Objective: Describe a case of deep brain stimulation (DBS) outcome for a patient with pathogenic variants of Shank2 and KMT2B genes.

Background: Prior reports have demonstrated significant improvement of generalized dystonia in KMT2B related dystonia (DYT28). We describe the first case of a positive DBS outcome in a patient with both KMT2B and Shank2 mutations.

Method: Description of clinical case and therapeutic approach.

Results: A 13 year old Caucasian boy with a complex syndrome, characterized by developmental delay, autism, and generalized dystonia, was referred for evaluation for DBS. He presented with hypotonia and global developmental delay starting at 8 months old, and was diagnosed with autism by age 4. He learned to walk, but developed spasticity and dystonia, and became wheelchair-bound by age 7. Trio whole exome sequencing (WES) revealed a pathogenic variant in the Shank2 gene (de novo c.2666dupC, p.P890SfsX32). At age 11, due to progressive worsening of dystonia involving the upper limbs and trunk not explained by the Shank2 variant, WES was re-analyzed revealing a de novo variant of the KMT2B gene (c.7613delC, p.T2539Pf*75). Tetrabenazine and trihexyphenidyl provided limited benefit. Bilateral globus pallidus internus (GPi) DBS was performed. Initial DBS settings were as follows: left–contacts 1+2-: amplitude (amp) 2.0mA, pulse width (pw) 60ms, and frequency (f) 130 hz, right–contacts C+2-: amp 2.0, pw 60, f 130. Within 1 month, he began to show improvement of truncal and limb dystonia, and reduction of dystonic spasms: he was able to sit unassisted upright in his wheelchair, and regained fine motor skills. At last follow-up, DBS settings were: left–contacts 1+2-: amp 4.5, pw 60, f 130, right–contacts C+1-2-3-: amp 4.0, pw 60, f 130.  Functional improvement of truncal and limb dystonia was sustained at 2.5 years after DBS.

Conclusion: KMT2B gene variants have now been established as one of the most frequent genetic causes of early onset, generalized dystonia. Additional common features include dysmorphisms, developmental delay, intellectual disability, and seizures. Shank genes are responsible for autism spectrum disorders, often associated with intellectual disability. Previous reports have shown significant improvement of dystonia in patients with KMT2B related dystonia after pallidal DBS. We report here the first case of a patient with both KMT2B and Shank2 mutations who demonstrated significant improvement of dystonia following pallidal DBS.

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