4 The effectiveness of α2‐ adrenergic agonists has been demonstrated in randomized, placebo‐controlled, clinical trials.128, 129 They are probably not as potent as neuroleptics, though, and are rarely used in Europe and in our own personal practice. The most frequently used dopamine‐blocking drugs are sulpride, pimozide, haloperidol, tiapride (in Europe), and aripiprazole.8, 130 Sulpiride monotherapy reduces tics and may also improve OCS/OCB/OCD.8 Atypical neuroleptics, such as risperidone and ziprasidone, have also been shown to be effective in some patients.131, 132 Neuroleptics, particularly pimozide, can prolong QT times so that regular electrocardiography should be carried out in the titration phase.

Nicotinic drugs have also shown efficacy in some studies.133 Also, the mixed D1/D2/D3‐dopamine receptor agonist, pergolide, has shown some effectiveness in a double‐blind cross‐over trial.134 Local botulinum toxin injections in affected body segments may reduce motor symptoms and also preceding urges.135, 136

There have been promising reports of habit reversal training in some patients with tics,137 but long‐term effects are less clear. As a last resort, DBS can be considered in otherwise treatment‐refractory cases. Target localization and stimulation parameters, though, are still a matter of debate.138

Conclusion

GTS is a common, yet complex, childhood‐onset neuropsychiatric disorder with a fluctuating course, variable symptoms and signs, and multiple comorbidities. Its features and patterns are characteristic, but severity ranges from very mild hardly warranting the label of a disease to very severe and debilitating. The near normality of many GTS facets makes it a very interesting, but also challenging disorder because confrontation with our own behavioral caricatures may raise denial, which, in turn, causes stigmatization and great distress. GTS is not a devastating neurodegenerative disease and is often manageable in a very satisfactory way, but it can also greatly impair quality of life if not treated adequately. Early diagnosis makes life easier for affected children, but whether, and in which way, it affects the natural course is currently unclear.

Author Roles

(1) Drafting/revising the manuscript for content, including medical writing for content; (2) Acquisition of data; (3) Study supervision or coordination.

C.G.: 1, 2, 3

A.M.: 1, 2, 3

K.P.B.: 1, 2, 3

Disclosures

Funding Sources and Conflicts of Interest: C. Ganos is funded by the German Forschungsgemeinschaft (GA2031/1‐1) and has no conflict of interest. A. Münchau has no conflict of interest. K. Bhatia has no conflict of interest.

Financial Disclosures for previous 12 months: Dr. Christos Ganos has also received travel grants by Ipsen and Actelion. A. Münchau is employed at the University of Lübeck and has received commercial research support in the form of grants by Pharm Allergan, Ipsen, Merz Pharmaceuticals, and Actelion and honoraria for lectures from Pharm Allergan, Ipsen, Merz Pharmaceuticals, Actelion, GlaxoSmithKline (GSK), and Desitin. He has also received support from nonprofit foundations or societies (Possehl‐Stiftung, Lübeck; Dystonia Coalition [USA]; Tourette Syndrome Association [Germany]; European Huntington Disease Network; and the N.E.MO. Charity supporting the research of pediatric movement disorders) and also research support by the Deutsche Forschungsgemeinschaft (MU1692/3‐1; SFB 936) and the University of Lübeck. K. Bhatia has received funding for travel from GSK, Orion Corporation, Ipsen, and Merz Pharmaceuticals, LLC; served on the editorial board of Movement Disorders and serves on the editorial boards of Movement Disorders Clinical Practice and Therapeutic Advances in Neurological Disorders; receives royalties from Oxford University Press; received speaker honoraria from GSK, Ipsen, Merz Pharmaceuticals, LLC, and Sun Pharmaceutical Industries Ltd.; personal compensation for scientific advisory board for GSK and Boehringer Ingelheim; received research support from Ipsen and from the Halley Stewart Trust through Dystonia Society UK, and the Wellcome Trust MRC strategic neurodegenerative disease initiative award (ref. no.: WT089698), a grant from the Dystonia Coalition, and a grant from Parkinson's UK (ref. no.: G‐1009).