Dissecting the Phenotypic Spectrum and Complexity of Movement Disorders in 22q11.2 Deletion Syndrome

ABSTRACT

Background and Purpose

Movement disorders are increasingly recognized as late‐occurring neurologic manifestations of 22q11.2 deletion syndrome (22q11.2DS). We aimed to dissect the spectrum of relevant movement disorders in 22q11.2DS, including clinical and electrophysiologic presentations and effective therapies.

Methods

Retrospective review of medical records, medication histories, and videotaped examinations was conducted in 31 unrelated adults (55% female) diagnosed with 22q11.2DS and a movement disorder who were seen at a major center of excellence from June 1996 to September 2023. Between‐group comparisons were performed to explore the influence of medications on movement disorder presentations.

Results

The median age at movement disorder onset was 35.5 (IQR: 22.0) years. Non‐parkinsonian tremor was the most common phenotype (21/31, 68%), followed by parkinsonism (13/31, 42%), dystonia (11/31, 36%), myoclonus (9/31, 29%), dyskinesia (6/31, 19%), stereotypies, and functional movement disorders (4/31, 13% each). The majority of patients (24/31, 77%) presented with two or more movement disorder phenotypes (median 3, range: 2–7). Similar trends in prevalence emerged after accounting for antipsychotic exposure and potential drug‐related movement disorders. Electrophysiological assessments identified both previously described and novel motor phenotypes. Treatment data for at least one movement disorder (available for 20/31, 65%) indicated a positive response to standard phenotype‐based interventions.

Conclusions

We demonstrate that movement disorders in adults with 22q11.2DS exhibit greater clinical complexity than previously reported, which could reflect innate vulnerability and pathologic mechanisms beyond medication side effects. In those with a confirmed 22q11.2 microdeletion, periodic neurologic evaluations, supported by electrophysiologic investigations, enable accurate diagnosis and implementation of personalized management strategies.

In this study, we deeply phenotyped 31 unrelated adults with molecular confirmation of 22q11.2 microdeletion who were referred for neurologic assessments at a major centre of excellence in movement disorders. At the group level, majority (77%) presented with two or more movement disorder phenotypes, with similar trends in prevalence after accounting for antipsychotic exposure and potential drug‐related movement disorders. Electrophysiological assessments identified both previously described and novel motor phenotypes. In those with a confirmed 22q11.2 microdeletion, periodic neurologic evaluations, supported by electrophysiologic investigations, enable accurate diagnosis and implementation of personalized management strategies.

1. Introduction

Over the last 30 years, 22q11.2 deletion syndrome (22q11.2DS) has been increasingly diagnosed [1]. This complex genomic syndrome presents with variably penetrant neuropsychiatric features, with movement disorders representing important late‐occurring manifestations [2, 3, 4]. Since 2013, evidence has identified the 22q11.2 microdeletion as a genetic risk factor for early‐onset Parkinson's Disease (PD) with a clinico‐pathologic presentation largely indistinguishable from sporadic PD [5, 6, 7]. Other studies have reported an expanding range of motor phenotypes, including other hypokinetic, hyperkinetic, functional, and drug‐induced movement disorders [3, 8, 9]. However, a systematic characterization of movement disorder phenomenologies, electrophysiologic features, and management in 22q11.2DS remains limited.

Here, we aimed to more deeply phenotype clinically relevant motor manifestations of 22q11.2DS based on comprehensive neurologic assessments at a major center of excellence in movement disorders. We focused on phenomenological classifications, electrophysiologic findings, and therapeutic response in an effort to enhance diagnosis and management. Recognizing the link between antipsychotic treatment and extrapyramidal motor symptoms in a condition with an elevated risk for schizophrenia [10], we explored the influence of antipsychotic use on movement disorder presentations in 22q11.2DS.

2. Methods

2.1. Phenotypic Characterization

We included adult patients (age ≥ 18 years) with a molecularly confirmed typical chromosome 22q11.2 microdeletion consecutively assessed at the Toronto Western Hospital Movement Disorders Centre, Toronto, Canada from June 1996 to September 2023. Patients without molecular confirmation of 22q11.2 microdeletion, and genetically diagnosed cases without a movement disorder based on detailed neurologic assessments were excluded.

