- Email: [email protected]
Response to: Evaluation of the serum matrix metalloproteinase-9 as a biomarker for monitoring disease progression in Duchenne muscular dystrophy
446
Letters to the Editor / Neuromuscular Disorders 25 (2015) 443–449
Myopathies (AFM). This work is a contribution to ADNA (Advanced Diagnostics for New Therapeutic Approaches), a program dedicated to personalised medicine, coordinated by Institut Mérieux, supported and partially funded by the French public agency OSEO. Reference [1] Nadarajah V.D., van Putten M., Chaouch A., et al. Serum matrix metalloproteinase-9 (MMP-9) as a biomarker for monitoring disease progression in Duchenne muscular dystrophy (DMD). Neuromuscul Disord 2011;21:569–78.
Aleksandar Zocevic a,1, Jeremy Rouillon a,1, Brenda Wong b, Laurent Servais c, Thomas Voit d,e, Fedor Svinartchouk a,* a Généthon, Evry, France b Division of Pediatric Neurology, Cincinnati Children’s Hospital Medical Center, USA c Service of Clinical Trials and Databases, Institut de Myologie, Paris, France d INSERM UMRS 974, CNRS FRE 3617, UPMC, Paris, France e Institut de Myologie, GH Pitié-Salpêtrière, Université Pierre et Marie Curie-Paris 6, Paris, France * Corresponding author. E-mail address: [email protected] (F. Svinartchouk). http://dx.doi.org/10.1016/j.nmd.2015.01.010 Response to: Evaluation of the serum matrix metalloproteinase-9 as a biomarker for monitoring disease progression in Duchenne muscular dystrophy We read with interest the letter by Zocevic and colleagues regarding matrix metalloproteinase 9 (MMP-9) in patients with Duchenne muscular dystrophy (DMD). Zocevic questioned the utility of MMP-9 as a biomarker for DMD given the observed increase in its serum levels as a consequence of corticosteroid intake. In an attempt to replicate the findings by Zocevic et al., we have analysed serum MMP-9 levels in a cohort of 116 DMD patients (of whom 53 are independent from our initial cohort described in [1]), among whom 25 were never treated with corticosteroids. We did not find a significant association between MMP-9 and corticosteroids treatment (p-value = 0.5 in univariate ANOVA using corticosteroid treatment and age as covariates). Moreover, initiation of corticosteroid treatment increases MMP-9 serum levels increase in some patients, but decreases them in others. In fact, this is not different from the study reported by Zocevic et al. where 40% of the patients do not show an increase of serum MMP-9 levels upon corticosteroids treatment. We also observe that MMP-9 levels may increase after discontinuing corticosteroid treatment. In support of this, it is reported in the literature that in several diseases such as Crohn’s disease, asthma (in children) and rheumatoid arthritis, 1
A. Zocevic and J. Rouillon contributed equally to this work.
treatment with corticosteroids causes a decrease in circulating MMP-9 levels or in MMP-9 gene expression [2–4]. It has also been shown that blood MMP-9 levels are not influenced by prednisolone in patients affected by Takayasu arteritis [5]. Moreover, Bossé et al. reported that asthmatic patients responding to treatment with corticosteroids show an increase in MMP-9 levels compared to non-responders [6]. We therefore believe that the increase in MMP-9 with DMD progression, observed in our initial study [1], and corroborated in independent studies from Hathout and colleagues [7] and our own group (submitted), cannot be explained by corticosteroid treatment. Zocevic et al. report MMP-9 serum levels in healthy controls of around 500 ng/ml for the young controls and above 500 ng/ml for older controls. These values are not consistent with our study [1] and three more studies, which all reported levels below 100 ng/ml for healthy children [8–10]. Another three studies report somewhat higher MMP-9 serum levels but still below 200, 300 and 400 ng/ml [11–13]. It is also surprising that Zocevic et al. observe an increase of serum MMP-9 with age in the control population, as it has been reported that serum MMP-9 levels are especially low in adults (below 200 ng/ml [14–17] or even below 50 ng/ml [18,19]). The high levels of MMP-9 in the reported control population are likely to mask the increase of MMP-9 in the Duchenne group. Since it is known that MMP-9 is released during clotting, it is possible that the high MMP-9 