Diagnostic approach to paediatric movement disorders: a clinical practice guide

IEMInborn error of metabolism NGS Next-generation sequencing PMD Paediatric movement disorder WES Whole-exome sequencingPaediatric movement disorders (PMDs) comprise a large group of disorders (tics, myoclonus, tremor, dystonia, chorea, Parkinsonism, ataxia), often with mixed phenotypes. Determination of the underlying aetiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This can make the diagnostic process time-consuming and difficult. In this overview, we present a diagnostic approach for PMDs, with emphasis on genetic causes. This approach can serve as a framework to lead the clinician through the diagnostic process in eight consecutive steps, including recognition of the different movement disorders, identification of a clinical syndrome, consideration of acquired causes, genetic testing including next-generation sequencing, post-sequencing phenotyping, and interpretation of test results. The aim of this approach is to increase the recognition and diagnostic yield in PMDs.
In recent years, the importance of recognition and treatment of paediatric movement disorders (PMDs) has increasingly been recognized.PMDs often comprise a mixed clinical picture with neurological and non-neurological features.In addition, the number of possible aetiologies is growing, especially those concerning genetic causes. Owing to a variable phenotype-genotype correlation, the diagnostic process for PMDs becomes challenging and time consuming, not only for the clinician but also for patients and caregivers. [bib_ref] Crossing barriers: a multidisciplinary approach to children and adults with young-onset movement..., Van Egmond [/bib_ref] Innovative next-generation sequencing (NGS) techniques have increased the diagnostic yield in paediatric neurology. [bib_ref] A post hoc study on gene panel analysis for the diagnosis of..., Van Egmond [/bib_ref] The use of NGS can speed up the diagnostic process and prevent unnecessary additional investigations, and shorten the time of uncertainty in patients and caregivers. Second, in some disorders, early treatment options are crucial to prevent further neurological decline.
The goal of this overview is to present a diagnostic algorithm that can serve as a framework for paediatricians and/ or (paediatric) neurologists with less experience in PMDs [fig_ref] Figure 1: A diagnostic approach to paediatric movement disorders [/fig_ref].

## Clinical phenotype
Step 1. Is it a movement disorder?
The first step is to distinguish normal, physiological developmental motor patterns and pathological movement disorders. Infantile fidgety movements and startles resembling chorea and myoclonus normally disappear around the age of 3 months. [bib_ref] The neurological phenotype of developmental motor patterns during early childhood, Kuiper [/bib_ref] Dystonic-like features may appear from birth and can persist until the age of 16 years. [bib_ref] The neurological phenotype of developmental motor patterns during early childhood, Kuiper [/bib_ref] The development of goal-directed movements coincides with the occurrence of ataxic-like features which can persist until the age of 12 years. [bib_ref] The neurological phenotype of developmental motor patterns during early childhood, Kuiper [/bib_ref] It may be difficult to distinguish physiological developmental motor patterns from pathological movement disorders. Children should be monitored to evaluate how the movement pattern develops. In general, physiological patterns will subside with typical psychomotor development. Besides developmental features, other neurological diseases (such as epilepsy) may resemble movement disorders.
Step 2. Classify the movement disorder phenotype and which movement disorder is the most prominent
The second step is to classify the movement disorder phenotype and denote which movement disorder is the most prominent. Clinical clues can be used to distinguish between different movement disorder phenotypes. Movement disorders are classified into three major groups: hyperkinetic and hypokinetic movement disorders and ataxia. In children, hyperkinetic movement disorders are more prevalent and include tics, dystonia, chorea, myoclonus, stereotypies, and tremor. Hypokinetic movement disorders, including Parkinsonism, are rare in children. Ataxia is not a hypo-or hyperkinetic movement disorder, but includes disorganized and poorly executed movements, and is relatively common in children. [bib_ref] Movement disorders in children, Schlaggar [/bib_ref] 

## Hyperkinetic movement disorders
Tics. Tics are defined as sudden, rapid, recurrent, nonrhythmic movements or vocalizations (Video S1, online supporting information; descriptions of the videos are found in Appendix S1, online supporting information).A distinction is made between motor and phonic tics and each is subdivided as simple or complex. Simple motor tics comprise a single muscle or localized muscle group, such as eye blinking. Complex motor tics involve either a cluster of simple actions or a coordinated sequence of movements. Simple phonic tics include sounds and noises such as humming or sniffing, whereas complex phonic tics comprise the repetition of words, syllables, or phrases. Positive clues are a waxing and waning course, worsening by stress or excitement, the report of a premonitory sensation, and brief voluntary suppressibility followed by a rebound. [bib_ref] Diagnosis and assessment of Parkinson disease and other movement disorders, Jankovic [/bib_ref] Dystonia. Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned, twisting, and may be tremulous (Video S2, online supporting information). Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Symptoms can be present in one body part (focal), additional/adjacent body parts (segmental), unilateral (hemidystonia), or generalized. Slow, continuous, involuntary writhing movements that prevent maintenance of a stable posture, previously known as athetosis, are considered as part of a dystonic phenotype. Features supporting the diagnosis dystonia include mirror movements and a sensory trick. [bib_ref] Dystonia in children and adolescents: a systematic review and a new diagnostic..., Van Egmond [/bib_ref] These features may help clinicians to differentiate between dystonia and 'dystonia mimics'. [bib_ref] Dystonia in children and adolescents: a systematic review and a new diagnostic..., Van Egmond [/bib_ref] The most important dystonia mimic is spasticity. Key features in distinguishing spasticity from dystonia are the presence of velocity-dependent hypertonia, hyperreflexia, and pathological plantar responses. Spastic posturing reveals prominent flexion of the elbow and wrist with adduction of the thumb. Chorea. Chorea is characterized by an excess of brief, continuous, unpatterned involuntary movements (Video S3, online supporting information).The continuous, non-suppressible movements give the appearance of restlessness. The presence of involuntary movements at rest, worsening during action, and incorporation of excessive movements in voluntary movements are clues for this phenotype. Myoclonus. Myoclonus is the fastest movement disorder, characterized by brief involuntary, irregular jerks caused by muscle contraction (positive myoclonus) or loss of muscle activity in active postural muscles (negative myoclonus) (Video S4, online supporting information). Myoclonus is classified according to the anatomical origin into cortical, subcortical, spinal, and peripheral myoclonus. [bib_ref] Parkinson Disease and other Movement Disorders, Zutt [/bib_ref] Cortical myoclonus is the most common myoclonus subtype whereas peripheral myoclonus is rare. [bib_ref] Parkinson Disease and other Movement Disorders, Zutt [/bib_ref] Clinical features and electrophysiological testing can help to differentiate between myoclonus subtypes and tremor.Stereotypies. Stereotypies encompass non-goal-directed fixed movement patterns or vocalizations that are repeated continuously for a period of time (seconds to minutes) in the same form (Video S5, online supporting information). These patterns occur on multiple occasions, are purposeless, and are typically distractible. [bib_ref] Stereotypies: a critical appraisal and suggestion of a clinically useful definition, Edwards [/bib_ref] Examples are hand/arm flapping and head nodding. [bib_ref] Stereotypies: a critical appraisal and suggestion of a clinically useful definition, Edwards [/bib_ref] Stereotypies usually manifest before the age of 3 years. [bib_ref] Stereotypic movement disorders, Katherine [/bib_ref] The movements are triggered by excitement, stress, or fatigue. Stereotypies are frequently upsetting to caregivers, but usually of little concern to the child.Tremor. Tremor is defined as an involuntary, rhythmic, oscillatory movement of a body part (hands, legs, head, or jaw) or the voice (Video S6, online supporting information). 14 It can occur at rest, during sustained postures, during movements, and at the end of intentional movements.

