Heterozygous POLG variant Ser1181Asn co-segregating in a family with autosomal dominant axonal neuropathy, proximal muscle fatigability, ptosis, and ragged red fibers

Maike F Dohrn; Corina Heller; Diana Zengeler; Carolin D Obermaier; Saskia Biskup; Joachim Weis; Stefan Nikolin; Kristl G Claeys; Ulrike Schöne; Danique Beijer; Natalie Winter; Pascal Achenbach; Burkhard Gess; Jörg B Schulz; Lejla Mulahasanovic

doi:10.1186/s42466-022-00169-w

Heterozygous POLG variant Ser1181Asn co-segregating in a family with autosomal dominant axonal neuropathy, proximal muscle fatigability, ptosis, and ragged red fibers

Neurol Res Pract. 2022 Feb 1;4(1):5. doi: 10.1186/s42466-022-00169-w.

Authors

Maike F Dohrn^{1

2}, Corina Heller^{3

4}, Diana Zengeler^{3

4}, Carolin D Obermaier^{3

4}, Saskia Biskup^{3

4}, Joachim Weis⁵, Stefan Nikolin⁵, Kristl G Claeys^{6

7}, Ulrike Schöne⁸, Danique Beijer⁹, Natalie Winter¹⁰, Pascal Achenbach^{8

5}, Burkhard Gess⁸, Jörg B Schulz^{8

11}, Lejla Mulahasanovic^{3

4}

Affiliations

¹ Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany. [email protected].
² Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA. [email protected].
³ Praxis Für Humangenetik Tübingen, Tuebingen, Germany.
⁴ CeGaT GmbH, Tuebingen, Germany.
⁵ Institute of Neuropathology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
⁶ Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
⁷ Laboratory for Muscle Diseases and Neuropathies, KU Leuven, Leuven, Belgium.
⁸ Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
⁹ Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.
¹⁰ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
¹¹ JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany.

Abstract

By whole-exome sequencing, we found the heterozygous POLG variant c.3542G>A; p.Ser1181Asn in a family of four affected individuals, presenting with a mixed neuro-myopathic phenotype. The variant is located within the active site of polymerase gamma, in a cluster region associated with an autosomal dominant inheritance. In adolescence, the index developed distal atrophies and weakness, sensory loss, afferent ataxia, double vision, and bilateral ptosis. One older sister presented with Charcot-Marie-Tooth-like symptoms, while the youngest sister and father reported exercise-induced muscle pain and proximal weakness. In none of the individuals, we observed any involvement of the central nervous system. Muscle biopsies obtained from the father and the older sister showed ragged-red fibers, and electron microscopy confirmed mitochondrial damage. We conclude that this novel POLG variant explains this family's phenotype.

Keywords: Autosomal dominant; Axonal neuropathy; Mitochondrial myopathy; Myo-neuropathy; Polymerase gamma.

Publication types

Letter