IRF2BPL gene variants: One new case

Abstract

To the Editor, Since the first association of pathogenic variants in IRF2BPL (interferon regulatory factor 2 binding protein like) gene with a neurological syndrome in 2018, with the crucial distinction between nonsense (leading to severe neurodevelopmental regression, hypotonia, progressive ataxia, lack of coordination, and epilepsy) and missense variants (with milder phenotype featuring developmental delay and epilepsy) (Marcogliese et al., 2018), there has been further delineation of the neurological spectrum, including complex movement disorder with iron deposits in the deep gray matter nuclei (Skorvanek et al., 2019) and developmental epileptic encephalopathy (DEE) with regression during childhood, often concomitant with seizure onset (Tran Mau-Them et al., 2019). The gene product is a zinc finger/RING finger protein acting as a transcriptional modulator (Marcogliese et al., 2018). Therefore we were very interested in the recently published paper describing one additional patient with Lennox–Gastaut syndrome, hypotonia, retinal dysfunction and gastrointestinal dysmotility (Shelkowitz, Singh, Larson, & Elias, 2019), and also providing a review of all described patients, highlighting a wide range of neurological presentations, with some core elements: childhood-onset epilepsy with developmental regression (impacting more on language), cerebral atrophy in the long-term follow-up, hypotonia and hyperreflexia. We wish to add some clinical observations made in a patient recently diagnosed in our unit. A now 31 years-old man was born to healthy nonconsanguineous parents after uneventful pregnancy and delivery. No concerns raised at birth, but developmental delay became apparent during infancy. He had a febrile seizure at 4 years of age, while the first afebrile seizure occurred at age 16, provoked by light stimulation. Since 17 years of age, myoclonic and myoclonic-tonic seizures ensued, involving both upper limbs, sometimes followed by loss of awareness and falling to the floor. He is also affected by episodes of instability with frequent falls and myoclonus of non-epileptic origin. Follow-up electroencephalograms (EEG s) documented paroxysmal abnormalities (sharp-and-slow waves, polyspike-and slow waves) either diffuse or over the frontal/temporal regions, increasing during photic stimulation (at low-medium-high frequencies) and upon eye closure, on a normal background. His neurological examination is dominated by speech impairment, hypotonia, increased deep tendon reflexes, and cerebellar signs (instability, lack of motor coordination, tremor, and ataxia). He has moderate intellectual disability and a psychiatric profile characterized by severe inhibition, anxiety and panic attacks, depression, obsessive– compulsive traits and aggressive bouts. His brain computed tomography (CT) and magnetic resonance imaging (MRI) were normal at 17 years of age. Negative genetic investigations include direct sequencing and multiplex ligation-dependent probe amplification (MLPA) for the solute carrier family 2 member 1 (SLC2A1) gene and direct sequencing of the Ubiquitin-protein ligase E3A (UBE3A) gene. Past pharmacological approaches for epilepsy include: lamotrigine, carbamazepine, oxcarbazepine, topiramate, valproic acid, and clonazepam. Currently he is on levetiracetam with partial seizure control. He is also on excitalopram and lorazepam for his psychiatric symptoms. He has developed severe obesity (body-mass index, BMI: 40) and was recently diagnosed with likely irritable bowel syndrome. By clinical whole-exome sequencing (WES) analysis, a likely pathogenic variant [(c.367C > T, p. (Gln123Ter)] was found in the heterozygous state in the IRF2BPL gene. This is predicted to lead to nonsense substitution and likely protein termination. It is absent from Single Nucleotide Polymorphism Database (dbSNP) and Genome Aggregation Database (gnomAD) and is not reported in The Human Gene Mutation Database (HGMD). Nonsense variants are the most frequent finding in described patients, and the IRF2BPL gene is highly intolerant to loss of function (Tran Mau-Them et al., 2019), therefore it was considered most likely causative of the patient s phenotype, although only the father was available for segregation analysis (negative). From the literature EEG and epilepsy phenotype seems to be unspecific, but myoclonic and tonic–clonic seizures recur in multiple patients (Marcogliese et al., 2018; Shelkowitz et al., 2019; Tran MauThem et al., 2019), while photosensitivity has been documented once (Marcogliese et al., 2018). Interestingly, there is one previous observation of associated psychiatric symptoms in a patient aged 23 years with anxiety (Tran MauThem et al., 2019). Based on the role for IRF2BPL during embryologic development and in neuronal maintenance (Marcogliese et al., 2018), it is possible to speculate that comorbidity with psychiatric disorders is causally linked to this variant and possibly currently underestimated, although at present it is not possible to rule out fortuitous association. The presence of gastrointestinal symptoms has been highlighted in different patients (Shelkowitz et al., 2019), and interpreted as possibly related to IRF2BPL gene products extra-neural location (The Gtex Consortium, 2013). Additional descriptions will hopefully further clarify the phenotypic (neurologic and extra-neurologic) phenotype associated to this recently described medical condition. Received: 2 October 2019 Revised: 15 October 2019 Accepted: 18 October 2019