Retrospective review of medical records was conducted to collect relevant clinico‐demographic variables and characterize motor phenotypes based on the clinical history, neurologic examination, and diagnostic impression made by the treating specialist. Medication histories and videotaped examinations were carefully reviewed, and standard definitions and clinical criteria were applied to further classify movement disorders. Where clinically indicated and data were available, results of special movement disorder electrophysiologic tests from our centre [11], as well as data regarding effective pharmacologic and non‐pharmacologic therapies were obtained. For patients with parkinsonism, we additionally noted the presence of motor fluctuations, levodopa‐induced dyskinesia, use of dopaminergic and adjunctive therapies, total levodopa equivalent daily dose (LEDD) [12], and Unified Parkinson's Disease Rating Scale Part III (UPDRS or MDS‐UPDRS III) scores in the OFF and ON states (additional details are in Supporting Information) [13, 14].

Within the full cohort, we delineated unpublished and previously reported cases. To assess the degree of individual‐level complexity of phenotypic presentations, we analyzed the full cohort to quantify the frequency of movement disorder phenomenologies per individual. To characterize novel phenotypes, we noted (1) movement disorders in unpublished cases, and (2) newly described clinical and/or electrophysiological diagnoses in previously reported cases during their follow‐up movement disorder assessments.

This study was approved by the local research ethics board. For more information regarding the methods, see Supporting Information.

2.2. Statistical Analysis

Descriptive statistics using median (interquartile range [IQR] or range) for continuous variables, and frequencies and proportions for categorical data were applied. Where appropriate, we used Fisher's exact test and Mann–Whitney U test to explore the relationship between antipsychotic exposure and relevant clinical and motor‐related features. Additional information regarding exploratory analyses can be found in the Supporting Information. Statistical analyses were performed using Stata Statistical Software: Release 17 (College Station, Tx: StataCorp LLC).

3. Results

3.1. General Demographic and Clinical Characteristics

Tables 1 and 2 summarize relevant demographic, clinical, and motor‐related features. Of the 34 unrelated individuals seen at our centre, 31 (91%)55% female) were included (Figure S1), who together had 111 clinic visits and were followed for a median of 1.5 (IQR: 5.8) years after excluding one outlier (i.e., one patient with hemifacial spasm receiving chemodenervation every 3 months). The majority (19/31, 61%) were unpublished, while all previously reported cases had new follow‐up data. Most (94%) had the common ~2.5 Mb 22q11.2 microdeletion confirmed, on average, in early adulthood (median age 25.8 [IQR: 28.5] years) with onset of the first movement disorder occurring later (median age 35.5 [IQR: 22.0] years). Compared to published estimates in 22q11.2DS [15], the sample tended to have a low prevalence of major congenital heart disease (5/31, 16%) and a higher prevalence of moderate to severe ID (7/31, 23%), recurrent seizures or epilepsy (12/31, 39%), and psychotic disorders (21/31, 68%). Of the 22 (71%) patients who had a lifetime history of antipsychotic treatment, more than half (12/22, 57%) had ongoing exposure to agents other than clozapine or quetiapine at the last assessment (Table S1 and Table S2).

TABLE 1.

Baseline demographic and clinical features of 31 adults with 22q11.2 microdeletion included in the study.

Demographic or clinical variable	Full cohort (n = 31)
Demographic features	Median or n	IQR or %
Age at confirmation of 22q11.2 microdeletion in years	25.8	28.5
22q11.2 microdeletion extent
Most common (i.e., LCR22A‐LCR22D)	29/31	93.5
Proximal nested (i.e., LCR22A‐LCR22B)	2/31	6.5
Sex
Male	14/31	45.2
Female	17/31	54.8
22q11.2DS‐associated major features
Velopharyngeal insufficiency	14/31	45.2
Surgically repaired	8/14	57.1
Major congenital heart disease (e.g., Tetralogy of Fallot)	5/31	16.1
Recurrent seizures/epilepsy	12/31	38.7
Moderate–severe intellectual disability	7/31	22.6
Non‐psychotic disorder (e.g., anxiety, mood disorders)	20/31	64.5
Psychotic disorder (e.g., schizophrenia)	21/31	67.8
Ever exposed to any antipsychotic medication	22/31	71.0 a

Abbreviations: 22q11.2DS, 22q11.2 deletion syndrome; IQR, interquartile range; LCR, low copy repeat.

^a n = 21/22 with psychotic disorder; n = 1/22 with non‐psychotic disorder (i.e., adjustment disorder with depressed mood).

TABLE 2.

Motor‐related features of 31 adults with 22q11.2 microdeletion based on comprehensive neurologic assessments.

