22q11.2 deletion syndrome (22q11.2DS) is associated with a broad spectrum of clinical phenotypes, including congenital heart defects and immune deficiencies. In addition, there is also an increased risk of psychiatric disorders, cognitive deficits and motor functional impairments [1–3]. To date, a systematic examination of movement disorders has not been undertaken in this group.
Nineteen participants with 22q11.2DS (11M:8F, median age=12.7 years, range=6.8–17.1), and 13 sibling controls (7M:6F, median age=11.2 years, range=7.5–17.5) were recruited following informed consent, via ongoing cohort studies at Cardiff University (CU) with no further selection criteria applied. Ethical approval was provided by CU School of Medicine Research Ethics (ref:17/69). The presence of the 3Mb 22q11.2 deletion was confirmed using the Infinium PsychArray-v1.1 (Illumina) platform, fluorescence in-situ hybridisation or genetic arrays through NHS medical genetics departments.
Data collected included: sex, age at examination, medical co-morbidities, and developmental history alongside assessment of full-scale IQ, psychiatric symptoms and coordination performance. Motor assessment involved a standardised videotaped clinical examination using a modified Burke-Fahn-Marsden Dystonia rating scale protocol[4]. Examinations were reviewed independently by three neurologists, blinded to all clinical information. Reviewers indicated if a movement disorder was observed and determined its phenomenology and body distribution. A movement disorder was considered present when there was agreement between all neurologists. Statistical analysis was carried out in R, using Fisher’s exact tests, Pearson’s correlations and t-tests as appropriate.
Sample demographics are presented in Table 1. There was a higher rate of movement disorders in the 22q11.2DS group compared to controls (p=0.0002), with consensus agreement for a movement disorder in 18/19 (94.7%) children with 22q11.2DS compared to 4/13 (30.8%) of controls. Dystonia was the most common movement disorder subtype, in isolation (94.4%, n=17) and combined with upper limb distal jerks (5.6%, n=1). The limbs and cranio-cervical region were most commonly affected, with upper limb involvement in all 18 cases (Videos 1–3). Three of four controls displayed isolated dystonia, with upper limb involvement in all four. In the 22q11.2DS cohort, dystonia severity was mild (mean BFMDRS=24.93/120) but was associated with lower IQ (p=0.03, r=−0.52) and higher anxiety symptoms (p=0.03, r=0.57).
Table 1:
Cohort demographic, motor and non-motor characteristics
| 22q11.2DS | Sibling Controls | 22q11.2DS vs. Sibling Controls | 22q11.2DS cohort: Correlation analysis with BFMDRS Severity Scores | |
|---|---|---|---|---|
| n (%)/mean (SD) | n (%)/mean (SD) | p-value (95% CI) | Correlation coefficient (r)(p-value) | |
| Total cohort (M: F) | 19 (11: 8) | 13 (7: 6) | − | |
| Age at Examination (years) (Median (range)) | 12.70 (6.8–17.1) | 11.12 (7.5–17.5) | 0.79 (−2.8, 2.2)* | −0.24 (0.34) |
| FSIQ | 78.83 (10.06) | 109 (15.13) | <0.0001 (21.16, 39.64)* | −0.52 (0.03) |
| BFMDRS severity score (maximum possible score = 120) | 24.93 (8.17) | |||
| Medication | ||||
| ≥1 medication prescribed | 12 (63.2%) | 0 (0%) | 0.0004∝ | |
| Melatonin | 5 (26.3%) | - | - | |
| Antibiotics | 4 (21.1%) | - | - | |
| Laxatives | 3 (15.8%) | - | - | |
| Vitamin/Mineral Supplementation | 3 (15.8%) | - | - | |
| Anti-depressants | 1 (5.3%) | - | - | |
