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ScienceDirect Neuromuscular Disorders 24 (2014) 88–89 www.elsevier.com/locate/nmd
Letters to the Editor Compound heterozygous mutations of the TNXB gene cause primary myopathy We read with great interest the report of Pe´nisson-Besnier et al. on a patient with muscle weakness and tenascin X (TNX)-deficient type Ehlers–Danlos syndrome (EDS) [1]. Remarkably, this patient presented more pronounced features of myopathy than of an inherited connective tissue disorder. Although he reported easy bruising, skin hyperextensibility was only mild, and he had no joint hypermobility. We are content to see that this shared phenotype has been recognized in a period of increasing attention for the clinical and molecular overlap between certain myopathies and inherited connective tissue disorders [2,3]. We would like to comment further on the concept of “muscle softness.” The authors report a striking lack of resistance while cutting the muscle tissue during the open muscle biopsy, which was suggested to be helpful as a key to diagnosis. We have experienced a similar softness in taking needle biopsies in patients with varies types of EDS, and mostly pronounced in the kyphoscoliotic type due to PLOD1 mutations (EDSVIA) [3,4] and in the recently identified EDS due to CHST14 deletions resulting in D4ST-1 deficiency [5]. In fact, these two types of EDS, together with the TNX-deficient type have the most pronounced muscle involvement [4–6]. Hence, this observation seems not to be distinctive for TNX-deficient EDS but also for these other EDS types. The lack of resistance experienced during muscle biopsy was considered to be a sign of muscle softness. The muscle biopsy showed areas reminiscent of myotendinous junctions. These areas were presumed to be a result of mislocalization of these junctions, which transmit mechanical forces from muscle fibers to tendons. This finding is indeed in line with results of our previous in vitro study in TNX-deficient EDS patients focusing of titin stiffening and on alterations in myofascial force transmission in TNX knockout mice [7,8]. Our group has subsequently performed an extensive in vivo muscular function study in seven patients with the TNX-deficient type EDS [9]. Isometric function of the thigh muscles was investigated at different joint angles (30°, 60°, and 90° of knee flexion) in 7 TNX-deficient EDS patients (of whom clinical features had been
reported before by Voermans [6]). Physical activity was assessed by the international physical activity questionnaire (IPAQ). The results indeed point to changes in the muscle matrix as a factor contributing to weakness: we measured reduced maximal voluntary torque of the knee extensors (but not knee flexors) across all joint angles in the patients. Time to reach maximal rate of torque development was delayed in patients compared to controls, particularly at 30°. Similarly as in the case reported by Pe´nisson-Besnier [1], muscle weakness in these seven patients could not be attributed to reduced physical activity. These results showed that muscle weakness in this EDS type is most likely due to the increased compliance or elasticity of the series-elastic component of muscle tissue, thus affecting the entire matrix-muscle unit. The mislocalization of the myotendinous junctions, which are the starting point of this series-elastic component, might contribute to this increase. The term “matrix myopathies” might therefore be useful as a description of both the phenotype and physiological features of this group of disorders. Further research is required to understand the additional finding of reduced voluntary activation on the muscle weakness and severe fatigue reported by EDS patients. In short, this letter has shed light on our recently published physiological studies on muscle function in TNX-deficient EDS patients, which results confirms the hypothesis of Pe´nisson-Besnier et al. [1] that TNX reduction induces muscle softness. Our in vivo study is an important step in the appropriate muscular investigations suggested by Pe´nisson-Besnier [1]. Together, these studies in TNX-deficient EDS patients contribute to the recognition and understanding of these matrix myopathies. References [1] Penisson-Besnier I, Allamand V, Beurrier P, et al. Compound heterozygous mutations of the TNXB gene cause primary myopathy. Neuromusc Disord 2013;23:664–9. [2] Kirschner J, Hausser I, Zou Y, et al. Ullrich congenital muscular dystrophy: connective tissue abnormalities in the skin support overlap with Ehlers–Danlos syndromes. Am J Med Genet Part A 2005;132A:296–301. [3] Voermans NC, van Engelen BG. Differential diagnosis of muscular hypotonia in infants: the kyphoscoliotic type of Ehlers–Danlos syndrome (EDS VI). Neuromusc Disord 2008;18:906. author reply 7.