Demographic or clinical variable	Full cohort (n = 31)
	Median	IQR or range
Ages in years
Initial movement disorder assessment	40.0	23.0
Last movement disorder assessment	45.0	21.0
AAO of first movement disorder	35.5	22.0 a
Symptom duration prior to movement disorder assessment in years a	3.5	7.0
Follow‐up duration	2.0	6.0
Number of visits	3.0	1 – 66 b

Proportion of individuals with movement disorder, n (%)	All c	Not/unlikely drug‐related	Potentially drug‐related
Non‐parkinsonian tremor	21 (67.7)	12 (57.1)	9 (42.9)
Parkinsonism	13 (41.9)	8 (61.5)	5 (38.5)
Dystonia	11 (35.5)	5 (45.5)	6 (54.5)
Myoclonus	9 (29.0)	6 (66.7)	3 (33.3)
Dyskinesia	6 (19.4)	0 (0)	6 (100)
Stereotypy	4 (12.9)	4 (100)	0 (0)
Functional movement disorder	4 (12.9)	4 (100)	0 (0)
Other movement disorders d	12 (38.7)	10 (83.3)	2 (16.7)
Individuals with multiple movement disorders, n (%)	24 (77.4)	14 (53.8) e	9 (52.9) f
Median (range) of movement disorders g	3 (2–7)	3 (2–4)	2 (2–4)

Abbreviations: AAO, age at onset; IQR, interquartile range.

^a n = 30 (1/31 with unknown age at onset of movement disorder).

^b Median 2.5 (range 1–15) number of visits when excluding one patient with repeated visits (every ~3 months) for chemodenervation therapy.

^c Includes both unlikely drug‐related and potentially drug‐related movement disorders.

^d Includes movement disorders occurring only in ≤ 2 individuals.

^e n = 26 (i.e., 5/31 only had potentially drug‐related movement disorders).

^f n = 17 (i.e., 14/31 only had movement disorders unlikely to be drug‐related).

^g Among those presenting with multiple movement disorders.

3.2. Movement Disorder Phenomenologies in 22q11.2DS

At the group level, non‐parkinsonian tremor was the most frequently identified movement disorder observed in 21 (68%) patients, followed by parkinsonism in 13 (42%), dystonia in 11 (36%), myoclonus in 9 (23%), dyskinesia in 6 (19%), and stereotypies and functional movement disorders (FMD) (4 each; 13%) (Table 2). Ten other motor phenotypes were collectively observed in 12 (39%) individuals (Table S3). There was a similar pattern of prevalence within subgroups of unpublished and previously reported cases (Table S2).

3.2.1. Non‐Parkinsonian Tremor

Among 21 patients with non‐parkinsonian tremor, nine (43%) were considered potentially related to or exacerbated by medications (Table 2 and Table S1). Postural and kinetic limb tremor were the most common subtypes observed, occurring in 19 (91%) and 16 (76%) cases, respectively. Two novel tremor syndromes were identified: one case each of dystonic tremor and slow orthostatic tremor (electrophysiologic features described below).

3.2.2. Parkinsonism

In the 13 patients with parkinsonism, the median AAO of motor symptoms was 41.0 (IQR: 11.0) years. Bradykinesia was seen in combination with rigidity in 12 (86%) and with rest tremor in 9 (64%) cases. Using current clinical criteria, a diagnosis of PD was made in 8 (62%) patients, while the remainder had parkinsonism of indeterminate etiology (Table S4). Ten (77%) individuals with parkinsonism had a concurrent psychotic disorder, and of these, 7 were on antipsychotic medications other than clozapine or quetiapine during the initial movement disorder assessment. Two of these patients were eventually diagnosed with PD on the basis of (1) symptom progression despite switching to clozapine or quetiapine and (2) a demonstrable levodopa response.

3.2.3. Dystonia

Six of the 11 cases of dystonia were considered potentially related to active exposure to antipsychotic medications (Table 2). Of the five cases deemed unlikely to be drug‐related, four had dystonia associated with PD, while the other patient presented with cervical and limb dystonia years before receiving any antipsychotic therapy (Table S1). Most (7/11, 64%) patients presented with segmental dystonia (Table S3). Of the remaining cases with focal dystonia (4/11, 36%), two had foot involvement, while one each had isolated cranial (oculogyric; associated with active antipsychotic use) and cervical (anterocollis) dystonia. Multifocal, generalized, and hemidystonia were not observed.

3.2.4. Myoclonus

In nine patients with myoclonus (assessed clinically), a temporal association between the movement disorder and selective serotonin reuptake inhibitor (SSRI) exposure could not be ruled out in three cases (Table 2 and Table S1). None of the patients with myoclonus were on clozapine. Five patients presented with spontaneous and action‐induced myoclonus; in the remaining four cases, it was exclusively action‐induced. None demonstrated stimulus sensitivity (Table S3). Electrophysiologic studies were performed in four individuals with clinically assessed myoclonus, and results are further discussed below.

