Dear Editor,

The interferon regulatory factor 2 binding protein-like (IRF2BPL) gene is an intronless gene located on chromosome 14 (14q24.3) and is expressed in various human tissues, including the brain. While the exact functions of IRF2BPL are not fully understood, it is believed to play crucial roles in neuronal development, homeostasis, transcriptional regulation, and the ubiquitin-proteasome pathway [1]. Autosomal dominant mutations in this gene have been linked to severe neurodevelopmental disorders, which typically present in early childhood with symptoms such as motor regression and epilepsy [1].

Recently, IRF2BPL has also been associated with a late-onset neurodegenerative phenotype [2,3]. We report a case of a 59-year-old patient with an IRF2BPL pathogenic mutation who presented with progressively worsening ataxia, chorea, dysarthria, and cognitive difficulties, thereby expanding the phenotypic spectrum of IRF2BPL-related disorders.

A 59-year-old Afro-Caribbean woman with a history of insomnia and depression diagnosed in her 20s presented with an 18-year history of progressively worsening imbalance, abnormal involuntary movements, and cognitive decline. Her symptoms initially began with mild instability and occasional falls but gradually advanced to severe ataxia, double incontinence, and significant cognitive decline, ultimately leading to a high level of dependence on her family for daily activities. No seizures were reported.

The patient achieved early childhood developmental milestones at the expected ages. However, around the age of 10, she experienced intellectual regression, which led to her transition to a special needs school by the age of 13. Despite early challenges, she maintained independence in adulthood, working as a carer in her twenties and managing daily activities until more severe neurological symptoms emerged later in her life. There was no familial consanguinity and no family history of movement disorders or cognitive problems. Her current medications include amitriptyline and escitalopram.

Neurological examination revealed generalized choreiform movements, which were most prominent in the face and lower limbs, marked dysarthric speech, marked postural instability and restricted vertical gaze. Coordination was bilaterally impaired, with limb and truncal ataxia (Supplementary Video 1 in the online-only Data Supplement). There were no parkinsonian or pyramidal signs. She had signs of marked dysexecutive function and memory impairment. On the cognitive assessment, the patient scored 14/30 on the Mini-Mental State Examination, indicating moderate cognitive impairment. Additionally, a score of 4/18 on the Frontal Assessment Battery was associated with severe executive dysfunction.

A computed tomography imaging revealed mild cerebellar vermis and temporoparietal atrophy (Figure 1). Extensive blood tests, including full blood count, thyroid-stimulating hormone, peripheral blood film, ceruloplasmin, serum alpha-fetoprotein, and serum uric acid, were all within normal limits. Initial genetic testing for neurodegenerative disorders presenting with her clinical phenotype, including Huntington’s disease, C9orf72 expansion, and spinocerebellar ataxias (SCA1, 2, 3, 6, 7) and FMR1 gene analysis and microarray analysis, was negative. Genetic testing using the “Adult onset dystonia, chorea or related movement disorder” panel in the National Health Service (NHS) Genomic Medicine Service did not identify any pathogenic variants.

Further genetic testing using an adult-onset neurodegenerative disorder panel at the NHS Genomic Medicine Service identified an IRF2BPL c.745C>T (p.Gln249Ter) mutation, which is classified as likely pathogenic, leading to a diagnosis of IRF2BPL-related neurodegeneration. This variant is predicted to result in a stop codon leading to premature termination of translation with loss of a large amount of the protein. There is an established association between IRF2BPL loss-of-function variants of this type and neurodevelopmental disorders [1].

IRF2BPL-related disorders cover a broad spectrum of neurodevelopmental and neurodegenerative conditions. Initially, IRF2BPL mutations were associated primarily with early-onset neurodevelopmental disorders characterized by severe developmental regression, abnormal movements, epilepsy, and cognitive decline, typically beginning in childhood. These early manifestations can lead to profound neurological impairment [1].

However, recent evidence has highlighted a late-onset, milder phenotype associated with IRF2BPL mutations, expanding the clinical spectrum of these disorders. Our case of a 59-year-old woman with an 18-year history of progressive imbalance, choreiform movements, and cognitive difficulties exemplifies this emerging late-onset presentation. This form typically presents in the third to fifth decades of life, with a progressive course involving motor dysfunction and cognitive decline.

Previous reports have described similar late-onset phenotypes, including symptoms such as gait impairment, ataxia, dystonia, and cognitive decline. Antonelli et al. [3] documented a family with late-onset dystonic and ataxic syndrome, where symptoms ranged from gait ataxia to pyramidal signs but without epilepsy. Heide et al. [4] reported a broader phenotype in a large family with mild early onset learning disability presenting later in life with progressive ataxia and pyramidal signs. These findings support the phenotypic variability of IRF2BPL-related disease, connecting both early-onset neurodevelopment disorders and late-onset neurodegeneration disorders even within the same family.

Our patient experienced insomnia for many years before the onset of motor symptoms, which may be significant in further defining the phenotype of this disorder. The loss of IRF2BPL has been associated with excessive Wnt signaling, a pathway known to influence sleep regulation and is linked to the development of insomnia [5,6].

Notably, the IRF2BPL c.745C>T (p.Gln249Ter) mutation identified in our patient has only been previously reported in a conference abstract and has not yet been described in a full peer-reviewed publication [7]. It is a nonsense mutation located in the N-terminal region of the protein, leading to a truncated protein product. N-terminal mutations in IRF2BPL have been associated with a later onset of symptoms such as dystonia and ataxia. This highlights the importance of considering the mutation’s specific location within the gene when evaluating the clinical phenotype and prognosis [8].

This case illustrates the expanding spectrum of IRF2BPL-related disorders, which are traditionally associated with neurodevelopmental conditions but are increasingly linked to adult-onset neurodegenerative diseases characterized by cerebellar ataxia, dystonia, chorea, and dementia. The identification of an IRF2BPL mutation in our patient highlights the importance of considering IRF2BPL gene testing in adults presenting with progressive ataxia, chorea, and cognitive decline. As the late-onset phenotype of IRF2BPL-related diseases remains incompletely understood, ongoing case reports are essential for enhancing knowledge and improving the clinical management of this disorder.

Supplementary Materials

Video 1.

Examination revealed generalized choreiform movements in the face and lower limbs, marked dysarthric speech, and an ataxic gait.

Notes

Ethics Statement

Written informed consent was taken from the patient’s next of kin for publication of this case report and any accompanying images and video.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Acknowledgments

None

Author Contributions

Conceptualisation : Amrit-Deep Samra, Mary O’Driscoll. Data curation: Salhin Alatrash. Formal analysis: Duncan Street. Investigation: Mary O’Driscoll. Method: Salhin Alatrash. Project administration: Salhin Alatrash. Resources: Salhin Alatrash. Software: Salhin Alatrash. Supervision: Amrit-Deep Samra. Validation: Duncan Street. Visualisation: Salhin Alatrash. Writing—original draft: Salhin Alatrash. Writing—review & editing: Salhin Alatrash, Duncan Street.

Figure 1.

Noncontrast head computed tomography revealed temporoparietal and cerebellar atrophy. A: Axial view. B: Sagittal view.

REFERENCES

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