| Medical Co-morbidities | ||||
| Cardiac Defect | 13 (68.4%) | 0 (0%) | 0.0001∝ | |
| ASD/VSD | 5 (26.3%) | - | - | |
| Tetralogy of Fallot | 4 (21.1%) | - | - | |
| Other | 4 (21.1%) | - | - | |
| Past/Present Seizures | 1 (5.3%) | 0 (0%) | >0.99∝ | |
| Cleft lip/palate | 6 (31.6%) | 0 (0%) | 0.06∝ | |
| Recurrent Respiratory Infections | 7 (36.8%) | 0 (0%) | 0.02∝ | |
| Recurrent Ear Infections | 6 (31.6%) | 1 (7.7%) | 0.20∝ | |
| Psychiatric Symptoms | ||||
| ADHD | 7 (36.8%) | 1 (7.7%) | 0.10∝ | |
| Anxiety Disorder (Overall) | 5 (26.3%) | 1 (7.7%) | 0.36∝ | |
| Social Phobia | 3 (15.8%) | 0 (0%) | 0.25∝ | |
| Generalised Anxiety Disorder | 1 (5.3%) | 0 (0%) | >0.99∝ | |
| Specific Phobia | 1 (5.3%) | 1 (7.7%) | >0.99∝ | |
| ADHD Count Score | 3.39 (3.38) | 1.00 (3.16) | 0.07 (−2,39, 1.3)* | 0.41 (0.10) |
| Anxiety Count Score | 2.13 (3.18) | 1.75 (2.96) | 0.78 (−3.17, 2.42)* | 0.57 (0.03) |
| Autism Trait Symptoms Score | 11.43 (5.16) | 2.50 (2.27) | <0.0001 (−12.55, −5.30)* | 0.42 (0.16) |
| Developmental History | ||||
| Pre-term Birth | 4 (21.1%) | 5 (38.5%) | 0.43∝ | |
| Failure to thrive | 8 (42.1%) | 0 (0%) | 0.01∝ | |
| Feeding Difficulties | 16 (84.2%) | 1 (7.7%) | <0.0001∝ | |
| Parental Reported Clumsiness | 15 (78.9%) | 3 (23.1%) | 0.003∝ | |
| Talking by 2 years of age | 6 (31.6%) | 12 (92.3%) | 0.0009∝ | |
| Walking by 1.5 years of age | 11 (57.9%) | 11 (84.6%) | 0.14∝ | |
| Statement of educational needs/Education and health care plan | 13 (68.4%) | 1 (7.7%) | 0.0009∝ | |
| Age at riding a bike (years) (Median (range)) | 6.5 (5–10) | 5 (3.5–7) | 0.09 (−27.6, 2.1)* | 0.02 (0.95) |
| Age at being able to buttons (years) (Median (range)) | 6.2 (3.5–10.25) | 4 (3–6.5) | 0.008(−41.6, −7.0)* | −0.10 (0.79) |
| Age at being able to do laces (years)(Median (range)) | 9.75 (6–11) | 6.9 (5–8.7) | 0.008 (−47.3, 8.4)* | 0.20 (0.63) |
| Movement Disorder | ||||
| Evidence of movement disorder on examination | 18 (94.7%) | 4 (30.8%) | 0.0002∝ | |
| Dystonia | 17 (94.4%) | 3 (23.1%) | 0.0002∝ | |
| Distal UL jerks (Possible myoclonus/possible Chorea) | 1 (5.6%) | 1 (7.7%) | >0.99∝ | |
| Body Part Affected | ||||
| Eyes | 0 (0%) | 0 (0%) | >0.99∝ | |
| Oromandibular Region | 6 (31.6%) | 0 (0%) | 0.03∝ | |
| Cervical | 8 (42.1%) | 1 (7.7%) | 0.05∝ | |
| Upper Limbs | 18 (94.7%) | 4 (30.8%) | 0.0002∝ | |
| Trunk | 0 (0%) | 0 (0%) | >0.99∝ | |
| Lower Limbs | 8 (42.1%) | 3 (23.1%) | 0.45∝ | |
| DCDQ Scores | ||||
| Overall | 37.37 (12.54) | 69.75 (6.90) | <0.0001 (24.27, 40.49)* | −0.29 (0.24) |
| Control During Movement | 15.21 (5.35) | 28.17 (2.89) | <0.0001 (9.51, 16.4)* | −0.11 (0.65) |
| Fine Motor Score | 10.95 (3.63) | 19.33 (1.44) | <0.0001 (6.13, 10.64)* | −0.41 (0.09) |
| General Co-ordination Score | 11.21 (5.34) | 22.25 (3.98) | <0.0001 (7.4, 14.7)* | −0.29 (0.23) |
Key: ADHD: Attention Deficit Hyperactivity Disorder, DCDQ: Developmental Co-ordination Disorder Questionnaire, FSIQ: Full Scale Intelligence Quota, SCQ: Social Communication Questionnaire, UL: Upper Limbs. Control during movement, fine motor score and general co-ordination score all form sub-sections of the DCDQ. The SCQ is used to measure Autism Trait Symptom Score, ADHD and Anxiety symptoms were measured using the child and adolescent psychiatric assessment (CAPA). Bold denotes p-value ≤0.05,
denotes statistical comparison using unpaired t-test,
denotes comparison using chi-square test,
denotes no value or no statistical analysis undertaken.
