De Novo DNM1L Variant in a Teenager With Progressive Paroxysmal Dystonia and Lethal Super-refractory Myoclonic Status Epilepticus

Ryan, Conor S. MD
Fine, Anthony L. MD
Cohen, Alexander L. MD, PhD
Schiltz, Brenda M. MD
Renaud, Deborah L. MD
Wirrell, Elaine C. MD
Patterson, Marc C. MD
Boczek, Nicole J. PhD
Liu, Raymond PhD
Babovic-Vuksanovic, Dusica MD
Chan, David C. MD, PhD
Payne, Eric T. MD

¹Department of Neurology, Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, MN, USA
²Department of Pediatrics, Division of Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
³Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
⁴Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
⁵Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
⁶Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA

Eric T. Payne, MD, Department of Neurology, Division of Child and Adolescent Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. Email: [email protected]

Received January 3, 2018

Received in revised form April 25, 2018

Accepted April 30, 2018

Journal of Child Neurology 33(10):p 651-658, September 2018. | DOI: 10.1177/0883073818778203

Background:

The dynamin 1-like gene (DNM1L) encodes a GTPase that mediates mitochondrial and peroxisomal fission and fusion. We report a new clinical presentation associated with a DNM1L pathogenic variant and review the literature.

Results:

A 13-year-old boy with mild developmental delays and paroxysmal dystonia presented acutely with multifocal myoclonic super-refractory status epilepticus. Despite sustained and aggressive treatment, seizures persisted and care was ultimately withdrawn in the context of extensive global cortical atrophy. Rapid trio-whole exome sequencing revealed a de novo heterozygous c.1207C>T (p.R403C) pathogenic variant in DNM1L. Immunofluorescence staining of fibroblast mitochondria revealed abnormally elongated and tubular morphology.

Conclusions:

This case highlights the diagnostic importance of rapid whole exome sequencing within a critical care setting and reveals the expanding phenotypic spectrum associated with DNM1L variants. This now includes progressive paroxysmal dystonia and adolescent-onset super-refractory myoclonic status epilepticus contributing to strikingly rapid and progressive cortical atrophy and death.