## Hypokinetic movement disorders
Parkinsonism. Parkinsonism is characterized by the core symptom bradykinesia with the occurrence of tremor, rigidity, or both (Video S7, online supporting information). [bib_ref] Juvenile parkinsonism: differential diagnosis, genetics, and treatment, Niemann [/bib_ref] Parkinsonism can be recognized by a generalized slowness of movements. When patients with bradykinesia are asked to perform repetitive movements, the amplitude decreases and becomes less rhythmic. The tremor in juvenile Parkinsonism is frequently a rest tremor, but postural or action tremor can also be found. [bib_ref] Juvenile parkinsonism: differential diagnosis, genetics, and treatment, Niemann [/bib_ref] Ataxia Ataxia is characterized by the presence of uncoordinated movements (Video S8, online supporting information). The symptoms are subdivided in four domains: (1) gait and stance with a broad-based gait, staggering, and swaying; (2) kinetic ataxia with an intentional tremor, dysmetria, and dysdiadochokinesis; (3) eye movements with nystagmus, saccadic intrusions, and dysmetria; and (4) cerebellar dysarthria.The difficulties in coordination are mainly present when turning during walking and the execution of faster, goal-directed movements. At rest, there are no involuntary movements.
Step 3. Could the movement disorder be functional?
Functional movement disorders can either be hyper-or hypokinetic, with the first being much more prevalent. The diagnosis of a functional movement disorder is no longer made per exclusion, but should be a positive diagnosis, based on features in the history and examination. [bib_ref] Functional neurologic symptoms: assessment and management, Stone [/bib_ref] These features are abrupt onset, varying (severity of) symptoms, and a temporary decrease of symptoms when the patient is distracted. Specifically in the case of tremor or jerky movements, entrainment can be objectified, a phenomenon in which the involuntary movements copy the rhythm of an externally cued voluntary movement (like finger-tapping).In functional dystonia, the posturing is frequently fixed instead of mobile.Additional features pointing in the direction of a functional movement What this paper adds - An up-to-date description and diagnostic framework for testing of paediatric movement disorders is presented.
- The framework helps to determine which patients will benefit from nextgeneration sequencing.
Clinical Practice Guide 253 disorder include a history of unexplained medical symptoms, prominent pain, paroxysmal symptoms, and sometimes a physical or psychosocial trigger and selective disability. [bib_ref] Psychogenic movement disorders in children, Ferrara [/bib_ref] Despite these characteristics, it sometimes remains difficult to distinguish functional movement disorders from non-functional ones, and they can coincide in the same patient.
Step 4. Determine the clinical syndrome
We denote the clinical syndrome as the constellation of all clinical features, including different movement disorders, as well as additional neurological signs (such as spasticity, epilepsy, polyneuropathy, deafness, blindness, and cognitive difficulties) and non-neurological signs (including dysmorphisms, skin and psychiatric abnormalities [e.g. obsessivecompulsive disorder, behavioural changes, apathy]). Sometimes the clinical syndrome strongly points to a specific diagnosis and prompts directed genetic testing. However, in children, clinical syndromes are usually less distinct. In these cases, it is advisable to select the main movement disorder as the starting point for diagnostic testing. In the following section we outline the basic approach grouped by the main movement disorder phenotype. We also provide references to diagnostic algorithms for some specific movement disorders.

## Tics
Tics are divided into either primary or secondary tic disorders. Primary tic disorders are the most common. Transient tic disorder is the most frequent primary tic disorder in children followed by Tourette syndrome. Secondary tic disorders are rare and can be caused by acquired or genetic disorders (chromosomal or heredo-degenerative). It has been hypothesized that an acute onset of tics with neuropsychiatric symptoms (such as obsessive-compulsive disorder) might be associated with an aberrant immune response to an infectious episode, described as paediatric auto-immune neuropsychiatric disorder associated with streptococcal infection; however, the true relation with streptococcal infection is still debated. [bib_ref] Movement disorders in children, Schlaggar [/bib_ref] If the patient has an isolated tic disorder, further diagnostic testing is not necessary.

## Dystonia
The aetiology of dystonia can be divided into acquired or genetic. Acquired causes can be divided in structural lesions, vascular insults, and infectious or auto-immune disorders. For genetic dystonia the list of causes is extensive. [bib_ref] Dystonia in children and adolescents: a systematic review and a new diagnostic..., Van Egmond [/bib_ref] Classification of the clinical characteristics of dystonia is important, because of the implications for diagnostic testing and treatment. [bib_ref] Dystonia in children and adolescents: a systematic review and a new diagnostic..., Van Egmond [/bib_ref] [bib_ref] Assessment of patients with isolated or combined dystonia: an update on dystonia..., Fung [/bib_ref] van Egmond et al. described a diagnostic algorithm to help clinicians decide which patients would benefit from NGS technologies or whether they would require other initial investigations. 8

## Chorea
To facilitate diagnosis, a (sub-)acute onset should be distinguished from chronic chorea. (Sub-)acute chorea is the most common form in children; the aetiology is frequently acquired and can be subdivided into auto-immune (Sydenham chorea), infectious/inflammatory, vascular, hypoxic, and drug-or toxin-induced. Chronic chorea is categorized as primary (isolated genetic chorea) or secondary (perinatal hypoxic ischemic injuries, neurodegenerative, and metabolic or auto-immune disorders). The secondary aetiologies are mainly multisystem diseases in which chorea can Could the MD be functional? be the main symptom, but it is often accompanied by other (non-)neurological symptoms. [bib_ref] Acute and chronic chorea in childhood, Gilbert [/bib_ref] In particular in the latter case, further genetic diagnostic work-up with NGS is warranted (see .

