Neuropediatrics 2018; 49(05): 330-338
DOI: 10.1055/s-0038-1661396
Original Article
Georg Thieme Verlag KG Stuttgart · New York

PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum

Bader Alhaddad*
1  Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
,
Anna Schossig*
2  Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
,
Tobias B. Haack
1  Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
3  Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
4  Institute of Medical Genetics and Applied Genomics, University of Tübingen, Germany
,
Reka Kovács-Nagy
1  Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
,
Matthias C. Braunisch
1  Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
5  Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
,
Christine Makowski
6  Department of Pediatrics, Technische Universität München (TUM), Munich, Germany
,
Jan Senderek
7  Department of Neurology, Friedrich Baur Institute, Ludwig Maximilians University Munich, Munich, Germany
,
Katharina Vill
8  Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
,
Wolfgang Müller-Felber
8  Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
,
Tim M. Strom
1  Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
3  Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
,
Birgit Krabichler
2  Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
,
Peter Freisinger
9  Department of Pediatrics, Kreisklinken Reutlingen, Reutlingen, Germany
,
Charu Deshpande
10  Department of Clinical Genetics, Guy's Hospital, London, United Kingdom
,
Tilman Polster
11  Department of Pediatric Epileptology, Bethel Epilepsy Centre, Bielefeld, Germany
,
Nicole I. Wolf
12  Department of Child Neurology and Amsterdam Neuroscience, VU University Medical Centre, Amsterdam, The Netherlands
,
Isabelle Desguerre
13  Department of Pediatric Neurology, Necker Enfants Malades Hospital, Paris, France
,
Friedrich Wörmann
11  Department of Pediatric Epileptology, Bethel Epilepsy Centre, Bielefeld, Germany
,
Agnès Rötig
14  INSERM U1163, Institut Imagine, Université Paris Descartes, Paris, France
,
Uwe Ahting
1  Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
,
Robert Kopajtich
1  Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
3  Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
,
Holger Prokisch
1  Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
3  Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
,
Thomas Meitinger
1  Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
3  Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
,
René G. Feichtinger
15  Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
,
Johannes A. Mayr
15  Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
,
Heinz Jungbluth
16  Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, United Kingdom
17  Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, United Kingdom
18  Department of Basic and Clinical Neuroscience, IoPPN, King's College London, London, United Kingdom
,
Michael Hubmann
19  Department of Neuropediatrics, Kinderärzte Zirndorf, Zirndorf, Germany
,
Johannes Zschocke
2  Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
,
Felix Distelmaier*
20  Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
,
Johannes Koch*
15  Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
› Author Affiliations
Funding This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (grant #FKZ 01ZX1405C), through the German Network for mitochondrial disorders (mitoNET, 01GM1113C), and the German Network for Charcot-Marie-Tooth neuropathies (CMT-NET, 01GM1511B, to J. Senderek) and the E-Rare project GENOMIT (01GM1207, I 2741-B26). Further support was provided by the Friedrich-Baur-Stiftung (to J. Senderek) and the Fritz-Thyssen-Stiftung (Az.10.15.1.021MN, to J. Senderek). FD was supported by a grant from the German Research Foundation / Deutsche Forschungsgemeinschaft (DI 1731/2–1).
Further Information

Publication History

03 December 2017

17 May 2018

Publication Date:
25 June 2018 (eFirst)

Abstract

Background Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations.

Methods Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms.

Results We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene.

ConclusionsPRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.

Patient Consent

All clinical data and samples for WES were obtained with written informed parental consent (see Methods section).


Web Resources

• The URLs for data presented herein are as follows:


 – Online Mendelian Inheritance in Man (OMIM, http://www.omim.org).


 – Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org).


• The Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org).


www.who.int/childgrowth/en.


Contributorship

• Bader Alhaddad: Molecular genetic studies, study conception and design, manuscript drafting, responsible for the overall content.


• Anna Schossig: Molecular genetic studies, study conception and design, manuscript drafting, responsible for the overall content.


• Tobias B. Haack: Molecular genetic studies, study conception and design, manuscript drafting.


• Reka Kovács-Nagy: Molecular genetic studies, exome data analysis.


• Matthias C. Braunisch: Molecular genetic studies, exome data analysis.


• Christine Makowski: Patient recruitment (F5), data collection, analysis of clinical data, manuscript drafting.


• Jan Senderek: Patient recruitment (F3), data collection, analysis of clinical data, manuscript drafting.


• Katharina Vill Patient recruitment (F5), data collection, analysis of clinical data, manuscript drafting.


• Wolfgang Müller-Felber: Patient recruitment (F5), data collection, analysis of clinical data, manuscript drafting.


• Tim M. Strom: Molecular genetic studies, supervision of the exome databank.


• Birgit Krabichler: Linkage analysis (F1), revision of manuscript.


• Peter Freisinger: Patient recruitment (F5), data collection, analysis of clinical data, manuscript drafting.


• Charu Deshpande: Biochemical and molecular genetic studies (F3).


• Tilman Polster: Patient recruitment (F2), data collection, analysis of clinical, manuscript drafting.


• Nicole I. Wolf: Patient recruitment (F1), Analysis of clinical and imaging data, manuscript drafting.


• Isabelle Desguerre: Patient recruitment (F6), data collection, analysis of clinical data, manuscript drafting.


• Wörmann Friedrich: Analysis of imaging data (F2).


• Agnès Rötig: Molecular genetic studies, linkage analysis (F6), manuscript drafting.


• Uwe Ahting: Biochemical and molecular genetic studies.


• Robert Kopajtich: Biochemical and molecular genetic studies.


• Holger Prokisch: Molecular genetic studies.


• Thomas Meitinger: Molecular genetic studies, manuscript drafting, supervision of the overall content.


• René G. Feichtinger: Biochemical and molecular genetic studies.


• Johannes A. Mayr: Biochemical and molecular genetic studies, manuscript drafting.


• Heinz Jungbluth: Patient recruitment (F3), data collection, analysis of clinical data, manuscript drafting.


• Michael Hubmann: Patient recruitment (F5), data collection, analysis of clinical data, manuscript drafting.


• Johannes Zschocke: Patient recruitment (F1), Molecular genetic studies, manuscript drafting.


• Felix Distelmaier: Patient recruitment (F2), data collection, analysis of clinical and imaging data, study conception and design, manuscript drafting, responsible for the overall content.


• Johannes Koch: Patient recruitment (F4), data collection, analysis of clinical and imaging data, study conception and design, manuscript drafting, responsible for the overall content.


* These authors contributed equally to this work.