Spectrum of movement disorders and motor abnormalities in adults with a 22q11.2 microdeletion: Comment on the literature and retrospective study of 92 adults

Accumulating evidence suggests that the 22q11.2 microdeletion, associated with 22q11.2 deletion syndrome (22q11.2DS, OMIM #192430, #188400), is a risk factor for the development of movement disorders along with better-known manifestations such as congenital heart defects, hypocalcemia, and schizophrenia [1]. While it is now well-recognized that adults are at increased risk for developing parkinsonism [2], including early-onset Parkinson disease [3, 4], an increasing number of case studies have reported on other movement disorders in adults with 22q11.2DS (summarized in Table 1). However, in contrast to the literature on parkinsonism, systematic studies examining other movement disorders and abnormalities are lacking, making generalizations to the wider adult 22q11.2DS population difficult.

Table 1.

Previously published cases of movement disorders and motor abnormalities in adults with 22q11.2 deletion syndrome.

Authors	Year	PMID	Age, y	Sex	Concurrent neurological/psychiatric disorders	Clinical presentation of movement disorder and motor abnormalities	Medications (daily dose)
Dystonia total (n = 24)
Van Iseghem et al.	2020	32002279	41 27	F F	- -	Dystonia in outstretched arms, and in hand with writing Dystonia in left hand, and in right hand with writing	- -
Hu et al.	2019	34316604	49	M	PD	Dystonia in right foot, ankle, leg, and arm, and in face, neck, and back	-
Rizvi et al.	2018	30345199	21	F	Fahr syndrome	Marked EPS, including rigidity and acute dystonia of neck and jaw	Olanzapine (20 mg), aripiprazole (10 mg)
Boot et al.	2018	29752303	30–54	4/15 F	Various	Study of 45 adults with PD; 15 had dystonia, including 7 at initial presentation of motor symptoms	5 out of the 7 were antipsychotic naive
Jones et al.	2017	29308211	19	M	Elevated homocysteine and NMDA-receptor antibodies	Oculogyric crises	Sulpiride (800 mg)
Boot et al.a	2015	25684639	45 38	M M	Schizophrenia Schizophrenia	Oculogyric crises Periodic oculogyric crises	Quetiapine (700 mg) Olanzapine (12.5 mg)
Kontoangelos et al.	2015	26605035	18	M	-	Acute cervical dystonia, torticollis, trunk dystonia	Haloperidol (2 mg)
Pinquier et al.	2001	11294038	17	F	Schizophrenia	Unknown	Unknown
Myoclonus total (n = 8)
Van Iseghem et al.	2020	32002279	41 27	F F	- -	Myoclonic jerks in upper and lower limbs Myoclonic jerks in upper limbs	- -
Meytin et al.b	2020	-	50	M	PD, epilepsy	Generalized myoclonus	-
Boot et al.	2015	25684639	45 54	M M	Schizophrenia Schizophrenia	Clozapine-induced myoclonus Clozapine-induced myoclonus or myoclonic epilepsy	Clozapine (150 mg) Clozapine (400 mg)
O’Hanlon	2003	12598825	33	F	PNOS	Seizure disorder with myoclonic jerking of all limbs	Antipsychotics, not specified
Baralle et al.	2002	12397165	NR	F	-	Long-standing pronounced myoclonus of the head, trunk, and limbs, exacerbated by startle	-
Sachdev et al.	2002	12169346	22	M	Mild cerebral atrophy, septum pellucidum, PNOS	Rapid involuntary movements of limbs	Olanzapine (10 mg)
Catatonia total (n = 16)
Butcher et al.c	2018	29777584	17–60	9/13 F	Various	Case series of 13 adults with catatonic features	11 took an antipsychotic
Sieberer et al.	2005	15967641	22	F	Basal ganglia calcifications, PNOS	Stupor, mutism	-
Sachdev	2002	12169346	22	M	Mild cerebral atrophy, septum pellucidum, PNOS	Posturing, stereotypies, grimacing	Olanzapine (10 mg)
Graf et al.	2001	11502905	18	F	PNOS	“Catatonic” agitation	-
Tic disorder total (n = 1)
Robertson et al.	2006	16938515	28	F	ADHD, ASD, ODD	Tourette syndrome, age at onset ~2–3 years	-

PD Parkinson disease, EPS extrapyramidal symptoms (usually attributed to medications, especially antipsychotics), PNOS psychosis not otherwise specified, ADHD attention deficit hyperactivity disorder, ASD autism spectrum disorder, ODD oppositional defiant disorder.

^aBoth patients reported by Boot et al. (2015) are also in the retrospective study (this study).

^bMovement Disorders Clinical Practice – volume 7, issue 0, pp. S83

^cFive patients reported by Butcher et al. (2018) are also in the retrospective study (this study).