## Myoclonus
Myoclonus can be the symptom of a wide variety of acquired and genetic disorders. A (sub-)acute onset and fast progression points towards acquired causes, whereas young-onset and a slow progressive course is more characteristic of a genetic disorder. The most common acquired causes include drug-induced, metabolic derangements, infection, or auto-immune disorders. In genetic disorders, myoclonus is often accompanied by ataxia, dystonia, or other movement disorders. Isolated myoclonic jerks can be seen in epileptic encephalopathies and familial cortical myoclonic tremor with epilepsy; for a comprehensive overview of genetic myoclonus disorders, see van der Veen et al. [bib_ref] Nomenclature of genetically determined myoclonus syndromes: recommendations of the International Parkinson and..., Van Der Veen [/bib_ref] A diagnostic approach to patients with myoclonus can be found in Zutt et al. [bib_ref] A novel diagnostic approach to patients with myoclonus, Zutt [/bib_ref] 

## Stereotypies
Causes of stereotypies can be divided into four groups. Physiological and primary stereotypies are seen during typical development and they will disappear over time. Secondary stereotypies are seen in children with a variety of underlying disorders, such as developmental delay, autism, (para)infectious, paraneoplastic, auto-immune, drug induced, or they are due to sensory deprivation. Only in rare cases are stereotypies due to genetic causes, including Rett syndrome. [bib_ref] Stereotypies: a critical appraisal and suggestion of a clinically useful definition, Edwards [/bib_ref] In a typically developing child, stereotypies will not need further diagnostic work-up. Further diagnostic work-up (such as infectious, auto-immune, and/or genetic testing) is indicated only if additional features are present.

## Tremor
In patients with tremor it is advisable to look for additional signs, such as dystonia, Parkinsonism, and cerebellar or brainstem signs, pointing towards a combined clinical syndrome that warrants specific diagnostic tests. 14 If no additional signs are present, the patient has an isolated tremor syndrome, such as essential or enhanced physiological tremor. Enhanced physiological tremor can be caused by several reversible conditions, such as anxiety, fatigue, hyperthyroidism, and numerous drugs. 14 Essential tremor is familial in half of the patients. [bib_ref] Essential tremor, Haubenberger [/bib_ref] Parkinsonism Isolated Parkinsonism is rare in childhood and is observed in young-onset Parkinson disease; in most cases there is a positive family history. In children, Parkinsonism is frequently accompanied by other movement disorders or other neurological signs (cognitive decline, behavioural disturbances). [bib_ref] Juvenile parkinsonism: differential diagnosis, genetics, and treatment, Niemann [/bib_ref] Parkinsonism can be due to acquired (e.g. medication, toxins, infectious) or genetic/metabolic causes, including Wilson disease, neurodegeneration with brain iron accumulation, and neurotransmitter disorders. Importantly, juvenile Parkinsonism can be caused by different trinucleotide disorders (such as Huntington disease and spinocerebellar ataxia type 3). It is important to realize that these disorders are not identified by current NGS techniques and require specific genetic testing. In case of Parkinsonism the first step will be to perform magnetic resonance imaging (MRI) with susceptibility-weighted images to give guidance to further diagnostic work-up, especially genetics.

