Universität zu Köln

Keller, Natalie, Mendoza-Ferreira, Natalia, Maroofian, Reza, Chelban, Viorica, Khalil, Youssef ORCID: 0000-0001-9025-3017, Mills, Philippa B., Boostani, Reza, Torbati, Paria Najarzadeh, Karimiani, Ehsan Ghayoor, Thiele, Holger ORCID: 0000-0002-0169-998X, Houlden, Henry, Wirth, Brunhilde and Karakaya, Mert (2020). Hereditary polyneuropathy with optic atrophy due to PDXK variant leading to impaired Vitamin B6 metabolism. Neuromusc. Disord., 30 (7). S. 583 - 590. OXFORD: PERGAMON-ELSEVIER SCIENCE LTD. ISSN 1873-2364

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Abstract

PDXK encodes for a pyridoxal kinase, which converts inactive B6 vitamers to the active cofactor pyridoxal 5'-phosphate (PLP). Recently, biallelic pathogenic variants in PDXK were shown to cause axonal Charcot-Marie-Tooth disease with optic atrophy that responds to PLP supplementation. We present two affected siblings carrying a novel biallelic missense PDXK variant with a similar phenotype with earlier onset. After detection of a novel PDXK variant using Whole Exome Sequencing, we confirmed pathogenicity through in silico protein structure analysis, determination of pyridoxal kinase activity using liquid chromatography-tandem mass spectrometry, and measurement of plasma PLP concentrations using high performance liquid chromatography. Our in silico analysis shows a potential effect on PDXK dimer stability, as well as a putative effect on posttranslational ubiquitination that is predicted to lead to increased protein degradation. We demonstrate that the variant leads to almost complete loss of PDXK enzymatic activity and low PLP levels. Our patients' early diagnosis and prompt PLP replacement restored the PLP plasma levels, enabling long-term monitoring of clinical outcomes. We recommend that patients presenting with similar phenotype should be screened for PDXK mutations, as this is a rare opportunity for treatment. (C) 2020 Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Keller, Natalie UNSPECIFIED UNSPECIFIED UNSPECIFIED Mendoza-Ferreira, Natalia UNSPECIFIED UNSPECIFIED UNSPECIFIED Maroofian, Reza UNSPECIFIED UNSPECIFIED UNSPECIFIED Chelban, Viorica UNSPECIFIED UNSPECIFIED UNSPECIFIED Khalil, Youssef UNSPECIFIED orcid.org/0000-0001-9025-3017 UNSPECIFIED Mills, Philippa B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boostani, Reza UNSPECIFIED UNSPECIFIED UNSPECIFIED Torbati, Paria Najarzadeh UNSPECIFIED UNSPECIFIED UNSPECIFIED Karimiani, Ehsan Ghayoor UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED orcid.org/0000-0002-0169-998X UNSPECIFIED Houlden, Henry UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirth, Brunhilde UNSPECIFIED UNSPECIFIED UNSPECIFIED Karakaya, Mert UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-327655
DOI:	10.1016/j.nmd.2020.04.004
Journal or Publication Title:	Neuromusc. Disord.
Volume:	30
Number:	7
Page Range:	S. 583 - 590
Date:	2020
Publisher:	PERGAMON-ELSEVIER SCIENCE LTD
Place of Publication:	OXFORD
ISSN:	1873-2364
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PYRIDOXAL; MUTATIONS; NEURONS Multiple languages Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32765