RMND1-Related Leukoencephalopathy With Temporal Lobe Cysts and Hearing Loss-Another Mendelian Mimicker of Congenital Cytomegalovirus Infection

Nicole Ulrick; Amy Goldstein; Cas Simons; Ryan J Taft; Guy Helman; Amy Pizzino; Miriam Bloom; Julie Vogt; Karen Pysden; Daria Diodato; Diego Martinelli; Ahmad Monavari; Daniela Buhas; Clara D M van Karnebeek; Imen Dorboz; Odile Boespflug-Tanguy; Diana Rodriguez; Martine Tétreault; Jacek Majewski; Genevieve Bernard; Yi Shiau Ng; Care4Rare Canada Consortium; Robert McFarland; Adeline Vanderver

doi:10.1016/j.pediatrneurol.2016.09.003

RMND1-Related Leukoencephalopathy With Temporal Lobe Cysts and Hearing Loss-Another Mendelian Mimicker of Congenital Cytomegalovirus Infection

Pediatr Neurol. 2017 Jan:66:59-62. doi: 10.1016/j.pediatrneurol.2016.09.003. Epub 2016 Sep 13.

Authors

Nicole Ulrick¹, Amy Goldstein², Cas Simons³, Ryan J Taft⁴, Guy Helman¹, Amy Pizzino¹, Miriam Bloom¹, Julie Vogt⁵, Karen Pysden⁶, Daria Diodato⁷, Diego Martinelli⁸, Ahmad Monavari⁹, Daniela Buhas¹⁰, Clara D M van Karnebeek¹¹, Imen Dorboz¹², Odile Boespflug-Tanguy¹³, Diana Rodriguez¹⁴, Martine Tétreault¹⁵, Jacek Majewski¹⁵, Genevieve Bernard¹⁶, Yi Shiau Ng¹⁷; Care4Rare Canada Consortium; Robert McFarland¹⁷, Adeline Vanderver¹⁸

Affiliations

¹ Department of Neurology, Children's National Medical Center, Washington, DC.
² Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.
³ Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
⁴ Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia; Illumina Inc, San Diego, California; School of Medicine and Health Sciences, The George Washington University, Washington, DC.
⁵ West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham, UK.
⁶ Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
⁷ Muscular and Neurodegenerative Disorders Unit, Ospedale Pediatrico Bambino Gesu, Rome, Italy.
⁸ Division of Metabolism, Bambino Gesu' Children's Hospital, IRCCS, Rome, Italy.
⁹ Temple Street Children's University Hospital, Dublin, Ireland.
¹⁰ Department of Medical Genetics, Montreal Children's Hospital, McGill University Health Center, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
¹¹ Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
¹² INSERM UMR 1141, DHU PROTECT, Paris Diderot University, Sorbonne Paris Cité, France.
¹³ INSERM UMR 1141, DHU PROTECT, Paris Diderot University, Sorbonne Paris Cité, France; AP-HP, Department of Neuropediatrics and Metabolic Diseases, National Reference Center for Leukodystrophies, Robert Debré Hospital, Paris, France.
¹⁴ INSERM UMR 1141, DHU PROTECT, Paris Diderot University, Sorbonne Paris Cité, France; APHP, Department of Neuropediatrics, National Reference Center for Neurogenetic Disorders, Hôpital Armand-Trousseau, GHUEP, Paris, France; GRC ConCer-LD, Sorbonne Universités, UPMC Université Paris 06, Paris, France.
¹⁵ Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada.
¹⁶ Department of Medical Genetics, Montreal Children's Hospital, McGill University Health Center, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada; Department of Pediatrics McGill University, Montreal, Quebec, Canada; Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
¹⁷ Wellcome Trust Centre for Mitochondrial Research, Newcastle University, UK.
¹⁸ Department of Neurology, Children's National Medical Center, Washington, DC; Department of Integrated Systems Biology, George Washington University, Washington, DC; Department of Pediatrics, George Washington University, Washington, DC. Electronic address: avanderv@childrensnational.org.

PMID: 27843092
DOI: 10.1016/j.pediatrneurol.2016.09.003

Abstract

Background: Leukoencephalopathy with temporal lobe cysts may be associated with monogenetic conditions such as Aicardi-Goutières syndrome or RNASET2 mutations and with congenital infections such as cytomegalovirus. In view of the fact that congenital cytomegalovirus is difficult to confirm outside the neonatal period, excluding a Mendelian disorder is extremely relevant, changing family planning and medical management in affected families. We performed diagnostic testing in individuals with leukoencephalopathy with temporal lobe cysts without a definitive diagnosis of congenital cytomegalovirus infection.

Methods: We reviewed a large-scale biorepository of patients with unsolved leukodystrophies and identified two individuals with required for meiotic nuclear division 1 (RMND1) mutations and similar magnetic resonance imaging (MRI) features, including temporal lobe cysts. Ten additional subjects with confirmed RMND1 mutations were identified as part of a separate disease specific cohort. Brain MRIs from all 12 individuals were reviewed for common neuroradiological features.

Results: MRI features in RMND1 mutations included temporal lobe swelling, with rarefaction and cystic evolution, enlarged tips of the temporal lobes, and multifocal subcortical white matter changes with confluent periatrial T2 signal hyperintensity. A combination of these features was present in ten of the 12 individuals reviewed.

Conclusions: Despite the small number of reported individuals with RMND1 mutations, a clinically recognizable phenotype of leukoencephalopathy with temporal lobe swelling, rarefaction, and cystic changes has emerged in a subset of individuals. Careful clinical phenotyping, including for lactic acidosis, deafness, and severe muscle involvement seen in RMND1 mutation positive individuals, and MRI pattern recognition will be important in differentiating these patients from children with congenital infections like cytomegalovirus.

Keywords: MRI pattern recognition; RMND1; cytomegalovirus; genetics; leukoencephalopathy.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Brain Neoplasms / diagnostic imaging
Brain Neoplasms / genetics*
Cell Cycle Proteins / genetics*
Child
Child, Preschool
Cohort Studies
Cysts / diagnostic imaging
Cytomegalovirus Infections / congenital*
Cytomegalovirus Infections / diagnostic imaging
Cytomegalovirus Infections / genetics
Deafness / diagnostic imaging
Deafness / genetics*
Diagnosis, Differential
Humans
Infant
Leukoencephalopathies / diagnostic imaging
Leukoencephalopathies / genetics*
Mutation
Phenotype
Temporal Lobe / diagnostic imaging

Substances

Cell Cycle Proteins
RMND1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding