Importance of Recurrent Falls: Adult-Onset Cerebellar Ataxia and an IRF2BPL Variant of Uncertain Significance
Year: 2026
Type: article
Study design: Case Report
Abstract: Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS) is a rare condition caused by heterozygous pathogenic variants in the interferon regulatory factor 2 binding protein-like (IRF2BPL) gene.It usually arises de novo and presents in childhood, although milder, later-onset phenotypes dominated by cerebellar ataxia have also been described.We report the case of a 45-year-old woman who first presented to primary care at 40 years of age with a twomonth history of imbalance and falls.She had no history of cognitive regression, seizures, or loss of speech, although learning difficulties had been reported in childhood without formal assessment.Generalized tremor developed two years later.Her mother and four of her mother's five siblings had progressive lateonset ataxia and speech disturbance, and the presence of affected individuals of both sexes in two consecutive generations, together with documented parent-to-child transmission, raised the clinical suspicion of a hereditary ataxia with autosomal dominant inheritance.Neurological examination showed mild gait instability, lumbar spine CT revealed degenerative changes without nerve root compression, and lower limb electromyography was normal.She was referred to neurology, where thoracolumbar MRI excluded radicular and spinal cord involvement.She was subsequently discharged from follow-up and referred to rheumatology for suspected fibromyalgia.The patient continued to experience falls.Brain CT showed moderate accentuation of the cortical sulci with pericentral predominance, prompting a second neurology referral, and brain MRI demonstrated predominantly vermian cerebellar atrophy together with frontoparietal cortical atrophy.After an etiological workup that included a normal serum vitamin E status and normal ATXN3 repeat sizing, a hereditary ataxia next-generation sequencing panel identified the heterozygous frameshift variant NM_024496.4(IRF2BPL):c.626del,p.(Pro209Glnfs*3), classified as a variant of uncertain significance.A cosegregation study has been requested but has not yet been performed, so the contribution of this variant to the patient's phenotype remains unconfirmed.This case highlights that recurrent falls in a young adult with a positive family history deserve longitudinal follow-up, which, together with a detailed family history, can lead primary care to recognize a hereditary ataxia even when initial assessments are inconclusive.In this patient, this approach led to the identification of an IRF2BPL variant of uncertain significance, whose role will be clarified by segregation analysis and the exclusion of repeat expansion ataxias.
Source: Cureus
Authors: Melanie Lopes, Osvaldo Parreira
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7225431293