Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands

Stacha F.I. Reumers; Corrie E. Erasmus; Karlijn Bouman; Maartje Pennings; Meyke Schouten; Benno Kusters; Floor A.M. Duijkers; Anneke van der Kooi; Bregje Jaeger; Corien C. Verschuuren-Bemelmans; Catharina G. Faber; Baziel G. van Engelen; Erik Jan Kamsteeg; Heinz Jungbluth; Nicol C. Voermans

doi:10.1111/cge.14054

Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands

Stacha F.I. Reumers, Corrie E. Erasmus, Karlijn Bouman, Maartje Pennings, Meyke Schouten, Benno Kusters, Floor A.M. Duijkers, Anneke van der Kooi, Bregje Jaeger, Corien C. Verschuuren-Bemelmans, Catharina G. Faber, Baziel G. van Engelen, Erik Jan Kamsteeg, Heinz Jungbluth, Nicol C. Voermans^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

Abstract

Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype–genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0–80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.

Original language	English
Pages (from-to)	692-702
Number of pages	11
Journal	Clinical Genetics
Volume	100
Issue number	6
Early online date	25 Sept 2021
DOIs	https://doi.org/10.1111/cge.14054
Publication status	Published - Dec 2021

Keywords

BIN1
centronuclear myopathy
cohort
DNM2
MTM1
Netherlands
RYR1

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10.1111/cge.14054

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Reumers, S. F. I., Erasmus, C. E., Bouman, K., Pennings, M., Schouten, M., Kusters, B., Duijkers, F. A. M., van der Kooi, A., Jaeger, B., Verschuuren-Bemelmans, C. C., Faber, C. G., van Engelen, B. G., Kamsteeg, E. J., Jungbluth, H., & Voermans, N. C. (2021). Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands. Clinical Genetics, 100(6), 692-702. https://doi.org/10.1111/cge.14054

@article{e7834a17ffa049abae68f34c4d4260bd,

title = "Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands",

abstract = "Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype–genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0–80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.",

keywords = "BIN1, centronuclear myopathy, cohort, DNM2, MTM1, Netherlands, RYR1",

author = "Reumers, {Stacha F.I.} and Erasmus, {Corrie E.} and Karlijn Bouman and Maartje Pennings and Meyke Schouten and Benno Kusters and Duijkers, {Floor A.M.} and {van der Kooi}, Anneke and Bregje Jaeger and Verschuuren-Bemelmans, {Corien C.} and Faber, {Catharina G.} and {van Engelen}, {Baziel G.} and Kamsteeg, {Erik Jan} and Heinz Jungbluth and Voermans, {Nicol C.}",

note = "Funding Information: We would like to thank all neuromuscular neurologists and clinical geneticists who contributed patients to our study cohort. Furthermore, we thank Spierziekten Nederland for dissemination of information about this study. We also thank Daan Zegers for his contribution in data collection, and St?phanie Hoffmann, Chris Freitag, and Leen Thielemans from Dynacure Inc. for contributing to the discussion on future studies concerning CNM. Several authors of this paper are members of the Netherlands Neuromuscular Center (NL-NMD), and the European Reference Network for rare neuromuscular diseases (EURO-NMD). Publisher Copyright: {\textcopyright} 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.",

year = "2021",

month = dec,

doi = "10.1111/cge.14054",

language = "English",

volume = "100",

pages = "692--702",

journal = "Clinical Genetics",

issn = "0009-9163",

publisher = "Wiley-Blackwell",

number = "6",

}

Reumers, SFI, Erasmus, CE, Bouman, K, Pennings, M, Schouten, M, Kusters, B, Duijkers, FAM, van der Kooi, A, Jaeger, B, Verschuuren-Bemelmans, CC, Faber, CG, van Engelen, BG, Kamsteeg, EJ, Jungbluth, H & Voermans, NC 2021, 'Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands', Clinical Genetics, vol. 100, no. 6, pp. 692-702. https://doi.org/10.1111/cge.14054

TY - JOUR

T1 - Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands

AU - Reumers, Stacha F.I.

AU - Erasmus, Corrie E.

AU - Bouman, Karlijn

AU - Pennings, Maartje

AU - Schouten, Meyke

AU - Kusters, Benno

AU - Duijkers, Floor A.M.

AU - van der Kooi, Anneke

AU - Jaeger, Bregje

AU - Verschuuren-Bemelmans, Corien C.

AU - Faber, Catharina G.

AU - van Engelen, Baziel G.

AU - Kamsteeg, Erik Jan

AU - Jungbluth, Heinz

AU - Voermans, Nicol C.

N1 - Funding Information: We would like to thank all neuromuscular neurologists and clinical geneticists who contributed patients to our study cohort. Furthermore, we thank Spierziekten Nederland for dissemination of information about this study. We also thank Daan Zegers for his contribution in data collection, and St?phanie Hoffmann, Chris Freitag, and Leen Thielemans from Dynacure Inc. for contributing to the discussion on future studies concerning CNM. Several authors of this paper are members of the Netherlands Neuromuscular Center (NL-NMD), and the European Reference Network for rare neuromuscular diseases (EURO-NMD). Publisher Copyright: © 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.

PY - 2021/12

Y1 - 2021/12

N2 - Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype–genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0–80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.

AB - Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype–genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0–80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.

KW - BIN1

KW - centronuclear myopathy

KW - cohort

KW - DNM2

KW - MTM1

KW - Netherlands

KW - RYR1

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U2 - 10.1111/cge.14054

DO - 10.1111/cge.14054

M3 - Article

C2 - 34463354

AN - SCOPUS:85115627136

SN - 0009-9163

VL - 100

SP - 692

EP - 702

JO - Clinical Genetics

JF - Clinical Genetics

IS - 6

ER -

Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands

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Keywords

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