Movement Disorder Phenotypes in Children With 22q11.2 Deletion Syndrome

The 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 functional motor impairments. To date, a systematic examination of movement disorders has not been undertaken in this group. Nineteen participants with 22q11.2DS (11 male: 8 female; median age, 12.7 years; range, 6.8–17.1 years), and 13 sibling controls (7 male: 6 female; median age, 11.2 years; range, 7.5– 17.5 years) 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 (reference: 17/69). The presence of the 3-Mb 22q11.2 deletion was confirmed using the Infinium PsychArray-v1.1 (Illumina) platform, fluorescence in situ hybridization or genetic arrays through the National Health Service medical genetics departments. Data collected included sex, age at examination, medical comorbidities, and developmental history alongside assessment of full-scale intelligence quotient (IQ), psychiatric symptoms, and coordination performance. Motor assessment involved a standardized videotaped clinical examination using a modified BurkeFahn-Marsden Dystonia (BFMDRS) rating scale protocol. Examinations were reviewed independently by 3 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, chisquared 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 with controls (P = 0.0002), with consensus agreement for a movement disorder in 18 of 19 children with 22q11.2DS (94.7%) compared with 4 of 13 of controls (30.8%). 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 craniocervical region were most commonly affected, with upper limb involvement in all 18 cases (Videos 1–3). Three of 4 controls displayed isolated dystonia, with upper limb involvement in all 4. In the 22q11.2DS cohort, dystonia severity was mild (mean BFMDRS, 24.93/120) but was associated with lower IQ (r = −0.52, P = 0.03) and higher anxiety symptoms (r = 0.57, P = 0.03). 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 neuromotor immaturity. More severe dystonia was associated with lower IQ and higher levels of anxiety. The 22q11.2 deletion is known to affect brain development, and genes in the region such as COMT are expressed in the brain. Our study is a cross-sectional, longitudinal examination throughout childhood, adolescence, and into adult-life and is required to gain a 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.