UBTF Mutation Causes Complex Phenotype of Neurodegeneration and Severe Epilepsy in Childhood

Abstract

Introduction Neurodegenerative diseases of childhood present with progressive decline in cognitive, social, and motor function and are frequently associated with seizures in different stages of the disease. Here we report a patient with severe progressive neurodegeneration with drug-resistant epilepsy of unknown etiology from the age of 2 years. Methods and Results Using whole exome sequencing, we found heterozygous missense de novo variant c.628G > A (p.Glu210Lys) in the UBTF gene. This variant was recently described as de novo in 11 patients with similar neurodegeneration characterized by developmental decline initially confined to motor development followed by language regression, appearance of an extrapyramidal movement disorder, and leading to severe intellectual disability. In 3 of the 11 patients described so far, seizures were also present. Conclusions Our report expands the complex phenotype of neurodegeneration associated with the c.628G > A variant in the UBTF gene and helps to clarify the relation between this one single recurrent pathogenic variant described in this gene to date and its phenotype. The UBTF gene should be considered a novel candidate gene in neurodegeneration with or without epilepsy.

Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations

“…These alterations of sodium currents can lead to abnormal neuronal activity, a phenomenon that also occurs in epilepsy 69 . It is interesting to note that all these four mutations have a strong association with epilepsy, and many of the patients also suffer from epilepsy 14,27,44,53 .. We also observed an increase in the EPSC rate and amplitude, indicating pre and postsynaptic changes that occur in the mutant neurons compared to the controls neurons. Similar findings were reported in mice models of autism [71][72][73][74][75] .…”

“…These alterations of sodium currents can lead to abnormal neuronal activity, a phenomenon that also occurs in epilepsy 69 . It is interesting to note that all these four mutations have a strong association with epilepsy, and many of the patients also suffer from epilepsy 14,27,44,53 ..…”

“…The degeneration starts with cognitive-motor deficits, reported in humans as well as knockout mice 49 . This regression is accompanied by dystonia, parkinsonism, severe intellectual disability, feeding difficulties, autistic-like behaviors, a slow loss of motor, cognitive and speech capabilities, as well as severe epilepsy 48,[50][51][52][53] . Recent MRI studies showed gradual widespread brain atrophy in both supratentorial and infratentorial areas affecting both grey and white matter in patients with similar neuroregression patterns 48,51 .…”

A novel, likely pathogenic variant in UBTF‐related neurodegeneration with brain atrophy is associated with a severe divergent neurodevelopmental phenotype

“…A recurrent, de novo pathogenic variant in UBTF (upstream binding transcription factor) (OMIM 600673), c.628G>A p.Glu210Lys (NM_014233.3), has been associated with childhood‐onset neurodegeneration with brain atrophy (CONDBA, OMIM 617672). CONDBA is characterized by a period of loss of motor and cognitive skills in the first decade of life following a period of normal development or mild/moderate developmental delay (Bastos et al, 2020; Edvardson et al, 2017; Ikeda et al, 2021; Sedláčková et al, 2019; Toro et al, 2018). This condition was first described in 2017 by Edvardson et al(Tinker et al, 2021) and to date, only 14 patients have been reported in the literature (Supplementary Table S1).…”

“…The median age of onset of neurodevelopmental regression is 3 years. Progressive cerebral and cerebellar atrophy results in loss of motor skills and language with profound intellectual disability in all patients with CONDBA (Bastos et al, 2020; Edvardson et al, 2017; Ikeda et al, 2021; Sedláčková et al, 2019; Toro et al, 2018). Mild developmental delay, microcephaly, ataxia, extrapyramidal and pyramidal signs, behavioral issues, dysarthria, dysphagia, epilepsy, abnormal EEG, and MRI abnormalities, including cerebellar and white matter atrophy, have been reported (Bastos et al, 2020; Edvardson et al, 2017; Ikeda et al, 2021; Sedláčková et al, 2019; Toro et al, 2018).…”