Based on our clinical experiences and the case literature, in a large adult 22q11.2DS sample, we predicted high prevalence, and a wide range of movement abnormalities, and expected those patients with a history of antipsychotic use and hypocalcemia to be at additional risk [5, 6]. We retrospectively reviewed the medical records of 92 adult participants of a movement disorder study, recording information on all previously documented motor abnormalities that were assessed by a medical specialist, and on demographic and other clinical variables, including age at assessment, history of antipsychotic use, and hypocalcemia [2]. All participants were ascertained through a multidisciplinary specialty clinic for adults with 22q11.2DS, referred through three main sources (a congenital cardiac disease clinic, medical geneticists, and psychiatry), and molecularly confirmed to have a chromosome 22q11.2 deletion using standard methods [2]. To determine differences in age and other demographic and clinical variables, we used Mann-Whitney U and Fisher’s exact tests, respectively. We focused on conditions other than parkinsonism, using a multiple logistic regression model to identify variables that were associated with the most frequently reported movement disorder (dystonia), considering sex, age, and lifetime history of antipsychotic use and of hypocalcemia. All analyses were two-tailed, with statistical significance defined as p < 0.05, using IBM SPSS software (Statistics 25; SPSS, Inc., Chicago, IL). Written informed consent was obtained from the participants and/or their substitute decision makers.

In the 22q11.2DS cohort of 92 individuals (median age 26 years), 42.4% had at least one movement abnormality documented in their medical chart (28.3% if parkinsonian features and tremor were not considered). Proportions were 29.8% and 17.5%, respectively, for the subset of 57 individuals with no antipsychotic exposure (median age 23 years). Sample characteristics are presented in Table 2; see Supporting Material for details of the substantial neuropsychiatric complexity within and between individuals. Dystonia (10.9%) was the most prevalent movement abnormality, aside from parkinsonian features and uncharacterized tremor. A logistic regression model showed that, as hypothesized, dystonia in adults with 22q11.2DS was more likely in patients with a history of antipsychotic use (odds ratio = 4.50, 95% confidence interval = 1.02–19.79, P < 0.05); results for hypocalcemia did not reach significance (Table 2). Other movement-related abnormalities included: myoclonus (7.6%), tic disorder (5.4%), functional neurological disorder (3.3%), and catatonia (2.2%).

Table 2.

History of movement disorders and other motor abnormalities in 92 adults with 22q11.2 deletion syndrome (22q11.2DS).

	Total 22q11.2DS cohort (n = 92)		22q11.2DS subgroups				Subgroup analyses
			History of antipsychotic use (n = 35)		Antipsychotic naïve (n = 57)		P a
Demographics and other clinical characteristics
Median age (range), years	26	(17–65)	34	(18–65)	23	(17–59)	0.03
	n	%	n	%	n	%
Male	47	51.1	19	54.3	28	49.1	0.67
Caucasian	72	78.3	28	80.0	44	77.2	0.80
Intellectual disability	53	57.6	21	60.0	32	56.1	0.83
Hypocalcemia	73	79.3	26	74.3	47	82.5	0.43
Movement disorder/motor abnormalitiesb
Dystoniac	10	10.9	7	20.0	3	5.3	0.04
Myoclonusd	7	7.6	4	11.4	3	5.3	0.42
Generalized shakinesse	6	6.5	3	8.6	3	5.3	0.67
Tic disorder	5	5.4	2	5.7	3	5.3	1.00
Dyskinesia	4	4.3	4	11.8	0	0	0.02
Functional neurological disorderf	3	3.3	3	8.6	0	0	0.05
Catatoniag	2	2.2	2	5.7	0	0	0.14
Parkinson’s disease (PD)h	2	2.2	1	2.9	1	1.8	1.00
Parkinsonian featuresh
Bradykinesia	5	5.4	3	8.6	2	3.5	0.37
Rigidity	11	12.0	9	25.7	2	3.5	0.002
Tremor at resti	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Tremor not otherwise specifiedi	28	30.4	18	51.4	10	17.5	0.001
History of any motor abnormalityj	39	42.4	22	62.9	17	29.8	0.002
History of any motor abnormality other than tremor, parkinsonian features or PD	26	28.3	16	45.7	10	17.5	0.005
Relationship with dystonia (regression model)k	B	S.E.	Wald	df	P	OR	95% CI
History of antipsychotic use	1.50	0.76	3.95	1	<0.05	4.50	1.02–19.79
Hypocalcemia	1.13	1.11	1.03	1	0.31	3.09	0.35–27.27
Sex	−0.06	0.72	0.01	1	0.93	0.94	0.23–3.86
Age	0.01	0.03	1.03	1	0.59	1.01	0.96–1.07

N/A not available, OR odds ratio, CI confidence interval

^aMann-Whitney U test for age, Fisher’s exact tests for comparisons of categorical data. Bold font indicates statistical significance.

^bOf any severity. Details for individuals with each of the seven conditions studied (not PD or parkinsonian features) are provided in the Supplementary Information.

^cOne antipsychotic naïve individual had multifocal dystonia from age 37 years, including cervical dystonia requiring long-term treatment with botulinum toxin A.

^dOne individual was described as having myoclonic seizures.

^eTwo individuals with generalized shakiness also had a diagnosis of myoclonus, one of whom was in the antipsychotic naïve subgroup.