reported levels are due to the sampling procedure and haemolysis [20]. Acknowledgements This work has been supported by the Association Française contre les Myopathies (grant no. 15092). References [1] Nadarajah VD, van Putten M, Chaouch A, et al. Serum matrix metalloproteinase-9 (MMP-9) as a biomarker for monitoring disease progression in Duchenne muscular dystrophy (DMD). Neuromuscul Disord 2011;21:569–78. [2] Klimiuk PA, Sierakowski S, Domyslawska I, Chwiecko J. Effect of repeated infliximab therapy on serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with rheumatoid arthritis. J Rheumatol 2004;31:238–42. [3] Hegazy LM, El Hana SA. Circulating MMP-9 and TIMP-1 in acute exacerbations and after remission induced by oral corticosteroids in asthmatic children. Egypt J Pediatr Allergy Immunol 2014;4. [4] Faubion WA Jr, Fletcher JG, O’Byrne S, et al. EMerging BiomARKers in Inflammatory Bowel Disease (EMBARK) study identifies fecal calprotectin, serum MMP9, and serum IL-22 as a novel combination of biomarkers for Crohn’s disease activity: role of cross-sectional imaging. Am J Gastroenterol 2013;108:1891–900. [5] Ishihara T, Haraguchi G, Tezuka D, Kamiishi T, Inagaki H, Isobe M. Diagnosis and assessment of Takayasu arteritis by multiple biomarkers. Circ J 2013;77:477–83. [6] Bossé M, Chakir J, Rouabhia M, Boulet LP, Audette M, Laviolette M. Serum matrix metalloproteinase-9:Tissue inhibitor of metalloproteinase-1 ratio correlates with steroid responsiveness in moderate to severe asthma. Am J Respir Crit Care Med 1999;159:596–602. [7] Hathout Y, Marathi RL, Rayavarapu S, et al. Discovery of serum protein biomarkers in the mdx mouse model and cross-species comparison to Duchenne muscular dystrophy patients. Hum Mol Genet 2014; 23:6458–69.
Letters to the Editor / Neuromuscular Disorders 25 (2015) 443–449 [8] Qin YH, Zhou TB, Lei FY, et al. Cut-off values for serum matrix metalloproteinase-9: is there a threshold to predict renal involvement for Henoch-Schonlein purpura in children? Nephrology (Carlton) 2011; 16:93–9. [9] Hong Z, Lin YM, Qin X, Peng JL. Serum MMP-9 is elevated in children with asthma. Mol Med Rep 2012;5:462–4. [10] Kofla-Dlubacz A, Matusiewicz M, Krzystek-Korpacka M, Iwanczak B. Correlation of MMP-3 and MMP-9 with Crohn’s disease activity in children. Dig Dis Sci 2012;57:706–12. [11] Dasu MR, Spies M, Barrow RE, Herndon DN. Matrix metalloproteinases and their tissue inhibitors in severely burned children. Wound Repair Regen 2003;11:177–80. [12] Voraphani N, Khongphatthanayothin A, Srikaew K, Tontulawat P, Poovorawan Y. Matrix metalloproteinase-9 (MMP-9) in children with dengue virus infection. Jpn J Infect Dis 2010;63:346–8. [13] Yilmaz U, Gucuyener K, Atak A, et al. Matrix metalloproteinase-7 and matrix metalloproteinase-9 in pediatric multiple sclerosis. Pediatr Neurol 2012;47:171–6. [14] Brajer B, Batura-Gabryel H, Nowicka A, Kuznar-Kaminska B, Szczepanik A. Concentration of matrix metalloproteinase-9 in serum of patients with chronic obstructive pulmonary disease and a degree of airway obstruction and disease progression. J Physiol Pharmacol 2008;59(Suppl. 6):145–52. [15] Nikkola J, Vihinen P, Vuoristo MS, Kellokumpu-Lehtinen P, Kahari VM, Pyrhonen S. High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma. Clin Cancer Res 2005;11:5158–66. [16] Yaman E, Yalcin BÃ, Utkan GÃ, et al. Prognostic significance of serum matrix metalloproteinase 9 (MMP-9) levels in patients with sarcomas. UHOD 2008;18:79. [17] Chen P, Yuan Y, Wang S, Zhan L, Xu J. Serum matrix metalloproteinase 9 as a marker for the assessment of severe acute pancreatitis. Tohoku J Exp Med 2006;208:261–6. [18] Leelawat K, Sakchinabut S, Narong S, Wannaprasert J. Detection of serum MMP-7 and MMP-9 in cholangiocarcinoma patients: evaluation of diagnostic accuracy. BMC Gastroenterol 2009;9:30. [19] Yadav SS, Mandal RK, Singh MK, et al. High serum level of matrix metalloproteinase 9 and promoter polymorphism – 1562 C:T as a new risk factor for metabolic syndrome. DNA Cell Biol 2014;33:816–22. [20] Mannello F, Tanus-Santos JE, Meschiari CA, Tonti GA. Differences in both matrix metalloproteinase 9 concentration and zymographic profile between plasma and serum with clot activators are due to the presence of amorphous silica or silicate salts in blood collection devices. Anal Biochem 2008;374:56–63.
