Objective: We describe two patients who presented with progressive, generalized dystonia and associated neurodevelopmental regression in early childhood found to have pathogenic variants in IRF2BPL. We describe their clinical courses, associated features, and marked response to benzodiazepines with accompanying video.

Background: Pathogenic variants in interferon regulatory factor 2 binding protein-like (IRF2BPL) were only recently described in 2018.  It is expressed in an autosomal dominant manner with characteristic features to include generalized dystonia, ataxia, hypotonia, seizures, keratoconus, anarthria, slow saccades, and severe neurodevelopmental regression.   As this is rare and a relatively newly described condition, treatment response has not been well described apart from a single patient with poor response to pallidal deep brain stimulation.

Method: Two recent cases of IRF2BPL-related neurodevelopmental disorder are described, 16 and 17 year-old females.  Both patients had onset of focal dystonia which subsequently generalized within the first decade of life.  Within the first five years of life, both experienced developmental regression and eventually complete loss of speech.  The first patient developed epilepsy in the second decade of life while the first had onset in early childhood.  Dystonia was so severe in both patients leading to significant pain.  Trials of carbidopa-levodopa and baclofen were ineffective in both cases, the latter case had no benefit with targeted botulinum neurotoxin injections.  Clonazepam (0.06 – 0.15 mg/kg/day) lead to clinically meaningful benefit and complete resolution of pain in the patients.

Results: These two cases with video examples of severe generalized dystonia and neurodevelopmental regression secondary to pathogenic variants in IRF2BPL had marked improvement of dystonia following titration of clonazepam.  Both presented to our center due to worsening symptoms and lack of response of multiple medications.

Conclusion: IRF2BPL-related neurodevelopmental disorder has a variety of neurologic symptoms including epilepsy, developmental regression, and generalized dystonia.  The dystonia is progressive and can lead to significant pain.  Clonazepam was effective and well-tolerated in these patients.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/two-cases-of-severe-generalized-dystonia-in-irf2bpl-and-response-to-treatment/