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Hum Mutat. 2018 Jul;39(7):934-938. doi: 10.1002/humu.23534. Epub 2018 May 3.

Abnormal function of the UBA5 protein in a case of early developmental and epileptic encephalopathy with suppression-burst.

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Aix Marseille Univ, Inserm, UMR-S 1251, MMG, Faculté de Médecine, Marseille, France.
Service de Neurologie Pédiatrique, Hôpital d'Enfants de La Timone, Marseille, France.
Department of Molecular Physiology, University of Muenster, Muenster, Germany.
Département de Génétique Médicale, Hôpital d'Enfants de La Timone, Marseille, France.


Early myoclonic epilepsy (EME) or Aicardi syndrome is one of the most severe epileptic syndromes affecting neonates. We performed whole exome sequencing in a sporadic case affected by EME and his parents. In the proband, we identified a homozygous missense variant in the ubiquitin-like modifier activating enzyme 5 (UBA5) gene, encoding a protein involved in post-translational modifications. Functional analysis of the UBA5 variant protein reveals that it is almost completely unable to perform its trans-thiolation activity. Although recessive variants in UBA5 have recently been associated with epileptic encephalopathy, variants in this gene have never been reported to cause EME. Our results further demonstrate the importance of post-translational modifications such as the addition of an ubiquitin-fold modifier 1 (UFM1) to target proteins (ufmylation) for normal neuronal networks activity, and reveal that the dysfunction of the ubiquitous UBA5 protein is a cause of EME.


Ohtahara syndrome; UBA5; early myoclonic epilepsy; encephalopathy

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