Neurodegeneration, Childhood-Onset, With Brain Atrophy

A number sign (#) is used with this entry because of evidence that childhood-onset neurodegeneration with brain atrophy (CONDBA) is caused by heterozygous mutation in the UBTF gene (600673) on chromosome 17q21.

Description

CONDBA is a severe progressive neurodegenerative disorder characterized by loss of motor and cognitive skills between ages 2 and 7 years. Affected individuals may have normal development or mild developmental delay, but all eventually lose all motor skills, resulting in inability to walk, absence of language, and profound intellectual disability. Brain imaging shows progressive cerebral and cerebellar atrophy (summary by Edvardson et al., 2017).

Clinical Features

Edvardson et al. (2017) reported 7 unrelated children, ranging in age from 8 to 23 years, with a childhood-onset neurodegenerative disorder. Almost all had normal pregnancies and deliveries aside from 1 C-section and 1 premature birth at 33 weeks' gestation. Four patients had normal early development, but 3 were reported to have mild developmental delay until 2 years of age. Developmental regression invariably occurred between ages 2.5 and 7 years. Five patients presented with motor deterioration with gradual loss of ambulation, fine motor abilities, and self-care skills, and with feeding difficulties, whereas the other 2 presented initially with cognitive and language impairment. All patients eventually had involvement of other domains, resulting in severe to profound intellectual disability and inability to ambulate. Motor abnormalities included an extrapyramidal movement disorder with dystonia, chorea, parkinsonism, or rigidity. Mild pyramidal signs and ataxia were present in 4 and 3 affected individuals, respectively. Three patients had focal and generalized seizures, and 1 had abnormal EEG. Head circumferences declined over time, but none of the patients had dysmorphic features or hearing or visual impairment.

Toro et al. (2018) reported 4 unrelated patients, aged 4, 11, 12, and 33 years, with CONDA. The patients showed neurodevelopmental regression between 2 and 3 years of age after normal early development. The patients progressively lost meaningful expressive and perceptive speech and developed dysarthria leading to anarthria in some. Two patients had a high-pitched voice. The patients also developed dysphagia, with the older patients requiring tube feeding. Motor skills also declined in all patients; common motor abnormalities included postural instability, ataxia, axial hypotonia, appendicular spasticity, and dystonia; 1 patient showed mild chorea. Most had behavioral abnormalities, including autistic features, compulsive or repetitive behaviors, hyperactivity, and mild impulsivity. Two patients had reduced sensation to noxious stimuli. Overall growth was basically normal, although most had poor weight gain. Brain imaging showed progressive brain atrophy affecting the supratentorial more than the infratentorial regions. There was thinning of the corpus callosum and progressive cerebral and cerebellar vermian atrophy. There was also evidence of periventricular gliosis, axonal loss, and demyelination. None of the patients had seizures or common notable dysmorphic features. The oldest patient (33 years) was institutionalized, mute, and required total care.

Molecular Genetics

In 7 unrelated patients with CONDBA, Edvardson et al. (2017) identified a recurrent de novo heterozygous missense mutation in the UBTF gene (E210K; 600673.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Studies of fibroblasts from 1 patient showed significantly increased binding of mutant UBTF to the rDNA promoter and to the 5-prime external transcribed spacer, consistent with a gain-of-function effect. This was associated with significantly increased expression of ribosomal subunit 18S, indicating that E210K UBTF acts as a hyperactive transcription factor. Patient cells showed enlarged nucleoli that were reduced in number per cell. The findings established a link between neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism. Edvardson et al. (2017) suggested that such chromatin dysregulation could have a profound impact on mitosis, DNA repair, and neural cells in particular, since rDNA heterochromatin status is tightly regulated during differentiation and has a broader effect on heterochromatin formation throughout the nucleus. However, the authors emphasized that all data were derived from a single cell line of an affected individual and 1 healthy control.

Toro et al. (2018) identified a recurrent de novo heterozygous E210K mutation in the UBTF gene in 4 unrelated patients with CONDBA. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Studies of patient fibroblasts showed that the mutant protein was expressed normally and showed normal nucleolar localization. However, patient cells had increased expression of pre-rRNA and 18S rRNA compared to controls, suggesting a gain of function. There were also abnormalities in the expression of putative UBTF2 targets. Patient fibroblasts showed increased DNA double-strand breaks, failure of progression to the G2 phase of the cell cycle, and a tendency towards apoptotic cell death. There was a trend for UBTF E210K fibroblasts to harbor fewer nucleoli per nucleus compared to controls, but there was no significant effect of the mutation on nucleolar area. The authors suggested that increased expression of rRNA and nucleolar stress in combination with dysregulation of UBTF2 target genes may cause progressive DNA breaks with an accumulation of damaged DNA, causing neurodegeneration.

Animal Model

Toro et al. (2018) found that pan-neuronal expression of the heterozygous E210K mutation (600673.0001) was lethal in Drosophila. Overexpression of wildtype UBTF1 restricted to the eye resulted in a small-eye phenotype, whereas expression of mutant UBTF in the eye resulted in embryonic lethality in the pupal stage with underdeveloped heads. The findings indicated that increased levels of rRNA is toxic to cells. Toro et al. (2018) noted that homozygous loss of Ubtf is lethal to mice, but the authors observed that heterozygous adult Ubtf +/- mice had only mild motor and behavioral abnormalities compared to wildtype.