This is the first cohort study investigating the prevalence and type of movement disorders in young people with 22q11.2DS. Dystonia was the most commonly observed subtype, although these features were mild and tended to be associated with action. Identification of true movement disorders is often challenging in this age range, but the frequency of dystonic signs in the 22q11.2DS group indicate that they were associated with the 22q11.2DS phenotype, rather than neuro-motor immaturity. More severe dystonia was associated with lower IQ and higher levels of anxiety. The 22q11.2DS is known to affect brain development[5,6] and genes in the region such as COMT, are expressed in the brain[7]. Our study is cross-sectional, longitudinal examination throughout childhood, adolescence and into adult-life is required to gain more comprehensive understanding of the 22q11.2DS motor phenotype. Although this cohort is relatively small, the high rate and preponderance of dystonia indicate that it is likely part of the neurodevelopmental phenotype of 22q11.2DS.
Supplementary Material
Video 1: Initial portion demonstrates evidence of retrocollis and evidence of mild upper limb dystonic features with action. The latter portion shows evidence of hand posture while writing, demonstrating altered pen grip and dystonic posturing.
Video 2: Demonstrated evidence of subtle involuntary fine finger movements, both at rest and with outstretched arms. With posture there is also evidence of left shoulder elevation.
Video 3: Evidence of cervical dystonia with slight retrocollis and laterocollis. Posture with outstretched arms demonstrates mild dystonic posturing of the upper limbs and shoulder elevation.
Acknowledgments
Study Funding: This research was funded by the Medical Research Council (MR/N022572/1 and MR/L011166/1), by the Baily Thomas Charitable Trust (2315/1), the Waterloo Foundation (918-1234), the National Institute for Mental Health (5UO1MH101724), Wellcome Trust Strategic Award (503147), Health & Care Research Wales (Welsh Government, 507556), Medical Research Council Centre grant (G0801418), Medical Research Council Programme grant (G0800509) and an Early Career Research Fellowship from The Waterloo Foundation awarded to ACC. THM is funded by an MRC Post-Doctoral Clinical Research Fellowship. KJP is funded by an MRC Clinician-Scientist Fellowship (MR/P008593/1).
Financial Disclosures: Drs Cunningham, Fung, Massey and Peall report no financial disclosures. Professors Hall, Owen and van den Bree are supported by a collaborative research grant from Takeda Pharmaceutical Company Limited. Takeda played no part in the conception, design, implementation, or interpretation of this study and there is no benefit to them in relation to the published work.
Appendices
Author Contributions
| Name | Location | Role | Contribution |
|---|---|---|---|
| Adam C Cunningham | Cardiff University, United Kingdom | Author | Major role in the acquisition of data; Interpreted the data; drafted the manuscript for intellectual content |
| Wilson Fung | Cardiff University, United Kingdom | Author | Major role in the acquisition of data; revised the manuscript for intellectual content. |
| Thomas H Massey | Cardiff University, United Kingdom | Author | Major role in the acquisition of data; revised the manuscript for intellectual content. |
| Jeremy Hall | Cardiff University, United Kingdom | Author | Interpreted the data, revised the manuscript for intellectual content. |
| Michael J Owen | Cardiff University, United Kingdom | Author | Interpreted the data, revised the manuscript for intellectual content. |
| Marianne B M van den Bree | Cardiff University, United Kingdom | Author | Design and conceptualised study; interpreted the data, revised the manuscript for intellectual content. |
| Kathryn J Peall | Cardiff University, United Kingdom | Author | Design and conceptualised study; analysed the data; drafted the manuscript for intellectual content. |
Footnotes
Statistical Analysis: undertaken by ACC and KJP (both Cardiff University, UK).
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Associated Data
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Supplementary Materials
Video 1: Initial portion demonstrates evidence of retrocollis and evidence of mild upper limb dystonic features with action. The latter portion shows evidence of hand posture while writing, demonstrating altered pen grip and dystonic posturing.
Video 2: Demonstrated evidence of subtle involuntary fine finger movements, both at rest and with outstretched arms. With posture there is also evidence of left shoulder elevation.
Video 3: Evidence of cervical dystonia with slight retrocollis and laterocollis. Posture with outstretched arms demonstrates mild dystonic posturing of the upper limbs and shoulder elevation.