Pietro Spitali, Annemieke Aartsma-Rus, Peter A.C. ’t Hoen * Department of Human Genetics, Leiden University Medical Center, Postzone S4-P, P.O. Box 9600, Leiden 2300 RC, Netherlands * Corresponding author. E-mail address: [email protected] (P.A.C. ’t Hoen)
http://dx.doi.org/10.1016/j.nmd.2015.02.011 PLEC1 mutation associated with left ventricular hypertrabeculation/noncompaction We read with interest the article by Villa et al. about a patient with epidermiolysis bullosa simplex due to a PLEC1 mutation, which manifested not only as skin and muscle abnormality but also as left ventricular hypertrabeculation/noncompaction (LVHT) [1]. We have the following comments and concerns.
447
LVHT has not only been reported in association with mutations in the taffazin, α-DTNA, ZASP, LMNA, dystrophin, β-MHC, α-cardiac actin, or cardiac troponin genes but also in the DMPK, TPM1, RYR1, ITGA7, MYH7B, MYH7, LAMP2, GAA, GBEI, MADD, SDH, COL7A1, MMACHC, PMP22, FXN, beta-globin, and GLA genes [2]. Additionally, LVHT is frequently associated with mitochondrial disorders due to mtDNA or nDNA mutations, in particular mitochondrial multiorgan disorder syndrome (MIMODS), and with chromosomal abnormalities [3]. Did the patient present with dysmorphic features of the head, limbs, or trunk? In quite a number of cases LVHT occurs familially [4]. Did any of the relatives, in particular the mother, father, or grandparents undergo echocardiography or cardiac MRI to find out if LVHT was familial and transmitted from the mother’s or father’s side? There are a few case reports showing that LVHT is not congenital in each of the cases (acquired LVHT) [5]. Were previous echocardiographic investigations available particularly was fetal or neonatal echocardiography carried out to assess if LVHT was truly congenital or even acquired? In rare cases LVHT disappears over time [6]. For how long was the patient followed-up and was LVHT still present at each of the follow-up echocardiographies? Was there any change in morphology or extension of LVHT over time? Complications of LVHT include heart failure, embolism, ventricular arrhythmias, or sudden cardiac death (SCD) [7]. Did the patient ever experience stroke/embolism? Did he ever undergo cerebral MRI to rule out or confirm subclinical embolic stroke? Was the individual or family history positive for stroke/embolism, syncope, fainting, palpitations, or SCD? Long-term ECG recording is essential for assessing the risk of malignant arrhythmias. Why was no loop recorder implanted and why was no telemetric ECG-recording carried out? Some of the LVHT patients may require implantation of an implantable cardioverter defibrillator to prevent fatal ventricular arrhythmias [8]. LVHT may be associated with late gadolinium enhancement (LGE) as an indicator of myocardial fibrosis or microvascular compromise [9]. Did the authors look for LGE? Were inversion recovery gradient echo (IR-FLASH) sequences done during cardiac MRI and did they show LGE? Was LVHT in the presented patient assessed as “isolated” LVHT or did he present with additional cardiac abnormalities other than LVHT? Overall, this interesting case shows that heterogeneity of gene mutations associated with LVHT is further increasing and that extensive work-up of LVHT patients may increase knowledge about LVHT. Physicians involved in the management of NMD patients should be sensitised for the necessity to screen NMD patients cardiologically and to report cases with NMD and LVHT to broaden our understanding of this still poorly understood phenomenon. References [1] Villa C.R., Ryan T.D., Collins J.J., Taylor M.D., Lucky A.W., Jefferies J.L. Left ventricular non-compaction cardiomyopathy associated with
Letters to the Editor / Neuromuscular Disorders 25 (2015) 443–449
Myopathies (AFM). This work is a contribution to ADNA (Advanced Diagnostics for New Therapeutic Approaches), a program dedicated to personalised medicine, coordinated by Institut Mérieux, supported and partially funded by the French public agency OSEO. Reference [1] Nadarajah V.D., van Putten M., Chaouch A., et al. Serum matrix metalloproteinase-9 (MMP-9) as a biomarker for monitoring disease progression in Duchenne muscular dystrophy (DMD). Neuromuscul Disord 2011;21:569–78.