3.2.5. Dyskinesia

All six cases of dyskinesia were considered potentially drug‐related (Table 2). Of these, five were observed in individuals with PD treated with levodopa. In two of these cases, an underlying tardive phenomenon was also considered and thought to be unmasked by levodopa therapy. One patient with no history of psychotic disorder or PD presented with longstanding orofacial dyskinesia deemed to be potentially SSRI‐related (Table S1).

3.2.6. Stereotypies

Four individuals presented with various kinds of stereotypies. Of these, only one patient with clinically relevant moderate–severe ID presented with stereotypies as the sole phenotype. Other than repetitive body‐rocking movements, which occurred in two individuals, stereotypic movements were highly variable and consisted of patterned foot inversion‐eversion with toe flexion‐extension, hand flapping, repetitive interlocking of the hands, and saluting movements.

3.2.7. Functional Movement Disorders (FMD)

Of the four individuals with FMD, three were diagnosed with functional tremor supported by positive clinical signs (i.e., incongruency, lack of internal consistency, suggestibility, prominent muscle co‐contraction). In one of these patients, a functional tremor was seen in conjunction with parkinsonism of indeterminate etiology. Functional gait disorder was diagnosed in two individuals, also supported by positive clinical findings (i.e., incongruency, variability in stride height, suggestibility). One patient with functional myoclonus/jerks presented with variable, high‐frequency movements of facial muscles and had electrophysiologic findings supportive of a functional etiology (see below).

3.2.8. Other Motor Phenotypes

Various infrequent motor phenotypes were each present in one or two individuals (Table S3). One patient had an isolated right hemifacial spasm (HFS). Another patient had bradykinesia as the only movement disorder in the absence of other cardinal motor manifestations of parkinsonism. Bradykinesia, limb‐kinetic apraxia, and akathisia were each present in two patients, whereas motor and vocal tics, RLS, catatonia, and ideomotor apraxia were each observed in individual cases. Two patients had involuntary movements of uncertain significance: one patient had mirror movements of the hand, and another presented with frequent eye blinking.

3.2.9. Multiplicity of Motor Disorders

Within the full cohort, 24 (77%) exhibited multiple (≥ 2) movement disorders with a median of 3 (range 2–7) phenotypes per individual (Table 2). Figure 1 depicts the overall interaction between all motor phenotypes in patients presenting with multiple movement disorders. Commonly observed combinations of movement disorders included non‐parkinsonian tremor associated with parkinsonism or dystonia, parkinsonism associated with dystonia or other less common phenotypes, and dystonia associated with myoclonus (Figure S2 and Table S5).

FIGURE 1.

Arc plot illustrating the co‐occurring movement disorder phenotypes in 22q11.2 deletion syndrome (n = 24/31, 77% of the cohort). Arc width represents the magnitude of phenotypic interactions within the subgroup of patients with multiple movement disorder phenotypes. Frequencies of phenotypic co‐occurrence are indicated within each arc. Representations of per‐phenotype interactions are illustrated in Figure S2. Dysk, dyskinesia unrelated to levodopa; DYT, dystonia; FMD, functional movement disorder; MYO, myoclonus; Non‐PARK TREM, non‐parkinsonian tremor; PARK, parkinsonism; STYPY, stereotypies.

3.3. Electrophysiologic Features Associated With Movement Disorders in 22q11.2DS

In six patients who underwent special movement disorder electrophysiologic studies, cortical myoclonus was diagnosed in four individuals based on published criteria [11, 16]. In these four cases, electrophysiology identified a coexisting 6.5–8 Hz non‐parkinsonian tremor in two patients, and an 8–10 Hz cortical tremor in one patient (Table 3).

TABLE 3.

Movement disorder electrophysiology findings of individuals with 22q11.2 deletion syndrome.