## Ataxia
Paediatric-onset ataxia is also caused by acquired or genetic disorders. [bib_ref] The natural history of degenerative ataxia: a retrospective study in 466 patients, Klockgether [/bib_ref] Acquired causes are recognized by the (sub)acute onset as genetic disorders reveal a more insidious onset. Acquired causes can be medication, toxins, (para-)infectious, paraneoplastic, vascular, or auto-immune. Many genetic disorders can cause a mixed ataxic disorder, which is combined with other movement disorders or (non)-neurological signs. The most prevalent ataxic disorder in children, Friedreich ataxia, which is a trinucleotide disorder, will not be picked up by current NGS techniques. For a diagnostic approach of ataxia in children, see Case example (steps 1-4 of the algorithm)
A 2-year-old male presented to the outpatient clinic with slowly progressive balance disturbances and frequent falls. The symptoms did not start after a febrile episode. Besides these complaints, there were no other problems. Cognitive development was typical. He was born at a gestational age of 40+3 weeks after an uncomplicated pregnancy. Apgar scores postpartum were normal. Gross motor development was delayed. Communicative skills and fine motor skills were normal. Family history was negative for movement disorders, epilepsy, or developmental disorders. Neurological examination revealed a severely unsteady and very broad-based gait. Beside the broad-based gait there were fast abrupt jerks of the extremities and the trunk resulting in more balance problems. During finger pointing these jerks were also present, without clear dysmetria. Reflexes were normal with normal plantar responses. Physical examination showed no abnormalities of the skin or signs of other organ involvement.
The findings of the history and neurological examination were compatible with prominent gait ataxia combined with jerky movements, probably myoclonus. Therefore, we defined the clinical syndrome as a progressive ataxia with myoclonus.

## Diagnostic testing
Step 5. Can the movement disorder be caused by an acquired cause?
Almost all movement disorders can be caused by acquired causes, but, as previously discussed, the onset in acquired movement disorders is more (sub)-acute. In this section we briefly discuss the additional investigations besides careful Clinical Practice Guide 255 history taking including prescribed medication [fig_ref] Table 1: Medication with movement disorders as side effects [/fig_ref] and intoxication.

## Mri
The first step in identifying an acquired cause is to perform MRI of the brain. Vascular and traumatic causes can be visualized. MRI might give clues for auto-immune disorders and some genetic/metabolic disorders.

## Laboratory testing
Especially in the case of infectious or auto-immune disease, laboratory testing can be helpful by determining infectious and auto-immune parameters. Serological testing of viral and bacterial agents is also useful.