Aleksandar Zocevic a,1, Jeremy Rouillon a,1, Brenda Wong b, Laurent Servais c, Thomas Voit d,e, Fedor Svinartchouk a,* a Généthon, Evry, France b Division of Pediatric Neurology, Cincinnati Children’s Hospital Medical Center, USA c Service of Clinical Trials and Databases, Institut de Myologie, Paris, France d INSERM UMRS 974, CNRS FRE 3617, UPMC, Paris, France e Institut de Myologie, GH Pitié-Salpêtrière, Université Pierre et Marie Curie-Paris 6, Paris, France * Corresponding author. E-mail address: [email protected] (F. Svinartchouk). http://dx.doi.org/10.1016/j.nmd.2015.01.010 Response to: Evaluation of the serum matrix metalloproteinase-9 as a biomarker for monitoring disease progression in Duchenne muscular dystrophy We read with interest the letter by Zocevic and colleagues regarding matrix metalloproteinase 9 (MMP-9) in patients with Duchenne muscular dystrophy (DMD). Zocevic questioned the utility of MMP-9 as a biomarker for DMD given the observed increase in its serum levels as a consequence of corticosteroid intake. In an attempt to replicate the findings by Zocevic et al., we have analysed serum MMP-9 levels in a cohort of 116 DMD patients (of whom 53 are independent from our initial cohort described in [1]), among whom 25 were never treated with corticosteroids. We did not find a significant association between MMP-9 and corticosteroids treatment (p-value = 0.5 in univariate ANOVA using corticosteroid treatment and age as covariates). Moreover, initiation of corticosteroid treatment increases MMP-9 serum levels increase in some patients, but decreases them in others. In fact, this is not different from the study reported by Zocevic et al. where 40% of the patients do not show an increase of serum MMP-9 levels upon corticosteroids treatment. We also observe that MMP-9 levels may increase after discontinuing corticosteroid treatment. In support of this, it is reported in the literature that in several diseases such as Crohn’s disease, asthma (in children) and rheumatoid arthritis, 1
A. Zocevic and J. Rouillon contributed equally to this work.
treatment with corticosteroids causes a decrease in circulating MMP-9 levels or in MMP-9 gene expression [2–4]. It has also been shown that blood MMP-9 levels are not influenced by prednisolone in patients affected by Takayasu arteritis [5]. Moreover, Bossé et al. reported that asthmatic patients responding to treatment with corticosteroids show an increase in MMP-9 levels compared to non-responders [6]. We therefore believe that the increase in MMP-9 with DMD progression, observed in our initial study [1], and corroborated in independent studies from Hathout and colleagues [7] and our own group (submitted), cannot be explained by corticosteroid treatment. Zocevic et al. report MMP-9 serum levels in healthy controls of around 500 ng/ml for the young controls and above 500 ng/ml for older controls. These values are not consistent with our study [1] and three more studies, which all reported levels below 100 ng/ml for healthy children [8–10]. Another three studies report somewhat higher MMP-9 serum levels but still below 200, 300 and 400 ng/ml [11–13]. It is also surprising that Zocevic et al. observe an increase of serum MMP-9 with age in the control population, as it has been reported that serum MMP-9 levels are especially low in adults (below 200 ng/ml [14–17] or even below 50 ng/ml [18,19]). The high levels of MMP-9 in the reported control population are likely to mask the increase of MMP-9 in the Duchenne group. Since it is known that MMP-9 is released during clotting, it is possible that the high MMP-9 reported levels are due to the sampling procedure and haemolysis [20]. Acknowledgements This work has been supported by the Association Française contre les Myopathies (grant no. 15092). References [1] Nadarajah VD, van Putten M, Chaouch A, et al. Serum matrix metalloproteinase-9 (MMP-9) as a biomarker for monitoring disease progression in Duchenne muscular dystrophy (DMD). Neuromuscul Disord 2011;21:569–78. [2] Klimiuk PA, Sierakowski S, Domyslawska I, Chwiecko J. Effect of repeated infliximab therapy on serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with rheumatoid arthritis. J Rheumatol 2004;31:238–42. [3] Hegazy LM, El Hana SA. Circulating MMP-9 and TIMP-1 in acute exacerbations and after remission induced by oral corticosteroids in asthmatic children. Egypt J Pediatr Allergy Immunol 2014;4. [4] Faubion WA Jr, Fletcher JG, O’Byrne S, et al. EMerging BiomARKers in Inflammatory Bowel Disease (EMBARK) study identifies fecal calprotectin, serum MMP9, and serum IL-22 as a novel combination of biomarkers for Crohn’s disease activity: role of cross-sectional imaging. Am J Gastroenterol 2013;108:1891–900. [5] Ishihara T, Haraguchi G, Tezuka D, Kamiishi T, Inagaki H, Isobe M. Diagnosis and assessment of Takayasu arteritis by multiple biomarkers. Circ J 2013;77:477–83. [6] Bossé M, Chakir J, Rouabhia M, Boulet LP, Audette M, Laviolette M. Serum matrix metalloproteinase-9:Tissue inhibitor of metalloproteinase-1 ratio correlates with steroid responsiveness in moderate to severe asthma. Am J Respir Crit Care Med 1999;159:596–602. [7] Hathout Y, Marathi RL, Rayavarapu S, et al. Discovery of serum protein biomarkers in the mdx mouse model and cross-species comparison to Duchenne muscular dystrophy patients. Hum Mol Genet 2014; 23:6458–69.
Letters to the Editor / Neuromuscular Disorders 25 (2015) 443–449 [8] Qin YH, Zhou TB, Lei FY, et al. Cut-off values for serum matrix metalloproteinase-9: is there a threshold to predict renal involvement for Henoch-Schonlein purpura in children? Nephrology (Carlton) 2011; 16:93–9. [9] Hong Z, Lin YM, Qin X, Peng JL. Serum MMP-9 is elevated in children with asthma. Mol Med Rep 2012;5:462–4. [10] Kofla-Dlubacz A, Matusiewicz M, Krzystek-Korpacka M, Iwanczak B. Correlation of MMP-3 and MMP-9 with Crohn’s disease activity in children. Dig Dis Sci 2012;57:706–12. [11] Dasu MR, Spies M, Barrow RE, Herndon DN. Matrix metalloproteinases and their tissue inhibitors in severely burned children. Wound Repair Regen 2003;11:177–80. [12] Voraphani N, Khongphatthanayothin A, Srikaew K, Tontulawat P, Poovorawan Y. Matrix metalloproteinase-9 (MMP-9) in children with dengue virus infection. Jpn J Infect Dis 2010;63:346–8. [13] Yilmaz U, Gucuyener K, Atak A, et al. Matrix metalloproteinase-7 and matrix metalloproteinase-9 in pediatric multiple sclerosis. Pediatr Neurol 2012;47:171–6. [14] Brajer B, Batura-Gabryel H, Nowicka A, Kuznar-Kaminska B, Szczepanik A. Concentration of matrix metalloproteinase-9 in serum of patients with chronic obstructive pulmonary disease and a degree of airway obstruction and disease progression. J Physiol Pharmacol 2008;59(Suppl. 6):145–52. [15] Nikkola J, Vihinen P, Vuoristo MS, Kellokumpu-Lehtinen P, Kahari VM, Pyrhonen S. High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma. Clin Cancer Res 2005;11:5158–66. [16] Yaman E, Yalcin BÃ, Utkan GÃ, et al. Prognostic significance of serum matrix metalloproteinase 9 (MMP-9) levels in patients with sarcomas. UHOD 2008;18:79. [17] Chen P, Yuan Y, Wang S, Zhan L, Xu J. Serum matrix metalloproteinase 9 as a marker for the assessment of severe acute pancreatitis. Tohoku J Exp Med 2006;208:261–6. [18] Leelawat K, Sakchinabut S, Narong S, Wannaprasert J. Detection of serum MMP-7 and MMP-9 in cholangiocarcinoma patients: evaluation of diagnostic accuracy. BMC Gastroenterol 2009;9:30. [19] Yadav SS, Mandal RK, Singh MK, et al. High serum level of matrix metalloproteinase 9 and promoter polymorphism – 1562 C:T as a new risk factor for metabolic syndrome. DNA Cell Biol 2014;33:816–22. [20] Mannello F, Tanus-Santos JE, Meschiari CA, Tonti GA. Differences in both matrix metalloproteinase 9 concentration and zymographic profile between plasma and serum with clot activators are due to the presence of amorphous silica or silicate salts in blood collection devices. Anal Biochem 2008;374:56–63.
