Objective: To describe an atypical cluster of three siblings with autosomal dominant third-to-fifth decade-onset generalized dystonia associated with a pathological IRF2BLP gene.

Background: Interferon regulatory factor 2 binding protein-like (IRF2BPL) is associated with a related disorder characterized by pediatric-onset ataxia, dystonia, and seizures. Adult onset of symptoms without prior childhood involvement arising from a pathogenic IRF2BPL mutation has been rarely described in literature. Here, we describe three affected family members who presented with generalized dystonia with symptom onset in the third to fifth decades, all of whom were found to have a pathologic variant in the gene IRF2BPL c.343C>T p.Gln115*. These individuals did not have evidence of childhood regression typically seen with IRF2BPL, such as epilepsy or developmental delay.

Method: N/A

Results: Three family members (P1, P2, and P3) presented during adulthood for evaluation of generalized dystonia with a mosaic phenotype. Workup for typical causes of dystonia, including EMG, copper, ceruloplasmin, and initial genetic causes associated with dystonia (SCA2, SCA3, DYT1, SCA17, and a PEO panel), were unremarkable. Neuroaxis MRI was negative for structural pathology.  The patient with the most severe and earliest onset phenotype (P1) ultimately had a deep brain stimulator placed along with undergoing pharmacological treatment, including Botox therapy. More comprehensive and extensive genetic sequencing was sent for P1, which demonstrated a pathologic variant in IRF2BPL c.343C>T p.Gln115*. This encouraged P2 and P3 to undergo the same testing, both of whom possessed the same variant.

Conclusion: IRF2BPL-related disorder typically has onset in childhood, with patients requiring multimodal and multidisciplinary treatment support. Other hallmark symptoms of IRF2BPL-related pathologies, such as seizures and childhood regression, were not seen in these patients. Our case highlights the importance of thorough genetic testing in movement disorders and illustrates an atypical cluster of patients with an aim to expand on the existing knowledge of IRF2BPL-related syndromes.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hereditary-adult-onset-generalized-dystonia-associated-with-pathogenic-irf2bpl-mutation/