## Cerebrospinal fluid
The presence of a pleiocytosis in cerebrospinal fluid points to an infectious or auto-immune disorder. Additional serological testing and determining auto-immune antibodies in cerebrospinal fluid can be performed thereafter.
Step 6. Does the clinical syndrome fit a treatable inborn error of metabolism?
Clinicians should be aware that, especially in children with more than one movement disorder, involvement of multiple organs, and/or cognitive difficulties, the underlying aetiology could be an inborn error of metabolism (IEM). Worsening of symptoms after dietary changes, fasting, or fever can be important clues for an IEM.
Treatment options are increasing for metabolic disorders and more therapies are expected. A fast recognition of a treatable IEM is crucial as timely treatment can prevent or lessen (brain) damage. [bib_ref] Movement disorders in treatable inborn errors of metabolism, Ebrahimi-Fakhari [/bib_ref] Therefore, in many countries, several treatable IEMs are included in newborn screening programmes and treatment can be started before symptoms have occurred. It is important to realize that IEMs comprise a large group of disorders which are all based on genetic mutations and can be detected by NGS techniques similar to other genetic disorders.
Therapeutic options for IEMs are divided into reduction of toxic substances, dietary interventions, vitamin supplementation, avoidance or management of triggers, specific medications, and others. [bib_ref] Treatable inherited rare movement disorders, Jinnah [/bib_ref] For a list of treatable metabolic disorders that can present with movement disorders, see [fig_ref] Table 1: Medication with movement disorders as side effects [/fig_ref] (online supporting information). [bib_ref] Movement disorders in treatable inborn errors of metabolism, Ebrahimi-Fakhari [/bib_ref] [bib_ref] Treatable inherited rare movement disorders, Jinnah [/bib_ref] [bib_ref] Clinical and biochemical footprints of inherited metabolic diseases. I. Movement disorders, Ferreira [/bib_ref] Step 7. Consider genetic testing If acquired causes are excluded, genetic testing should be the next step. Below, we discuss which genetic testing is most appropriated to perform first. (1) In the case of a clear phenotype/genotype correlation or in case of a positive family history, the performance of directed genetic testing of a single gene (Sanger sequencing) is warranted.
(2) If there is no clear phenotype/genotype correlation, a first-tier test in PMD can be comparative genomic hybridization. The diagnostic yield will increase if patients have a movement disorder combined with cognitive difficulties, autism, and/or dysmorphisms. (3) We recommend that when there is a genetic differential diagnosis of two or more genes it is cheaper (and faster) to perform NGS instead of single gene analysis.
Whole-exome sequencing (WES) is the most applied basic technique for NGS. [bib_ref] Exome sequencing: how to understand it, Keogh [/bib_ref] In general, the first step in the genetic diagnostic process of PMDs is the use of a WES with a movement-disorder-specific filter. In these cases, a filter with predefined genes associated with the main movement disorder phenotype will be analysed. When the diagnosis is not established by using this filter, an analysis of the data set of all the genes captured (open WES) can be performed next.
When using NGS techniques one should be aware of the limitations: (1) the genes in the filter need to be selected carefully and be update regularly; (2) trinucleotide repeat expansion disorders, large rearrangement deletions and duplications, mutations in the non-coding part of the genome (such as deep intronic regions or promotor regions) are not detected; [bib_ref] Exome sequencing: how to understand it, Keogh [/bib_ref] (3) mitochondrial diseases due to mutations in mitochondrial DNA are not detected by most laboratories using WES; one should realize that the
[formula] Anticonvulsants U U U U U U Antipsychotics U U U U Antidepressants U U U U Antihypertensives U Antiparkinson drugs U U Antibiotics U U Antineoplastic U U U Opiates U Anxiolytics U U Anaesthetics U Oral contraceptives U Anti-emetics U U Immunosuppressants U U Corticosteroids U U [/formula]
The table shows groups of medication known to cause different movement disorders. The list is not complete and only shows the main classes of drugs that may induce movement disorders.
current diagnostic yield of NGS techniques is only 15% to 40%, but probably will increase in forthcoming years.
Step 8. Post-NGS phenotyping
The results of NGS techniques can be difficult to interpret. Frequently, results reveal variants of unknown significance or heterozygotic mutations in a gene associated with a recessive disease. In these cases, it is extremely important that focused phenotyping for specific movement disorder features is performed. If the movement disorder phenotype is congruent with the phenotype of the disease (in which a variant of unknown significance or heterozygous mutation is present), further genetic investigations will be necessary to determine whether the variant(s) found explain the clinical phenotype of the patient. This includes a multiplex ligation-dependent probe amplification of the gene involved to find structural rearrangements such as duplications or deletions, which in combination with a heterozygous mutation may explain the phenotype. Also, genetic testing of parental DNA (for de novo mutations) and functional studies of the candidate gene may be warranted. Unfortunately, a definitive diagnosis cannot always be made with the help of post-NGS phenotyping.
Case example (steps 5-8 of the algorithm)
Brain MRI revealed slight hypoplasia/atrophy of the superior part of the vermis of the cerebellum, with no other cerebellar or cerebral abnormalities. Laboratory investigations were all normal. We performed genetic testing by using a WES technique with an ataxia filter (the most prominent movement disorder). This revealed a heterozygotic pathogenic mutation in the KCNC3 gene (c.1268G>A, p.
[Arg423His]) compatible with autosomal dominant spinocerebellar ataxia type 13. However, spinocerebellar ataxia type 13 is not associated with (negative) myoclonus. By post-phenotyping with the help of a polymyography, we found that the jerky movements did not fit with myoclonus but were more compatible with an intention tremor, changing the clinical syndrome to a purer ataxic disorder.

## Treatment
With or without a diagnosis, one should always consider treatment options. In movement disorders, mechanismbased treatment modalities for specific (especially metabolic) disorders or symptomatic treatment for the main movement disorder can be chosen.

# Conclusion
PMDs concern a large group of disorders with heterogeneous phenotypes and genotypes, and diagnostic work-up can be challenging and time-consuming. In this paper, we have presented an up-to-date overview of PMDs and provided a diagnostic framework to facilitate early recognition of movement disorder phenotypes and guidance during the diagnostic process.

# Data availability statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

## Supporting information
The following additional material may be found online:
Video S1: Tics. Appendix S1: Legends to the videos. [fig_ref] Table 1: Medication with movement disorders as side effects [/fig_ref] : Treatable inborn errors of metabolism that can present with pediatric movement disorders
[fig] Figure 1: A diagnostic approach to paediatric movement disorders (PMDs). The diagnostic approach of PMDs divided in a clinical part (history and examination) and diagnostic part (diagnostic testing). Each step of this approach is explained in the text. [Colour figure can be viewed at wileyonlinelibrary.com] [/fig]
[table] Table 1: Medication with movement disorders as side effects [/table]