Pietro Spitali, Annemieke Aartsma-Rus, Peter A.C. ’t Hoen * Department of Human Genetics, Leiden University Medical Center, Postzone S4-P, P.O. Box 9600, Leiden 2300 RC, Netherlands * Corresponding author. E-mail address: [email protected] (P.A.C. ’t Hoen)
http://dx.doi.org/10.1016/j.nmd.2015.02.011 PLEC1 mutation associated with left ventricular hypertrabeculation/noncompaction We read with interest the article by Villa et al. about a patient with epidermiolysis bullosa simplex due to a PLEC1 mutation, which manifested not only as skin and muscle abnormality but also as left ventricular hypertrabeculation/noncompaction (LVHT) [1]. We have the following comments and concerns.
447
LVHT has not only been reported in association with mutations in the taffazin, α-DTNA, ZASP, LMNA, dystrophin, β-MHC, α-cardiac actin, or cardiac troponin genes but also in the DMPK, TPM1, RYR1, ITGA7, MYH7B, MYH7, LAMP2, GAA, GBEI, MADD, SDH, COL7A1, MMACHC, PMP22, FXN, beta-globin, and GLA genes [2]. Additionally, LVHT is frequently associated with mitochondrial disorders due to mtDNA or nDNA mutations, in particular mitochondrial multiorgan disorder syndrome (MIMODS), and with chromosomal abnormalities [3]. Did the patient present with dysmorphic features of the head, limbs, or trunk? In quite a number of cases LVHT occurs familially [4]. Did any of the relatives, in particular the mother, father, or grandparents undergo echocardiography or cardiac MRI to find out if LVHT was familial and transmitted from the mother’s or father’s side? There are a few case reports showing that LVHT is not congenital in each of the cases (acquired LVHT) [5]. Were previous echocardiographic investigations available particularly was fetal or neonatal echocardiography carried out to assess if LVHT was truly congenital or even acquired? In rare cases LVHT disappears over time [6]. For how long was the patient followed-up and was LVHT still present at each of the follow-up echocardiographies? Was there any change in morphology or extension of LVHT over time? Complications of LVHT include heart failure, embolism, ventricular arrhythmias, or sudden cardiac death (SCD) [7]. Did the patient ever experience stroke/embolism? Did he ever undergo cerebral MRI to rule out or confirm subclinical embolic stroke? Was the individual or family history positive for stroke/embolism, syncope, fainting, palpitations, or SCD? Long-term ECG recording is essential for assessing the risk of malignant arrhythmias. Why was no loop recorder implanted and why was no telemetric ECG-recording carried out? Some of the LVHT patients may require implantation of an implantable cardioverter defibrillator to prevent fatal ventricular arrhythmias [8]. LVHT may be associated with late gadolinium enhancement (LGE) as an indicator of myocardial fibrosis or microvascular compromise [9]. Did the authors look for LGE? Were inversion recovery gradient echo (IR-FLASH) sequences done during cardiac MRI and did they show LGE? Was LVHT in the presented patient assessed as “isolated” LVHT or did he present with additional cardiac abnormalities other than LVHT? Overall, this interesting case shows that heterogeneity of gene mutations associated with LVHT is further increasing and that extensive work-up of LVHT patients may increase knowledge about LVHT. Physicians involved in the management of NMD patients should be sensitised for the necessity to screen NMD patients cardiologically and to report cases with NMD and LVHT to broaden our understanding of this still poorly understood phenomenon. References [1] Villa C.R., Ryan T.D., Collins J.J., Taylor M.D., Lucky A.W., Jefferies J.L. Left ventricular non-compaction cardiomyopathy associated with