A 12-year-old boy developed his first paroxysmal episode at age 10.5 years. Episodes were triggered by sudden movement after a period of inactivity such as sitting in a car or watching television on a couch. During attacks, there was dystonia of both arms and trunk with flexion of the left elbow and extension of the right elbow, sometimes back arching, typically lasting 5-10 seconds (Video 1). The frequency of the episodes was initially one or two times per month, but subsequently increased to 4-12 times per day without treatment. He did not lose consciousness during the events, and electroencephalography was unremarkable.
After one of his dystonic episodes, he developed back pain, and spine imaging revealed grade 2 spondylolisthesis involving the lower back. No other vertebral abnormality was identified. His history was also notable for features of Asperger's syndrome with mild delay in language milestone acquisition, which prompted speech and occupational therapies around age 4-5 years. Motor milestones were normal and there was no history of seizures. He currently attends regular school. He was treated with carbamazepine, up to 250 mg/day, with marked improvement in the frequency and severity of the episodes, but with worsening anxiety. He also had good response to phenytoin but developed swollen gums. Carbamazepine was reintroduced, up to 200 mg/day with improvement, but he then developed leukopenia (white blood cell count of 2,800/microL). He could not tolerate oxcarbazepine, and topiramate was not effective.
Genetic testing included Sanger sequencing of the PRRT2 coding regions and flanking splice sites, and whole-genome microarray-based comparative genomic hybridization (aCGH; 180K oligonucleotide + SNP microarray, Agilent Technologies). Although no pathogenic PRRT2 mutations were detected by sequencing, aCGH identified a 533.9-kb deletion on chromosome 16 [arr 16p11.2(29564185-30098069)x1; hg18], encompassing over 20 genes and transcripts and including four Mendelian disease genes (KIFF22, PRRT2, ALDOA, and TBX6) (Figure 1). This proximal 16p11.2 deletion was confirmed by fluorescence in situ hybridization (FISH) using a bacterial artificial chromosome (BAC) probe that hybridized to 16p11.2 and a control probe that hybridized to the subtelomere of chromosome 16q (Figure 1). Both parents subsequently were tested by aCGH and were negative for the aberration, indicating that the 16p11.2 microdeletion occurred de novo in the proband.
In addition to the 16p11.2 deletion, aCGH analysis detected a 170.5-kb duplication on chromosome 21 [21q22.11q22.12(34656524-34827038)x3; hg18], including four genes, two of which are Mendelian disease genes (KCNE2 and KCNE1). Parental aCGH analysis indicated that this duplication was paternally inherited, suggesting that it is likely a benign familial copy number variant (CNV).