Case	Indication for electrophysiologic testing	Approximate age in years		Recurrent seizures or epilepsy	Electrophysiologic Findings a	EMG burst duration (ms)	Final Classification of Movement Disorder(s)
		Movement disorder onset	Electrophysiologic testing
002	Delineate nature of hyperkinetic movements	Late 40s	Early 50s	+	Positive and negative myoclonus (UE)	40	Cortical myoclonus
008	Delineate nature of hyperkinetic movements	Early 20s	Late 30s	−	Positive and negative myoclonus (UE) 6.5‐Hz postural and action tremor (UE, LE) 7.5‐Hz broad‐based, narrow‐peak with waxing envelope, recruitment of motor units with semi‐rhythmic jerky discharges during finger‐to‐target task, co‐contraction, and motor overflow	20–35	Cortical myoclonus Postural and action tremor Dystonic tremor
015	Delineate nature of hyperkinetic movements	Mid 40s	Late 40s	−	Small‐amplitude, action‐induced surface EMG bursts involving the bilateral orbicularis oculi without involvement of frontalis muscles Normal nerve conduction and needle EMG study of the limbs	120–700	Considered normal MUAPs; Supportive of functional myoclonus/jerks
020	Delineate nature of hyperkinetic movements	Early 20s	Early 20s	−	Irregular surface EMG bursts (bilateral UE and LE) synchronous between agonist–antagonist muscles 8‐Hz postural tremor (bilateral LE)	20–45	Cortical myoclonus Postural tremor
021	Delineate nature of hyperkinetic movements	Adolescence	Late 20s	+	Intermittent multifocal bursts, at times synchronous (bilateral UE) Superimposed rhythmic 8–10 Hz bursts synchronous between agonist–antagonist muscles (bilateral UE)	16–60	Cortical myoclonus Cortical tremor
023	Confirmation of clinically suspected orthostatic tremor	Late 30s	Early 50s	−	Slow tremor with 8–10 Hz rhythmic surface EMG bursts (bilateral LE) with coherence between the two limbs, which transferred to the bilateral UE with leaning forward onto surface and bearing weight on the arms	< 100	Slow orthostatic tremor

Abbreviations: 22q11.2DS, 22q11.2 deletion syndrome; AAO, age at onset; EMG, electromyography; FMD, functional movement disorder; ms, milliseconds; LE, lower extremities; MUAP, muscle unit action potential; UE, upper extremities.

^a Electrophysiology test protocols included surface electromyography, electroencephalography, or a combination of these techniques (see Supporting Information).

Electrophysiologic investigations aided the confirmation of dystonic tremor based on findings of recruitment of motor units with semi‐rhythmic 7.5 Hz discharges of the upper limbs while performing a task. This occurred in association with agonist–antagonist muscle co‐contraction and motor overflow (i.e., activation of muscles not involved in the movement required to perform the task). Slow orthostatic tremor was diagnosed in one patient based on a finding of well‐formed, continuous rhythmic bursts with a frequency of 8–10 Hz (characteristic of tremor) while in the standing position. The muscle activation exhibited high coherence between bilateral homologous leg muscles and proximal agonist–antagonist muscles (Figure S3). The tremulous activity was evident in both arms when leaning forward with weight bearing supported by arms, further assisting the diagnosis.

In one patient with jerky facial movements on clinical examination, surface electromyography (EMG) revealed highly variable, action‐induced EMG bursts lasting between 120 to 700 milliseconds restricted to the orbicularis oculi and oris muscles. Needle EMG showed normal muscle unit action potentials. These findings aided in excluding diagnoses of hemifacial spasm, facial myokymia, or myorhythmia, and supported the diagnosis of functional myoclonus/jerks (Table 3).

3.4. Management of 22q11.2DS‐Associated Movement Disorders

Therapeutic information for at least one movement disorder phenotype based on historical or follow‐up data was available for 20/31 (65%) patients. In general, pharmacologic agents were initiated to treat parkinsonism (including PD), non‐parkinsonian tremor, dystonia, myoclonus, tics, RLS, and hemifacial spasm (see below). Standard symptom‐directed, non‐pharmacologic approaches, including motor retraining physiotherapy and active gait coaching and cueing, were efficacious in FMD cases (Table S6).

All clinically diagnosed PD cases were treated with levodopa, and six out of eight patients received adjunctive therapies (median LEDD 775 [IQR: 525] mg). Typical treatment responses such as improved UPDRS/MDS‐UPDRS Part III scores and development of motor fluctuations and dyskinesia were observed (Table S4). None of the PD cases received advanced therapies such as levodopa intestinal infusion or deep brain stimulation. In three out of five individuals with parkinsonism of indeterminate etiology, a change in the antipsychotic drug class or dose led to symptom improvement (Table S6).

Management of non‐parkinsonian tremor consisted of close monitoring in five cases, while the remainder demonstrated a response to pharmacologic approaches, including modifications in antipsychotic type or dose (2/21, 10%), as well as trials of anti‐seizure drugs (4/21, 20%), beta‐blockers (2/21, 10%), anticholinergic drugs (2/21, 10%), or levodopa (2/21, 20%). Dystonia responded to standard management and pharmacologic approaches such as antipsychotic adjustments (3/11, 27%), anticholinergic drugs (2/11, 18%), and levodopa therapy (1/21, 9%). Myoclonus responded to trials of anti‐seizure drugs (3/9, 33%). Cortical myoclonus in one patient with PD responded to levodopa therapy, alongside improvements in other parkinsonian features based on follow‐up clinical assessments (Table 3, Case 002). Individual cases of tics, RLS, and hemifacial spasm were effectively managed with standard therapeutic approaches (Table S6).