Letters to the Editor / Neuromuscular Disorders 24 (2014) 88–89 [4] Voermans NC, Bonnemann CG, Lammens M, van Engelen BG, Hamel BC. Myopathy and polyneuropathy in an adolescent with the kyphoscoliotic type of Ehlers–Danlos syndrome. Am J Med Genet Part A 2009;149A:2311–6. [5] Voermans NC, Kempers M, Lammens M, et al. Myopathy in a 20year-old female patient with D4ST-1 deficient Ehlers–Danlos syndrome due to a homozygous CHST14 mutation. Am J Med Genet Part A 2012;158A:850–5. [6] Voermans NC, van Alfen N, Pillen S, et al. Neuromuscular involvement in various types of Ehlers–Danlos syndrome. Ann Neurol 2009;65:687–97. [7] Ottenheijm CA, Voermans NC, Hudson BD, et al. Titin-based stiffening of muscle fibers in Ehlers–Danlos Syndrome. J Appl Physiol 2012;112:1157–65. [8] Huijing PA, Voermans NC, Baan GC, Buse TE, van Engelen BG, de Haan A. Muscle characteristics and altered myofascial force transmission in tenascin-X-deficient mice, a mouse model of Ehlers– Danlos syndrome. J Appl Physiol 2010;109:986–95. [9] Gerrits KH, Voermans NC, de Haan A, van Engelen BG. Neuromuscular properties of the thigh muscles in patients with Ehlers–Danlos syndrome. Muscle Nerve 2013;47:96–104.
Nicol C. Voermans Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands Tel.: +31 24 361 33 96; fax: +31 24 354 11 22. E-mail address: [email protected] Karin Gerrits Research Institute MOVE, Faculty of Human Movement Sciences, VU University, Amsterdam, The Netherlands Baziel G. van Engelen Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Arnold de Haan Research Institute MOVE, Faculty of Human Movement Sciences, VU University, Amsterdam, The Netherlands
http//dx.doi.org/10.1016/j.nmd.2013.10.007
Response We were very interested in the points raised by Voermans et al., who commented on the notion of ‘muscle softness’ at the time of biopsy from a patient with TNX-deficiency we recently reported. Sadly, the first author and lead clinician in our study, Dr. Isabelle Pe´nisson-Besnier, recently passed away, but we feel that we can convey how unique this observation was to her, in the context of her practice at the Reference Centre for Neuromuscular Disorders in Angers (France). In particular, although Dr. Pe´nisson-Besnier had
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previously taken numerous biopsies from patients with other ‘matrix myopathies’, such as collagen VI-related myopathies [1], she felt that the consistency of this TNX-deficient muscle was striking enough to be of value as a diagnostic clue and should be brought to the attention of other clinicians who, like her, mostly see patients with stricto sensu primary myopathies or muscular dystrophies. As mentioned by Voermans et al., it is very interesting that this observation can be made in various types of Ehlers-Danlos syndrome since it clearly correlates with alterations in muscle extracellular matrix, or ‘myomatrix’ as it is increasingly referred to [2,3]. References [1] Brinas L, Richard P, Quijano-Roy S, et al. Early onset collagen VI myopathies: genetic and clinical correlations. Ann Neurol 2010;68(4):511–20. [2] Bonnemann CG. The collagen VI-related myopathies: muscle meets its matrix. Nat Rev Neurol 2011;7(7):379–90. [3] Rutkowski A, Bonnemann C, Brown S, et al. Report on the myomatrix conference april 22–24, 2012, University of Nevada, Reno, Nevada USA. Neuromuscul Dis 2013;23(2):188–91.
