Early-onset epileptic-dyskinetic encephalopathy due to a novel indel compound heterozygous pathogenic variant in UBA5

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Abstract

Case Presentation: A full-term female was born via cesarean birth with no complications. At four months old, she developed frequent focal tonic seizures with concurrent regression of motor skills. She lost cephalic sustain and tracking abilities in the following months and also developed progressive failure to thrive. Her neurological examination showed axial hypotonia with appendicular hypertonia and tendon reflex were 3+/4 globally. She also had poor visual fixation and displayed choreoathetosis and dystonic posture during examination. She had microcephaly and mild facial dysmorphisms, such as a slightly upturned nose and mild hypertelorism. General labs and screening for metabolic diseases were negative, and her brain MRI at 6 months old was normal. There was a high index of clinical suspicion of an epileptic-dyskinetic encephalopathy, so a genetic test was performed and resulted in a compound pathogenic heterozygous variant in UBA5: a missense variant, c.1111G>A;p.(Ala371Thr); allele frequency of 0.116% and a frameshift variant c.36_37delCC.

Discussion: Ubiquitin-like modifier-activating 5 (UBA5) encodes an enzyme that mediates conjugation of the ubiquitin fold modifier 1 (UFM1) to intracellular proteins. This post-translational modification is implicated in cellular stress response and, consequently, in breast cancer development and several neurological syndromes. Seizures were described in 87.5% and movement disorders were described in 83% of UBA5 related encephalopathy. Collin et al. and Daida et al. reported six patients with UBA5 variants and early-onset encephalopathy; in their reports, severe motor skill disability, microcephaly, and failure to thrive were observed in all cases. Briere et al. described five patients with compound heterozygous in UBA5 causing movement disorders and epilepsy. One of them without microcephaly. All had the recurrent c.1111G > A (p.Ala371Thr) variant in trans with a second missense UBA5 variant. Our patient had the same c.1111G>A variant, but associated with a novel pathogenic deletion UBA5:c.36_37del, not previously described.

Final Comments: UBA5 biallelic mutations should be considered in patients with epileptic-dyskinetic encephalopathy, especially if presenting with acquired microcephaly, early-onset epileptic encephalopathy and dystonic-choreoathetotic movements.

Publication History

Article published online:
12 May 2025