3.5. Exploratory Analyses Based on Antipsychotic Exposure

There were no significant differences between antipsychotic‐naïve and ‐ever exposed individuals with respect to relevant clinico‐demographic variables, onset of first movement disorder, and proportion of individuals having multiple movement disorder phenotypes (p > 0.05). Among the more common (n $\ge$ 5) movement disorders, only a higher proportion of dyskinesia in antipsychotic‐naïve individuals was nominally significant (antipsychotic‐naïve vs. ever‐exposed, 4/9 (44%) vs. 2/22 (9%), p = 0.04) (Table 4). Similar trends were observed when accounting for lifetime antipsychotic‐exposed individuals who were eventually weaned off treatment or switched to clozapine or quetiapine (Table S7).

TABLE 4.

Between‐group comparison of demographic and clinical features of adults with 22q11.2 microdeletion stratified based on antipsychotic exposure status.

Variable	Antipsychotic exposure
	Ever exposed (n = 22)		Never exposed (n = 9)		p
	Median or n	IQR or %	Median or n	IQR or %
Age at confirmation of 22q11.2 microdeletion in years	21.5	21.8	43.2	27.5	0.12 a
AAO of first movement disorder in years b	39.0	15.0	35.0	20.0	0.54 a
Symptom duration prior to movement disorder assessment in years b	5.0	7.0	3.0	5.0	0.90 a
Presence of multiple movement disorders
All movement disorders	17/22	77.3	7/9	77.8	> 0.99 c
Excluding potentially drug‐related movement disorders	9/22	52.9	5/9	55.6	> 0.99 c
Common movement disorder phenotypes d
Non‐parkinsonian tremor	14/22	66.7	7/9	70.0	> 0.99 c
Parkinsonism, including PD	9/22	42.7	4/9	40.0	> 0.99 c
Dystonia	9/22	42.9	2/9	20.0	0.26 c
Myoclonus	6/22	28.6	3/9	30.0	> 0.99 c
Dyskinesia	2/22	9.1	4/9	44.4	0.04 c

Note: Bold font indicates statistical significance.

Abbreviations: AAO, age at onset; IQR, interquartile range; PD, Parkinson's Disease; SD, standard deviation.

^a Mann–Whitney U test.

^b Missing data (n = 1) due to one patient with antipsychotic exposure and unknown AAO of movement disorder.

^c Fisher's exact test.

^d Movement disorders occurring in ≥ 5 individuals.

4. Discussion

Despite the growing body of evidence suggesting an increased prevalence of movement disorders in 22q11.2DS [3, 5, 17], these remain underreported and poorly understood. In this retrospective study involving 31 adults with a 22q11.2 microdeletion who had undergone detailed neurologic assessments over 111 clinic visits at a major center of excellence in movement disorders, we broaden the spectrum of motor phenotypes in 22q11.2DS. This includes not only previously described [3], but also novel phenotypes such as cortical myoclonus and tremor, slow orthostatic tremor, dystonic tremor, functional gait disorder and jerks, hemifacial spasm, apraxic movements, and eyelid movements of uncertain significance. We further highlight the complexity of the clinical presentation and the importance of incorporating electrophysiologic and therapeutic response data.

The main novel finding was the observed multiplicity of movement disorders in 22q11.2DS, with a median of three phenotypes per individual, seen in the majority of cases, and with similar prevalence in those with and without antipsychotic exposure. This complexity remained evident even when potentially drug‐related movement disorders were excluded from analyses. These results suggest that motor presentation in 22q11.2DS is more complex than previously reported, likely stemming from mechanisms inherent to the 22q11.2 microdeletion beyond those merely related to dopamine receptor blockade or other medication side effects [3]. Additionally, the complexity observed in 22q11.2DS parallels motor presentations seen in children and adults with other single‐gene and chromosomal disorders [18, 19, 20, 21] and an increasing number of developmental epileptic‐dyskinetic encephalopathies [22]. We hypothesize that movement disorders, particularly when occurring in combination, represent a motor signature of genetically defined neurodevelopmental syndromes, especially in affected individuals who are followed into adulthood. Although this hypothesis awaits further exploration, the current findings lend support to the crucial role of genetic testing, including clinical microarray, as a first‐tier investigation for patients at any age presenting with mixed movement disorder phenotypes. In addition, our data highlight the importance of periodic neurologic assessments in individuals diagnosed with 22q11.2DS [2].

The current study also offers valuable insights regarding potentially effective management strategies for 22q11.2DS‐associated movement disorders. Our results suggest that, despite the complexity of clinical presentations, movement disorders in 22q11.2DS can be effectively managed when accurately diagnosed. They are amenable to: (1) close monitoring when non‐progressive or non‐bothersome, as seen in stereotypies and some non‐parkinsonian tremor cases; (2) non‐pharmacologic, rehabilitative approaches such as those applied for FMD cases [23]; (3) medication adjustments for presumed drug‐related parkinsonism and dystonia; and (4) pharmacologic therapies tailored to specific movement disorder phenotypes. Importantly, these findings suggest that judicious trial of standard management practices can be implemented in 22q11.2DS, guided by proper recognition of motor phenotypes [2].

Our study additionally reveals key insights into the clinical presentation and diagnosis of individual motor phenotypes in 22q11.2DS.

The clinical features of individuals with parkinsonism align with findings reported in previous studies [6, 7, 24]. When combined with bradykinesia, rigidity was a more frequent accompanying motor feature than rest tremor among individuals assessed to have parkinsonism. Levodopa‐induced dyskinesia was also prevalent among treated PD cases, regardless of their history of antipsychotic exposure or subsequent treatment with clozapine or quetiapine. Collectively, these findings suggest (1) the potential existence of distinct clinical motor subtypes of 22q11.2DS‐associated parkinsonism, (2) a greater tendency for these individuals to exhibit an akinetic‐rigid rather than a tremor‐dominant syndrome, (3) and perhaps an increased susceptibility to developing levodopa‐induced dyskinesia, all consistent with typical features reported in early‐onset PD [25]. The finding of levodopa‐responsive cortical myoclonus in 22q11.2DS‐associated parkinsonism is novel, yet draws parallels with previous rare case reports of myoclonus in idiopathic PD and other atypical parkinsonian syndromes [26, 27, 28]. Further investigations are needed to elucidate the mechanism behind the observed drug response and whether levodopa could represent a therapeutic option for 22q11.2DS‐associated myoclonus. Additionally, future studies are needed to disentangle the clinical heterogeneity and understand the underlying neurobiology of 22q11.2DS‐associated parkinsonism, especially with the advent of in vivo biomarkers [29].

The results further demonstrate that hyperkinetic movements, including non‐parkinsonian tremor, myoclonus, and stereotypies are prevalent in 22q11.2DS and are likely intrinsic to the condition. In some of these cases, our findings highlight the added value of using electrophysiologic tests and criteria—not only in identifying novel motor phenotypes but also in precise subtyping as exemplified by the diagnosis of several tremor and myoclonic syndromes in our sample [3, 11, 16]. For dystonia presentation, focal and segmental distributions were more commonly observed, consistent with prior reports [3]. In contrast to previous observations [3], we found no differences in dystonia occurrence between those with and without lifetime antipsychotic exposure. This discrepancy may be partially attributed to our limited sample size, which precluded further inferential analyses. Notably, our study identified a case of dystonia unrelated to drug exposure or parkinsonism. These findings suggest that while dystonia in 22q11.2DS is often linked to drug exposure or parkinsonism, it can also manifest independently as a motor feature of the syndrome. Further research is needed to explore the innate risk and phenotypic variability of dystonia within this population.

The diagnosis of FMD in 22q11.2DS was made following a framework comparable to the approach to FMD in the general population where historical information, positive clinical signs, and supportive laboratory criteria are integrated to reach a diagnosis [30, 31]. This underscores the value of dedicating sufficient time to elicit core and supportive FMD features in 22q11.2DS, especially since these patients are likely to possess several predisposing, precipitating, and perpetuating factors for this motor phenotype. The finding of functional tremor in a patient with parkinsonism, although only observed in a single case, is worth noting as FMD may occasionally serve as a harbinger of a neurodegenerative disease [30, 32]. Given the elevated risk of PD in 22q11.2DS, longitudinal follow‐up of patients clinically presenting with FMD, alone or in combination with other motor phenotypes, is thus crucial.

