PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum

Bader Alhaddad; Anna Schossig; Tobias B. Haack; Reka Kovács-Nagy; Matthias C. Braunisch; Christine Makowski; Jan Senderek; Katharina Vill; Wolfgang Müller-Felber; Tim M. Strom; Birgit Krabichler; Peter Freisinger; Charu Deshpande; Tilman Polster; Nicole I. Wolf; Isabelle Desguerre; Friedrich Wörmann; Agnès Rötig; Uwe Ahting; Robert Kopajtich; Holger Prokisch; Thomas Meitinger; René G. Feichtinger; Johannes A. Mayr; Heinz Jungbluth; Michael Hubmann; Johannes Zschocke; Felix Distelmaier; Johannes Koch

doi:10.1055/s-0038-1661396

Neuropediatrics, Inhaltsverzeichnis

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^*

¹Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

,

Anna Schossig^*

²Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

,

Tobias B. Haack

¹Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

³Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany

⁴Institute of Medical Genetics and Applied Genomics, University of Tübingen, Germany

,

Reka Kovács-Nagy

¹Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

,

Matthias C. Braunisch

¹Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

⁵Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

,

Christine Makowski

⁶Department of Pediatrics, Technische Universität München (TUM), Munich, Germany

,

Jan Senderek

⁷Department of Neurology, Friedrich Baur Institute, Ludwig Maximilians University Munich, Munich, Germany

,

Katharina Vill

⁸Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany

,

Wolfgang Müller-Felber

⁸Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany

,

Tim M. Strom

¹Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

³Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany

,

Birgit Krabichler

²Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

,

Peter Freisinger

⁹Department of Pediatrics, Kreisklinken Reutlingen, Reutlingen, Germany

,

Charu Deshpande

¹⁰Department of Clinical Genetics, Guy's Hospital, London, United Kingdom

,

Tilman Polster

¹¹Department of Pediatric Epileptology, Bethel Epilepsy Centre, Bielefeld, Germany

,

Nicole I. Wolf

¹²Department of Child Neurology and Amsterdam Neuroscience, VU University Medical Centre, Amsterdam, The Netherlands

,

Isabelle Desguerre

¹³Department of Pediatric Neurology, Necker Enfants Malades Hospital, Paris, France

,

Friedrich Wörmann

¹¹Department of Pediatric Epileptology, Bethel Epilepsy Centre, Bielefeld, Germany

,

Agnès Rötig

¹⁴INSERM U1163, Institut Imagine, Université Paris Descartes, Paris, France

,

Uwe Ahting

¹Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

,

Robert Kopajtich

¹Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

³Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany

,

Holger Prokisch

¹Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

³Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany

,

Thomas Meitinger

¹Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

³Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany

,

René G. Feichtinger

¹⁵Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria

,

Johannes A. Mayr

¹⁵Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria

,

Heinz Jungbluth

¹⁶Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, United Kingdom

¹⁷Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, United Kingdom

¹⁸Department of Basic and Clinical Neuroscience, IoPPN, King's College London, London, United Kingdom

,

Michael Hubmann

¹⁹Department of Neuropediatrics, Kinderärzte Zirndorf, Zirndorf, Germany

,

Johannes Zschocke

²Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

,

Felix Distelmaier^*

²⁰Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany

,

Johannes Koch^*

¹⁵Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria

› Institutsangaben

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.

Conclusions PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.

Keywords

PRUNE1 deficiency - microcephaly - refractory epilepsy - spasticity - developmental delay

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Referenzen

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