Mitochondrial tRNA mutations manifest not only as hypertrophic cardiomyopathy but also as noncompaction Josef Finsterer MD PhD, Sinda Zarrouk-Mahjoub PII: DOI: Reference:
S0046-8177(14)00189-0 doi: 10.1016/j.humpath.2014.01.023 YHUPA 3303
To appear in:
Human Pathology
Received date: Accepted date:
15 December 2013 16 January 2014
Please cite this article as: Finsterer Josef, Zarrouk-Mahjoub Sinda, Mitochondrial tRNA mutations manifest not only as hypertrophic cardiomyopathy but also as noncompaction, Human Pathology (2014), doi: 10.1016/j.humpath.2014.01.023
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Mitochondrial tRNA mutations manifest not only as hypertrophic cardiomyopathy but also as noncompaction
T
Dear Editor,
RI P
With interest we read the article by Giordano et al about mitochondrial cardiomyopathy due to the mitochondrial tRNA mutations m.4277T>C and m.4300A>G in three cases
SC
(two carried mutation m.4277T>C) without other clinical manifestations of a
NU
mitochondrial disorder (MID) [1]. We have the following comments and concerns.
The authors claim that cardiomyopathy was the sole manifestation of the MID in all
MA
patients. First, patient 3 also presented with hearing loss. Second, how can the authors be sure as long as patients were not systematically screened for involvement of organs other
ED
than the heart? Was there weakness, wasting, reduced tendon reflexes, creatine-kinase elevation, or a myogenic needle–electromyography? Was an MRI of the cerebrum carried
PT
out? Was there any dysmorphism? Were the patients investigated by a neurologist?
AC CE
We do not agree with the statement that the pattern of myocardial hypertrophy is an important clue to the diagnosis of MID. The morphological pattern of hypertrophy itself does not imply MID. A “symmetric pattern of hypertrophy in the absence of left ventricular outflow obstruction” does not necessarily implicate MID. MID is usually suspected upon the clinical presentation but if left ventricular hypertrophy is the only manifestation, the suspicion would be very low. Did any of the first-degree relatives of any of the three patients screened for cardiomyopathy manifest with MID?
The main concern about this manuscript is that the authors did not mention that the heart of patient 3 (Fig. 1D) showed left ventricular hypertrabeculation/noncompaction (LVHT). LVHT is an unclassified cardiomoypathy characterized by a two-layered structure of the left ventricular myocardium distal to the papillary muscles located most frequently in the apex and the lateral wall [2]. The inner (endocardial) layer is noncompacted and thicker than the outer (epicardial) layer, which is thinner than the inner layer and compacted. The
ACCEPTED MANUSCRIPT intertrabecular spaces of the noncompacted layer are perfused from the ventricular side. Fig. 1D of the paper clearly shows LVHT of the apex but also the two-layered structure of the left ventricular myocardium. LVHT is a frequent finding in MIDs [3] and is associated with left ventricular systolic dysfunction, ventricular arrhythmias, and cardiac
T
embolism [4]. Did any of the patients’ individual histories reveal ischemic stroke or
RI P
peripheral embolism, palpitations, syncope, leg edema, exertional dyspnea, or previous systolic dysfunction? The cause of LVHT is unknown but the frequent association with
SC
primary NMDs [[Author: please spell out this abbreviation]] and chromosomal abnormalities suggest a pathogenetic link between these mutations and LVHT. Why was
NU
LVHT missed on the echocardiography in patient 3? Was it due to poor image quality, severe hypertrophy, ignorance, unawareness, or severe dilatation? Since LVHT is familial
MA
in many cases, it would be interesting to know if any of the first-degree family members screened for cardiomyopathy had a history indicative of LVHT complications. It is
ED
important to diagnose LVHT since it may require implantation of a cardioverter
PT
defibrillator, administration of an oral anticoagulant, or treatment of heart failure.
Overall, this interesting case series definitively presents a patient with nonrecognized
AC CE
LVHT. This patient has undergone heart transplantation and now
receives
immunosuppressive treatment. If this patient suffers from a subclinical myopathy, it might have eventually become evident. Re-evaluation of patient 3 is strongly recommended in order to not miss the point at which complications of LVHT have become intractable.
Josef Finsterer, MD, PhD Krankenanstalt Rudolfstiftung Postfach 20 1180 Vienna, Austria E-mail address: [email protected] Sinda Zarrouk-Mahjoub Laboratory of Biochemistry UR “Human Nutrition and Metabolic Disorders” 2
ACCEPTED MANUSCRIPT
T
Faculty of Medicine Monastir, Tunisie
RI P
References
SC
[1] Giordano C, Perli E, Orlandi M, et al. Cardiomyopathies due to homoplasmic mitochondrial tRNA mutations: morphologic and molecular features. HUM PATHOL 2013;44:1262–70.
MA
NU
[2] Engberding R, Yelbuz TM, Breithardt G. Isolated noncompaction of the left ventricular myocardium—a review of the literature two decades after the initial case description. Clin Res Cardiol 2007;96:481–8.
ED
[3] Tang S, Batra A, Zhang Y, Ebenroth ES, Huang T. Left ventricular noncompaction is associated with mutations in the mitochondrial genome. Mitochondrion 2010;10:350–7.
AC CE
PT
[4] Finsterer J. Cardiogenetics, neurogenetics, and pathogenetics of left ventricular hypertrabeculation/noncompaction. Pediatr Cardiol 2009;30:659–81.