Preclinical and clinical studies offer preliminary insights into how hemizygosity at the 22q11.2 locus increases the predisposition for various movement disorders. Proposed mechanisms include (1) aberrant neurogenesis and neuromigration [33]; (2) dysregulated dopaminergic neurotransmission [5, 7, 34], in part, related to reduced dosage of candidate genes such as COMT (coding for catechol‐O‐methyltransferase) and PRODH (coding for proline dehydrogenase) [15, 35]; (3) impaired microRNA (miRNA) biogenesis and miRNA‐dependent cortical gene regulation [36, 37]; and (4) mitochondrial dysfunction resulting from decreased expression of mitochondrial genes within the deleted region [38]. Future efforts are needed to clarify the relationship between these putative mechanisms and motor expression in 22q11.2DS.

To our knowledge, this is the first study to deeply phenotype movement disorder presentations in 22q11.2DS using standard criteria and definitions, electrophysiology, and treatment response data. Nevertheless, our study has some limitations. The retrospective design, coupled with the enrichment of neuropsychiatric comorbidities in our cohort, likely reflects the influence of selection bias. The small sample size—a common challenge in studies of rare disorders—limited our ability to analyze other clinico‐demographic factors and medications beyond antipsychotic exposure. Nonetheless, our primary aim was to provide a descriptive overview rather than establish causal links between 22q11.2DS and movement disorder phenotypes. Efforts are currently underway to delineate the spectrum of movement disorders in the largest well‐characterized cohort of adults with 22q11.2DS. Future multisite efforts and integrated biological and longitudinal assessments are needed to clarify the epidemiology, natural history, diagnostic markers, and mechanisms underlying motor phenotypes in 22q11.2DS.

5. Conclusion

With better detection of 22q11.2DS in adults due to improved diagnostic capabilities and clinical care in children, there is a pressing need to improve our identification and understanding of associated movement disorders. Our analysis indicates that movement disorders in 22q11.2DS are more heterogenous and complex than previously reported. This could reflect multiple, possibly interrelated disease‐related mechanisms that importantly are not wholly attributable to medication effects. In addition to individuals with early‐onset PD, clinicians should consider clinical genetic testing for 22q11.2 microdeletion in adults presenting with mixed movement disorder phenotypes, especially when occurring alongside multisystemic features. Periodic neurologic evaluations and accurate diagnosis of movement disorders in 22q11.2DS, supported by electrophysiologic investigations, are paramount to the implementation of personalized management strategies for 22q11.2DS. The 22q11.2 microdeletion offers a valuable, high‐risk model for investigating the genetic and neurobiological underpinnings of motor dysfunction in complex neuropsychiatric and developmental conditions.

Author Contributions

Nikolai Gil D. Reyes: conceptualization, methodology, data curation, investigation, formal analysis, writing – original draft. Talyta Grippe: investigation, formal analysis, writing – review and editing. Marcus Callister: investigation, writing – review and editing, formal analysis. Tarig Abkur: investigation, writing – review and editing, formal analysis. Emilio Q. Villanueva III: formal analysis, data curation, software, writing – review and editing. Tracy Heung: data curation, software, formal analysis, writing – review and editing. Robert Chen: investigation, formal analysis, data curation, writing – review and editing. Erik Boot: data curation, formal analysis, investigation, writing – review and editing. Anne S. Bassett: data curation, formal analysis, supervision, writing – review and editing, investigation. Anthony E. Lang: conceptualization, methodology, formal analysis, investigation, data curation, writing – review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1.

Figure S1. Study Flow Diagram.

Figure S2. Arc plots illustrating the interactions between each individual movement disorder identified in 31 adults with 22q11.2 microdeletion.

Figure S3. Electrophysiologic findings supporting the diagnosis of slow orthostatic tremor in an individual with 22q11.2 microdeletion.

Table S1.

Table S2. Demographic and clinical data of unpublished and previously reported cases of adults with 22q11.2 microdeletion and movement disorders.

Table S3. Detailed classification of all movement disorders identified in 31 adults with 22q11.2 microdeletion (excluding parkinsonism)*.

Table S4. Subgroup analysis of demographic and clinical features of 13 individuals with 22q11.2DS‐associated parkinsonism.

Table S5. Frequencies and proportions of motor phenotype interactions in 22q11.2DS.

Table S6. Summary of pharmacologic and non‐pharmacologic treatment approaches for movement disorders observed in patients with 22q11.2 microdeletion.

Table S7. Exploratory analysis comparing demographic and clinical features of adults with 22q11.2 microdeletion based on antipsychotic exposure at last movement disorder assessment.

Reyes N. G. D., Grippe T., Callister M., et al., “Dissecting the Phenotypic Spectrum and Complexity of Movement Disorders in 22q11.2 Deletion Syndrome,” European Journal of Neurology 32, no. 6 (2025): e70256, 10.1111/ene.70256.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.