^fOne individual had a history of psychogenic nonepileptic seizures, another suffered from impaired ambulation needing a wheelchair, and a third individual had intermittent diffuse tremors/shakiness (in arms, legs, and body, needing assistance with eating and dressing), difficulties with articulation, stuttered with slow speech, and suffered from impaired ambulation (shuffling, slow gait, poor balance, needing assistance and a walker, and subsequently a wheelchair). All were designated functional by a treating neurologist, and all were receiving or had received antipsychotic medications. See Supplementary Information for details.

^gWhen we repeated the subgroup analysis with four additional patients, all with a history of psychotic illness with catatonic features, but who did not meet the retrospectively applied criteria for a DSM-5 diagnosis of catatonia, history of catatonic features was statistically significantly greater in those with a history of antipsychotic exposure (P = 0.002).⁴ See Supplementary Information for details.

^hThe parkinsonian features numbers include the patients with PD. Additional details on PD and parkinsonian features in this cohort may be found for cases previously reported elsewhere.^1-2

ⁱWe reported all tremor as ‘tremor not otherwise specified’, as in many cases, the type was not reported e.g., “tremor at rest” data were not available.

^jHistory of one or more of the motor abnormalities listed above.

^kThe multiple logistic regression model predicting dystonia in adults with 22q11.2DS fit the data adequately, as assessed with the Hosmer-Lemeshow test (χ² = 5.75, df = 8, P = 0.68).

The results of the previous case literature and this study of a relatively young sample suggest that movement abnormalities are prevalent in adults with 22q11.2DS, with dystonia the most commonly reported movement disorder aside from parkinsonian features. Even in those without antipsychotic exposure, dystonia appeared more prevalent than in the general population [7]. This may also apply to other movement abnormalities, e.g., myoclonus and tic disorder (Table 2), and thus suggest that patients with 22q11.2DS are more prone in general to develop movement disorders, including those that are attributed to antipsychotics. This is analogous to findings with respect to a lowered seizure threshold in 22q11.2DS, for both provoked and unprovoked seizures [8].

The higher proportion of patients with a history of any motor abnormality, and earlier age of onset of the motor abnormality, in those with a history of antipsychotic use may be related to an effect of increased attention by physicians, in addition to true susceptibility. Direct comparison of dystonia prevalence in 22q11.2DS to a matched control group would be required to draw firmer conclusions. The data indicate a minority of the patients were evaluated by a movement disorder specialist. This could lead to an underestimation of the prevalence of movement disorders and abnormalities, and could also introduce some uncertainty of the specific movement phenomenology; we have thus been careful not to make assumptions beyond the descriptions provided.

Potential mechanisms underlying neuropsychiatric disorders in 22q11.2DS, including those relevant to movement disorders, were recently reviewed [9]. One possibility involves disruption of the dopaminergic system. Patients with a 22q11.2 deletion carry only one copy of the COMT gene that is involved in the degradation of catecholamines, including dopamine, and disturbances in dopaminergic neurotransmission have been found in many studies of 22q11.2DS. Another potential mechanism implicates mitochondrial dysfunction, given that at least six genes in the typical 22q11.2 deletion region are involved in aspects of mitochondrial function.

Collectively, the findings of this study, both from the literature and new data, support a complex motor phenotype in adults with 22q11.2DS that cannot be explained by antipsychotic use alone. The results suggest elevated prevalence of several movement disorders in addition to parkinsonism, highlighting a possible spectrum of motor abnormalities that may be found in adults with 22q11.2DS. These data add to the complex neuropsychiatric expression previously known for this condition [1–4], emphasizing the importance of periodic motor evaluations in 22q11.2DS, and consideration of involving a movement disorder sub-specialist. There are thus implications for clinical practice, and for research across the lifespan. Awareness of the possibility of a 22q11.2 deletion when assessing individuals with unexplained dystonia or other complex history of movement abnormalities, in combination with neurodevelopmental/neuropsychiatric disorders and/or any of the many other manifestations of 22q11.2DS [1], would be prudent. Here, it should be emphasized that “classical features” of 22q11.2DS, such as congenital heart defects and “dysmorphic facial features” are absent in many individuals, that most 22q11.2 deletions arise as de novo events (new to a family), and that 22q11.2 deletions are found in 1 in 2148 newborns based on a recent study [1, 10].

Author contributions

All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, interpretation of data, writing, or revision of the manuscript. Furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication before its appearance in the European Journal of Human Genetics. EB had a major role in the design and conceptualization of the study, collected the data, undertook the statistical analysis, interpreted the data and drafted the manuscript for intellectual content. CM reviewed the manuscript critically for important intellectual content. ASB had a role in the design and conceptualization of the study and reviewed the manuscript critically for important intellectual content.

Data availability

The data that support the findings of this study are available in the supplementary material of this article.

Competing interests

The authors declare no competing interests.

Ethical approval

The study was approved by the Research Ethics Boards of the University Health Network (#15-8964) and Centre for Addiction and Mental Health (# 009/2016), Toronto.

Supplementary information

The online version contains supplementary material available at 10.1038/s41431-022-01152-4.