2. Academic Validation
  3. Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course

Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course

  • Brain. 2019 Dec 1;142(12):3876-3891. doi: 10.1093/brain/awz326.
Alessandro Esposito 1 2,  Antonio Falace 3,  Matias Wagner 4 5 6,  Moran Gal 7,  Davide Mei 3,  Valerio Conti 3,  Tiziana Pisano 3,  Davide Aprile 2,  Maria Sabina Cerullo 1 2,  Antonio De Fusco 1 2,  Silvia Giovedì 2,  Annette Seibt 8,  Daniella Magen 9 10,  Tilman Polster 11,  Ayelet Eran 9 12,  Sarah L Stenton 4 5,  Chiara Fiorillo 13 14,  Sarit Ravid 9 15,  Ertan Mayatepek 8,  Hava Hafner 9 16,  Saskia Wortmann 4 5 17,  Erez Y Levanon 7,  Carla Marini 3,  Hanna Mandel 9 18,  Fabio Benfenati 1 19,  Felix Distelmaier 8,  Anna Fassio 2 19,  Renzo Guerrini 3 20
Affiliations

Affiliations

  • 1 Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genoa, Italy.
  • 2 Department of Experimental Medicine, University of Genoa, Genoa, Italy.
  • 3 Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
  • 4 Institute of Human Genetics, Klinikum rechts der Isar, Technical University of München, Munich, Germany.
  • 5 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
  • 6 Institute for Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
  • 7 The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
  • 8 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Medical faculty, Heinrich Heine University, Duesseldorf, Germany.
  • 9 Rappaport School of Medicine, Technion, Haifa, Israel.
  • 10 Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel.
  • 11 Pediatric Epileptology, Bethel Epilepsy Centre, Bielefeld, Germany.
  • 12 Department of Radiology, Rambam Health Care Campus, Haifa, Israel.
  • 13 Paediatric Neurology and Neuromuscular Disorders, IRCCS Gaslini, Genoa, Italy.
  • 14 DINOGMI, University of Genoa, Italy.
  • 15 Pediatric Neurology Unit and Epilepsy Service, Meyer Children's Hospital, Rambam Health Care Campus, Haifa, Israel.
  • 16 Neurosurgery laboratory, Rambam Health Care Campus, Haifa, Israel.
  • 17 Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
  • 18 Metabolic Unit, Rambam Health Care Campus, Haifa, Israel.
  • 19 IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
  • 20 IRCCS Fondazione Stella Maris, Pisa, Italy.
PMID: 31688942 DOI: 10.1093/brain/awz326
Abstract

Ohtahara syndrome, early infantile epileptic encephalopathy with a suppression burst EEG pattern, is an aetiologically heterogeneous condition starting in the first weeks or months of life with intractable seizures and profound developmental disability. Using whole exome sequencing, we identified biallelic DMXL2 mutations in three sibling pairs with Ohtahara syndrome, belonging to three unrelated families. Siblings in Family 1 were compound heterozygous for the c.5135C>T (p.Ala1712Val) missense substitution and the c.4478C>G (p.Ser1493*) nonsense substitution; in Family 2 were homozygous for the c.4478C>A (p.Ser1493*) nonsense substitution and in Family 3 were homozygous for the c.7518-1G>A (p.Trp2507Argfs*4) substitution. The severe developmental and epileptic encephalopathy manifested from the first day of life and was associated with deafness, mild peripheral polyneuropathy and dysmorphic features. Early brain MRI investigations in the first months of life revealed thin corpus callosum with brain hypomyelination in all. Follow-up MRI scans in three patients revealed progressive moderate brain shrinkage with leukoencephalopathy. Five patients died within the first 9 years of life and none achieved developmental, communicative or motor skills following birth. These clinical findings are consistent with a developmental brain disorder that begins in the prenatal brain, prevents neural connections from reaching the expected stages at birth, and follows a progressive course. DMXL2 is highly expressed in the brain and at synaptic terminals, regulates v-ATPase assembly and activity and participates in intracellular signalling pathways; however, its functional role is far from complete elucidation. Expression analysis in patient-derived skin fibroblasts demonstrated absence of the DMXL2 protein, revealing a loss of function phenotype. Patients' fibroblasts also exhibited an increased LysoTracker® signal associated with decreased endolysosomal markers and degradative processes. Defective endolysosomal homeostasis was accompanied by impaired Autophagy, revealed by lower LC3II signal, accumulation of polyubiquitinated proteins, and Autophagy receptor p62, with morphological alterations of the autolysosomal structures on electron microscopy. Altered lysosomal homeostasis and defective Autophagy were recapitulated in Dmxl2-silenced mouse hippocampal neurons, which exhibited impaired neurite elongation and synaptic loss. Impaired lysosomal function and Autophagy caused by biallelic DMXL2 mutations affect neuronal development and synapse formation and result in Ohtahara syndrome with profound developmental impairment and reduced life expectancy.

Keywords

Ohtahara syndrome; autophagy; developmental and epileptic encephalopathy; neuropathy; progressive disorder.

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