FV 735. UBTF-Related Dementia and Parkinsonism—Case Report of a Novel Disease Entity

Background: Recently, a heterozygous de novo c.628G>A UBTF gain-of-function variant has been reported in 11 patients with developmental regression starting at the age of 2 to 7 years, leading to profound intellectual disability (ID) and severely impaired motor function (Edvardson et al, 2017 and Toro et al, 2018). Additional features are acquired microcephaly and loss of speech. Patients become nonambulatory due to a variable movement disorder (mostly ataxia and dystonia). In all patients, MRI over time revealed severe cerebral and cerebellar atrophy and diffuse white matter abnormalities in T2.

UBTF encodes a transcription factor and is instrumental in the generation of rRNA transcripts. It exists in two isoforms which are responsible for regulation of ribosomal RNA and mRNA transcription by RNA polymerases I and II. In fibroblasts of affected individuals, the variant leads to gain of function and a markedly increased amount of rRNA with alteration of nucleoli size and number.

Case report: An 11-year-old boy is the second child of nonrelated Asian parents. Family history is unremarkable. Pregnancy was inconspicuous besides preterm labor. Birth weight, length, and head circumference were normal as was in the neonatal period. Motor and cognitive milestones in the first and second years of life were achieved within normal range. At age 2.5 years, tremor and stagnation of speech-language development were noted.

First neurological examination at the age of 4 years revealed ataxia and ID with impaired speech (expressive language four–five words). EEG and somatosensory evoked potentials were normal, and no giant SEPs could be detected. Cranial MRI at the age of 4 years was normal, MRI at 5 and 8 years revealed a progressive supra- and infratentorial atrophies of white and gray matters. Metabolic work-up in blood, cerebrospinal fluid, and urine, as well as filipin staining in fibroblasts was normal. Array-CGH genetic testing showed no deletions or duplications. On follow-up deterioration of cognitive and motor skills was observed including loss of speech and acquired microcephaly. At the age of 6 years, he was no longer able to perform simple tasks and ataxia deteriorated. At the age of 11 years, the patient presented with a pyramidal and extrapyramidal movement disorder including spasticity, a positive Babinski sign, a small step gait, camptocormia, and rigor. Up to now, the patient has no epileptic seizures. Trio whole exome sequencing revealed a heterozygous de novo missense variant in the UBTF (upstream binding transcription factor) gene.

Conclusion: Mutations in UBTF cause dementia and neurodegeneration in childhood without typical EEG or MRI findings in the early stage of disease. This new entity should be considered as a differential diagnosis of lysosomal storage disorders affecting gray matter (e.g., neuronal ceroid lipofuscinosis or NPC), especially when seizures are absent. The 11 patients reported so far all harbored the same heterozygous de novo missense mutation (c.628G>A) and showed a fairly consistent phenotype.