3
S0046-8177(14)00189-0 doi: 10.1016/j.humpath.2014.01.023 YHUPA 3303
To appear in:
Human Pathology
Received date: Accepted date:
15 December 2013 16 January 2014
Please cite this article as: Finsterer Josef, Zarrouk-Mahjoub Sinda, Mitochondrial tRNA mutations manifest not only as hypertrophic cardiomyopathy but also as noncompaction, Human Pathology (2014), doi: 10.1016/j.humpath.2014.01.023
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Mitochondrial tRNA mutations manifest not only as hypertrophic cardiomyopathy but also as noncompaction
T
Dear Editor,
RI P
With interest we read the article by Giordano et al about mitochondrial cardiomyopathy due to the mitochondrial tRNA mutations m.4277T>C and m.4300A>G in three cases
SC
(two carried mutation m.4277T>C) without other clinical manifestations of a
NU
mitochondrial disorder (MID) [1]. We have the following comments and concerns.
The authors claim that cardiomyopathy was the sole manifestation of the MID in all
MA
patients. First, patient 3 also presented with hearing loss. Second, how can the authors be sure as long as patients were not systematically screened for involvement of organs other
ED
than the heart? Was there weakness, wasting, reduced tendon reflexes, creatine-kinase elevation, or a myogenic needle–electromyography? Was an MRI of the cerebrum carried
PT
out? Was there any dysmorphism? Were the patients investigated by a neurologist?
AC CE
We do not agree with the statement that the pattern of myocardial hypertrophy is an important clue to the diagnosis of MID. The morphological pattern of hypertrophy itself does not imply MID. A “symmetric pattern of hypertrophy in the absence of left ventricular outflow obstruction” does not necessarily implicate MID. MID is usually suspected upon the clinical presentation but if left ventricular hypertrophy is the only manifestation, the suspicion would be very low. Did any of the first-degree relatives of any of the three patients screened for cardiomyopathy manifest with MID?
The main concern about this manuscript is that the authors did not mention that the heart of patient 3 (Fig. 1D) showed left ventricular hypertrabeculation/noncompaction (LVHT). LVHT is an unclassified cardiomoypathy characterized by a two-layered structure of the left ventricular myocardium distal to the papillary muscles located most frequently in the apex and the lateral wall [2]. The inner (endocardial) layer is noncompacted and thicker than the outer (epicardial) layer, which is thinner than the inner layer and compacted. The
ACCEPTED MANUSCRIPT intertrabecular spaces of the noncompacted layer are perfused from the ventricular side. Fig. 1D of the paper clearly shows LVHT of the apex but also the two-layered structure of the left ventricular myocardium. LVHT is a frequent finding in MIDs [3] and is associated with left ventricular systolic dysfunction, ventricular arrhythmias, and cardiac
T
embolism [4]. Did any of the patients’ individual histories reveal ischemic stroke or
RI P
peripheral embolism, palpitations, syncope, leg edema, exertional dyspnea, or previous systolic dysfunction? The cause of LVHT is unknown but the frequent association with
SC
primary NMDs [[Author: please spell out this abbreviation]] and chromosomal abnormalities suggest a pathogenetic link between these mutations and LVHT. Why was
NU
LVHT missed on the echocardiography in patient 3? Was it due to poor image quality, severe hypertrophy, ignorance, unawareness, or severe dilatation? Since LVHT is familial
MA
in many cases, it would be interesting to know if any of the first-degree family members screened for cardiomyopathy had a history indicative of LVHT complications. It is
ED
important to diagnose LVHT since it may require implantation of a cardioverter
PT
defibrillator, administration of an oral anticoagulant, or treatment of heart failure.
Overall, this interesting case series definitively presents a patient with nonrecognized
AC CE
LVHT. This patient has undergone heart transplantation and now
receives
immunosuppressive treatment. If this patient suffers from a subclinical myopathy, it might have eventually become evident. Re-evaluation of patient 3 is strongly recommended in order to not miss the point at which complications of LVHT have become intractable.
Josef Finsterer, MD, PhD Krankenanstalt Rudolfstiftung Postfach 20 1180 Vienna, Austria E-mail address: [email protected] Sinda Zarrouk-Mahjoub Laboratory of Biochemistry UR “Human Nutrition and Metabolic Disorders” 2
ACCEPTED MANUSCRIPT
T
Faculty of Medicine Monastir, Tunisie
RI P
References
SC
[1] Giordano C, Perli E, Orlandi M, et al. Cardiomyopathies due to homoplasmic mitochondrial tRNA mutations: morphologic and molecular features. HUM PATHOL 2013;44:1262–70.
MA
NU
[2] Engberding R, Yelbuz TM, Breithardt G. Isolated noncompaction of the left ventricular myocardium—a review of the literature two decades after the initial case description. Clin Res Cardiol 2007;96:481–8.
ED
[3] Tang S, Batra A, Zhang Y, Ebenroth ES, Huang T. Left ventricular noncompaction is associated with mutations in the mitochondrial genome. Mitochondrion 2010;10:350–7.
AC CE
PT
[4] Finsterer J. Cardiogenetics, neurogenetics, and pathogenetics of left ventricular hypertrabeculation/noncompaction. Pediatr Cardiol 2009;30:659–81.
3
