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Acta Neuropathol. 2017 Dec;134(6):889-904. doi: 10.1007/s00401-017-1748-0. Epub 2017 Jul 6.

Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues.

Author information

1
Laboratoire Diagnostic Génétique, Faculté de Médecine, CHRU, Nouvel Hôpital Civil, 1 place de l'Hôpital, 67091, Strasbourg, France. valerie.biancalana@chru-strasbourg.fr.
2
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. valerie.biancalana@chru-strasbourg.fr.
3
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. valerie.biancalana@chru-strasbourg.fr.
4
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France. valerie.biancalana@chru-strasbourg.fr.
5
Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Illkirch, France. valerie.biancalana@chru-strasbourg.fr.
6
Laboratoire Diagnostic Génétique, Faculté de Médecine, CHRU, Nouvel Hôpital Civil, 1 place de l'Hôpital, 67091, Strasbourg, France.
7
Department of Pathology, Normandie Univ, UNIROUEN, INSERM U1245, Rouen University Hospital, F76000, Rouen, France.
8
Center for Research in Myology, GH Pitié-Salpêtrière, Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Paris, France.
9
Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
10
Departamento de Neurologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
11
Service de Génétique Médicale, Unité de Génétique Clinique, CHU, Nantes, France.
12
Atlantic Gene Therapy Institute, University of Nantes, Nantes, France.
13
Centre de Référence des Maladies Neuromusculaires Nantes-Angers, CHU de Nantes, Nantes, France.
14
Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands.
15
Department Clinical Genetics, University Hospital, Turku, Finland.
16
Greenwood Genetic Center, Greenwood, SC, USA.
17
Service de Génétique, Neurogénétique et Médecine Prédictive, Hôpital de la Croix Rousse, Lyon, France.
18
Heartlands Hospital, Birmingham, UK.
19
Pôle de psychiatrie et neurologie, CHU Grenoble, Grenoble, France.
20
Sourasky Medical Center, Tel Aviv University, Tel-Aviv, Israel.
21
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
22
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
23
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
24
Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Illkirch, France.
25
Service de Génétique Médicale, CHU de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.
26
Centre de référence de pathologie neuromusculaire Paris-Est, Groupe Hospitalier-Universitaire Pitié-Salpêtrière, Paris, France.
27
National center of Expertise for Neuromuscular Disorders, University Hospital La Timone, APHM, Aix-Marseille University, Marseille, France.
28
Service de Génétique Clinique, CHRU de Lille, Hôpital Jeanne de Flandre, Lille, France.
29
Service de Génétique Clinique, CHU de Rennes, Hôpital Sud, Rennes, France.
30
Service anatomie et cytologie pathologique, Centre de compétence Breton des maladies neuromusculaires, CHRU Brest, Brest, France.
31
EA 4586 LNB, Université de Bretagne Occidentale, Brest, France.
32
Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.
33
Hospices Civils de Lyon, Université Claude Bernard Lyon1, Institut NeuroMyogène, CNRS, UMR 5310, INSERM U1217, Lyon, France.
34
Neurologie, CHU de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.
35
ICube, UMR7357, CSTB Complex Systems and Translational Bioinformatics, Faculté de Médecine, Strasbourg, France.
36
Service cytogénétique constitutionnelle et prénatale, CHU de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.
37
Department of Medical Genetics, APHM, GMGF, Timone Hospital, Aix Marseille University, Marseille, France.
38
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
39
Institut de Myologie, Laboratoire de résonnance magnétique, Groupe Hospitalier-Universitaire Pitié-Salpêtrière, Paris, France.
40
Service de radiologie, Hôpital Raymond Poincaré, Garches, France.
41
CNRGH, Institut de Biologie François Jacobs, CEA, Evry, France.

Abstract

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.

KEYWORDS:

Centronuclear myopathy; Congenital myopathy; MTM1; X inactivation; X-linked myotubular myopathy

PMID:
28685322
DOI:
10.1007/s00401-017-1748-0
[Indexed for MEDLINE]

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