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Acta Neuropathol Commun. 2019 Aug 27;7(1):138. doi: 10.1186/s40478-019-0781-8.

Clinical, histological, and genetic characterization of PYROXD1-related myopathy.

Lornage X1,2,3,4, Schartner V1,2,3,4, Balbueno I1,2,3,4, Biancalana V1,2,3,4,5, Willis T6, Echaniz-Laguna A7,8,9, Scheidecker S10, Quinlivan R11, Fardeau M12,13,14, Malfatti E15, Lannes B16, Sewry C6,17, Romero NB12,13,14, Laporte J18,19,20,21, Böhm J22,23,24,25.

Author information

1
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404, Illkirch, France.
2
Inserm U1258, Illkirch, France.
3
CNRS UMR7104, Illkirch, France.
4
Strasbourg University, Illkirch, France.
5
Laboratoire de Diagnostic Génétique, Faculté de Médecine, CHRU, Strasbourg, France.
6
Wolfson Centre of Inherited Neuromuscular Disorders, RJAH Orthopaedic Hospital, Oswestry, UK.
7
Department of Neurology, APHP, CHU de Bicêtre, Le Kremlin Bicêtre, France.
8
French National Reference Center for Rare Neuropathies (NNERF), Le Kremlin Bicêtre, France.
9
Inserm U1195 & Paris-Sud University, Le Kremlin Bicêtre, France.
10
Laboratoire de Génétique Médicale, Strasbourg University, Strasbourg, France.
11
MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK.
12
Université Sorbonne, UPMC Paris 06 University, Inserm UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, Paris, France.
13
Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
14
Neuromuscular Morphology Unit, Myology Institute, GHU Pitié-Salpêtrière, Paris, France.
15
Service Neurologie Médicale, Centre de Référence Maladies Neuromusculaire Paris-Nord, CHU Raymond-Poincaré, Garches, U1179 UVSQ-INSERM Handicap Neuromusculaire: Physiologie, Biothérapie et Pharmacologie appliquées, UFR des sciences de la santé Simone Veil, Université Versailles-Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
16
Department of Pathology, Strasbourg University Hospital, Strasbourg, France.
17
Dubowitz Neuromuscular Centre, UCL Institute for Child Health and Great Ormond Street Hospital, London, UK.
18
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404, Illkirch, France. jocelyn@igbmc.fr.
19
Inserm U1258, Illkirch, France. jocelyn@igbmc.fr.
20
CNRS UMR7104, Illkirch, France. jocelyn@igbmc.fr.
21
Strasbourg University, Illkirch, France. jocelyn@igbmc.fr.
22
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404, Illkirch, France. johann@igbmc.fr.
23
Inserm U1258, Illkirch, France. johann@igbmc.fr.
24
CNRS UMR7104, Illkirch, France. johann@igbmc.fr.
25
Strasbourg University, Illkirch, France. johann@igbmc.fr.

Abstract

Recessive mutations in PYROXD1, encoding an oxidoreductase, were recently reported in families with congenital myopathy or limb-girdle muscular dystrophy. Here we describe three novel PYROXD1 families at the clinical, histological, and genetic level. Histological analyses on muscle biopsies from all families revealed fiber size variability, endomysial fibrosis, and muscle fibers with multiple internal nuclei and cores. Further characterization of the structural muscle defects uncovered aggregations of myofibrillar proteins, and provided evidence for enhanced oxidative stress. Sequencing identified homozygous or compound heterozygous PYROXD1 mutations including the first deep intronic mutation reinforcing a cryptic donor splice site and resulting in mRNA instability through exonisation of an intronic segment. Overall, this work expands the PYROXD1 mutation spectrum, defines and specifies the histopathological hallmarks of the disorder, and indicates that oxidative stress contributes to the pathomechanism. Comparison of all new and published cases uncovered a genotype/phenotype correlation with a more severe and early-onset phenotypic presentation of patients harboring splice mutations resulting in reduced PYROXD1 protein levels compared with patients carrying missense mutations.

KEYWORDS:

Congenital myopathy; LGMD; Myofibrillar inclusions; Oxidoreductase; PYROXD1

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