Vale´rie Allamand Inserm, U974, Paris, France CNRS, UMR7215, Paris, France UPMC Univ Paris 06 UM76, Institut de Myologie, Paris, France Tel.: +33 1 42 16 57 07; fax: +33 1 42 16 57 00. E-mail address: [email protected] Philippe Beurrier Centre de traitement de l’He´mophilie, Centre Hospitalier Universitaire d’Angers, France Ludovic Martin Service de Dermatologie, Centre Hospitalier Universitaire d’Angers, France Fransiska Malfait Delfien Syx Anne De Paepe Center for Medical Genetics, Ghent University Hospital, Belgium
http//dx.doi.org/10.1016/j.nmd.2013.10.008
ScienceDirect Neuromuscular Disorders 24 (2014) 88–89 www.elsevier.com/locate/nmd
Letters to the Editor Compound heterozygous mutations of the TNXB gene cause primary myopathy We read with great interest the report of Pe´nisson-Besnier et al. on a patient with muscle weakness and tenascin X (TNX)-deficient type Ehlers–Danlos syndrome (EDS) [1]. Remarkably, this patient presented more pronounced features of myopathy than of an inherited connective tissue disorder. Although he reported easy bruising, skin hyperextensibility was only mild, and he had no joint hypermobility. We are content to see that this shared phenotype has been recognized in a period of increasing attention for the clinical and molecular overlap between certain myopathies and inherited connective tissue disorders [2,3]. We would like to comment further on the concept of “muscle softness.” The authors report a striking lack of resistance while cutting the muscle tissue during the open muscle biopsy, which was suggested to be helpful as a key to diagnosis. We have experienced a similar softness in taking needle biopsies in patients with varies types of EDS, and mostly pronounced in the kyphoscoliotic type due to PLOD1 mutations (EDSVIA) [3,4] and in the recently identified EDS due to CHST14 deletions resulting in D4ST-1 deficiency [5]. In fact, these two types of EDS, together with the TNX-deficient type have the most pronounced muscle involvement [4–6]. Hence, this observation seems not to be distinctive for TNX-deficient EDS but also for these other EDS types. The lack of resistance experienced during muscle biopsy was considered to be a sign of muscle softness. The muscle biopsy showed areas reminiscent of myotendinous junctions. These areas were presumed to be a result of mislocalization of these junctions, which transmit mechanical forces from muscle fibers to tendons. This finding is indeed in line with results of our previous in vitro study in TNX-deficient EDS patients focusing of titin stiffening and on alterations in myofascial force transmission in TNX knockout mice [7,8]. Our group has subsequently performed an extensive in vivo muscular function study in seven patients with the TNX-deficient type EDS [9]. Isometric function of the thigh muscles was investigated at different joint angles (30°, 60°, and 90° of knee flexion) in 7 TNX-deficient EDS patients (of whom clinical features had been
reported before by Voermans [6]). Physical activity was assessed by the international physical activity questionnaire (IPAQ). The results indeed point to changes in the muscle matrix as a factor contributing to weakness: we measured reduced maximal voluntary torque of the knee extensors (but not knee flexors) across all joint angles in the patients. Time to reach maximal rate of torque development was delayed in patients compared to controls, particularly at 30°. Similarly as in the case reported by Pe´nisson-Besnier [1], muscle weakness in these seven patients could not be attributed to reduced physical activity. These results showed that muscle weakness in this EDS type is most likely due to the increased compliance or elasticity of the series-elastic component of muscle tissue, thus affecting the entire matrix-muscle unit. The mislocalization of the myotendinous junctions, which are the starting point of this series-elastic component, might contribute to this increase. The term “matrix myopathies” might therefore be useful as a description of both the phenotype and physiological features of this group of disorders. Further research is required to understand the additional finding of reduced voluntary activation on the muscle weakness and severe fatigue reported by EDS patients. In short, this letter has shed light on our recently published physiological studies on muscle function in TNX-deficient EDS patients, which results confirms the hypothesis of Pe´nisson-Besnier et al. [1] that TNX reduction induces muscle softness. Our in vivo study is an important step in the appropriate muscular investigations suggested by Pe´nisson-Besnier [1]. Together, these studies in TNX-deficient EDS patients contribute to the recognition and understanding of these matrix myopathies. References [1] Penisson-Besnier I, Allamand V, Beurrier P, et al. Compound heterozygous mutations of the TNXB gene cause primary myopathy. Neuromusc Disord 2013;23:664–9. [2] Kirschner J, Hausser I, Zou Y, et al. Ullrich congenital muscular dystrophy: connective tissue abnormalities in the skin support overlap with Ehlers–Danlos syndromes. Am J Med Genet Part A 2005;132A:296–301. [3] Voermans NC, van Engelen BG. Differential diagnosis of muscular hypotonia in infants: the kyphoscoliotic type of Ehlers–Danlos syndrome (EDS VI). Neuromusc Disord 2008;18:906. author reply 7.
