To perform a clinical comparison of three cases with a c.2152 delT frameshift mutation in IRF2BPL gene to determine whether it can predict clinical severity.

It has recently been reported that heterozygous mutation in the IRF2BPL gene on chromosome 14q24 affect the central nervous system, leading to a highly heterogeneous phenotypic spectrum, collectively referred to as NEDAMMS disease (neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures [OMIM 618088]). We report a new case of a male child with severe hypotonia in the neonatal period, progressively developing neurological symptoms and drug-resistant epilepsy, evolving to West Syndrome. The mutation identified in our patient coincides with two recently published cases. We have therefore synthesized a case comparison to evaluate similarities in clinical progression and severity.

The c.2152delT(p.Cys718Alafs*49) mutation in the IRF2BPL gene was identified through Whole Exome Sequencing. The patient's clinical data were collected retrospectively. A literature search was performed, up to September 2024, identifying 23 articles with clinical details of 50 cases. Two cases shared the same IRF2BPL mutation, and a clinical comparison was made.

The three patients developed severe early-onset neurodevelopmental symptoms, including epilepsy, dystonia, axial hypotonia and spasticity. All had normal prenatal histories. Facial and limb dysmorphisms were noted. Neurodevelopment regression began between 2-6 months, preventing the acquisition of milestones such as sitting, walking, or speaking. Epilepsy onset average 4.5 months, with seizures varying from tonic seizures to infantile spasms. Two cases progressed to West Syndrome, while one developed Lennox-Gastaut Syndrome. MRI findings varied, but a thin corpus callosum and increased extra-axial space were common. Two patients required gastrostomy. Ophthalmological involvement was described in two patients, while one showed possible hearing impairment.

Our results suggest that c.2152delT(p.Cys718Alafs*49) IRF2BPL mutation could be related to an earlier onset with severe symptoms, and therefore, a worse prognosis.