Letters to the Editor / Neuromuscular Disorders 24 (2014) 88–89 [4] Voermans NC, Bonnemann CG, Lammens M, van Engelen BG, Hamel BC. Myopathy and polyneuropathy in an adolescent with the kyphoscoliotic type of Ehlers–Danlos syndrome. Am J Med Genet Part A 2009;149A:2311–6. [5] Voermans NC, Kempers M, Lammens M, et al. Myopathy in a 20year-old female patient with D4ST-1 deficient Ehlers–Danlos syndrome due to a homozygous CHST14 mutation. Am J Med Genet Part A 2012;158A:850–5. [6] Voermans NC, van Alfen N, Pillen S, et al. Neuromuscular involvement in various types of Ehlers–Danlos syndrome. Ann Neurol 2009;65:687–97. [7] Ottenheijm CA, Voermans NC, Hudson BD, et al. Titin-based stiffening of muscle fibers in Ehlers–Danlos Syndrome. J Appl Physiol 2012;112:1157–65. [8] Huijing PA, Voermans NC, Baan GC, Buse TE, van Engelen BG, de Haan A. Muscle characteristics and altered myofascial force transmission in tenascin-X-deficient mice, a mouse model of Ehlers– Danlos syndrome. J Appl Physiol 2010;109:986–95. [9] Gerrits KH, Voermans NC, de Haan A, van Engelen BG. Neuromuscular properties of the thigh muscles in patients with Ehlers–Danlos syndrome. Muscle Nerve 2013;47:96–104.
Nicol C. Voermans Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands Tel.: +31 24 361 33 96; fax: +31 24 354 11 22. E-mail address: [email protected] Karin Gerrits Research Institute MOVE, Faculty of Human Movement Sciences, VU University, Amsterdam, The Netherlands Baziel G. van Engelen Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Arnold de Haan Research Institute MOVE, Faculty of Human Movement Sciences, VU University, Amsterdam, The Netherlands
http//dx.doi.org/10.1016/j.nmd.2013.10.007
Response We were very interested in the points raised by Voermans et al., who commented on the notion of ‘muscle softness’ at the time of biopsy from a patient with TNX-deficiency we recently reported. Sadly, the first author and lead clinician in our study, Dr. Isabelle Pe´nisson-Besnier, recently passed away, but we feel that we can convey how unique this observation was to her, in the context of her practice at the Reference Centre for Neuromuscular Disorders in Angers (France). In particular, although Dr. Pe´nisson-Besnier had
89
previously taken numerous biopsies from patients with other ‘matrix myopathies’, such as collagen VI-related myopathies [1], she felt that the consistency of this TNX-deficient muscle was striking enough to be of value as a diagnostic clue and should be brought to the attention of other clinicians who, like her, mostly see patients with stricto sensu primary myopathies or muscular dystrophies. As mentioned by Voermans et al., it is very interesting that this observation can be made in various types of Ehlers-Danlos syndrome since it clearly correlates with alterations in muscle extracellular matrix, or ‘myomatrix’ as it is increasingly referred to [2,3]. References [1] Brinas L, Richard P, Quijano-Roy S, et al. Early onset collagen VI myopathies: genetic and clinical correlations. Ann Neurol 2010;68(4):511–20. [2] Bonnemann CG. The collagen VI-related myopathies: muscle meets its matrix. Nat Rev Neurol 2011;7(7):379–90. [3] Rutkowski A, Bonnemann C, Brown S, et al. Report on the myomatrix conference april 22–24, 2012, University of Nevada, Reno, Nevada USA. Neuromuscul Dis 2013;23(2):188–91.
Vale´rie Allamand Inserm, U974, Paris, France CNRS, UMR7215, Paris, France UPMC Univ Paris 06 UM76, Institut de Myologie, Paris, France Tel.: +33 1 42 16 57 07; fax: +33 1 42 16 57 00. E-mail address: [email protected] Philippe Beurrier Centre de traitement de l’He´mophilie, Centre Hospitalier Universitaire d’Angers, France Ludovic Martin Service de Dermatologie, Centre Hospitalier Universitaire d’Angers, France Fransiska Malfait Delfien Syx Anne De Paepe Center for Medical Genetics, Ghent University Hospital, Belgium
http//dx.doi.org/10.1016/j.nmd.2013.10.008
