Mitochondrial tRNA mutations manifest not only as hypertrophic cardiomyopathy but also as noncompaction—reply Carla Giordano, Camillo Autore, Giulia d’Amati, Policlinico Umberto I PII: DOI: Reference:
S0046-8177(14)00190-7 doi: 10.1016/j.humpath.2014.01.024 YHUPA 3304
To appear in:
Human Pathology
Received date: Accepted date:
9 January 2014 16 January 2014
Please cite this article as: Giordano Carla, Autore Camillo, d’Amati Giulia, I Policlinico Umberto, Mitochondrial tRNA mutations manifest not only as hypertrophic cardiomyopathy but also as noncompaction—reply, Human Pathology (2014), doi: 10.1016/j.humpath.2014.01.024
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—reply Dear Editor,
RI PT
We welcome the opportunity to respond to the comments of Drs Finsterer and ZarroukMahjoub and thank these investigators for their interest in our report. We are well aware that hypertrophic cardiomyopathy is not the sole feature of cardiac involvement in mitochondrial disease, and we take this opportunity to address and clarify the important issues they have
SC
raised.
First, we never claimed that hypertrophic cardiomyopathy was the sole clinical
NU
manifestation of mitochondrial disease in all patients. In fact, as reported in our paper [1], patient 3 also showed progressive hearing impairment from the age of 2 years. A more
MA
detailed clinical history of this patient was previously reported by Perli et al [2]. Briefly, the patient was diagnosed with hypertrophic cardiomyopathy at the age of 12. There was no family history of hypertrophic cardiomyopathy or premature sudden death. Besides the
PT ED
finding of hearing loss, general neurological examination was normal. He had no evidence of ptosis or external ophthalmoplegia. Based on the association of hypertrophic cardiomyopathy and hearing loss, a skeletal muscle biopsy was performed and confirmed our suspicion of mitochondrial disease. There was only a mild increase in serum creatine kinase levels (324
CE
IU/L, normal range 22–269 IU/L). The patient, along with his unaffected mother and brother, is currently followed at our institution. Regarding patients 1 and 2, they belong to a large
AC
kindred, previously described in detail by members of our group [3]. All family members underwent both cardiologic and neurologic screening. The latter excluded a coexisting neuropathology or myopathy. There were no dysmorphisms. Out of 38 family members screened, 14 showed hypertrophic cardiomyopathy as the sole clinical manifestation of mitochondrial disease. In addition to the two patients with transplants considered in the present study, one family member died of congestive heart failure at 28 years of age, after information about the family was published. Several members of this large kindred are currently followed at our institution for their cardiomyopathy, and it is our common practice to perform clinical assessment with a multidisciplinary approach, with a close interface between the cardiologist and other medical specialties. Regarding the specific question about an MRI of the brain, this study was not performed in the index cases and their relatives, since neurologic examination was unremarkable. Second, we agree with the observation that “a ‘symmetric pattern of hypertrophy in
ACCEPTED MANUSCRIPT the absence of left ventricular outflow obstruction’ does not necessarily implicate MID.” In fact, in our paper we never stated that the echocardiographic pattern of symmetric left ventricular hypertrophy is sufficient to make a diagnosis of mitochondrial etiology [1].
RI PT
However, concentric hypertrophy is common in metabolic, storage, infiltrative, and mitochondrial disorders. Thus, a mitochondrial cardiomyopathy with a hypertrophic phenotype must be considered in the diagnostic flow chart of unexplained cardiac hypertrophy when the more frequent familial hypertrophic "sarcomeric" cardiomyopathy has
SC
been excluded. Other “red flags” must be accurately searched for, including maternal inheritance, increased serum levels of CK, and other signs, such as hearing loss, ptosis, etc [4],
NU
as is current practice at our institution.
Third, Finsterer et al state that the morphological aspects of the left ventricle in Fig. 1D
MA
of patient 3 suggest a diagnosis of left ventricular noncompaction (LVNC) and that the diagnosis was missed by the authors of the original article by Giordano et al [1]. We definitely disagree with this observation. In fact, LVNC was excluded by serial echocardiographic
PT ED
examinations performed before transplantation by a cardiologist (C. A.) with a specific expertise in cardiomyopathies, including LVNC [5]. Cardiac magnetic resonance confirmed the anatomical and functional features of the echocardiogram, in absence of morphological features fulfilling the diagnostic criteria for LVNC [6]. More importantly, we had the
CE
opportunity to thoroughly examine the explanted heart, both at gross and microscopic level, and we recorded only a slight increase in left ventricular trabeculation, with well-formed
AC
papillary muscles and in absence of deep intertrabecular recesses lined by endothelium [7], thus confirming the echocardiographic findings. The presence of increased left ventricular trabeculation in our case is not surprising since, as suggested by Elliott et al [8], it is possible that normal left ventricular trabeculations may become more prominent in certain disease states, such as left ventricular hypertrophy. Carla Giordano Department of Radiological, Oncological and Pathological Sciences Sapienza University of Rome Camillo Autore Department of Clinical and Molecular Medicine Sapienza University of Rome Giulia d’Amati Department of Radiological, Oncological and Pathological Sciences Sapienza University of Rome
ACCEPTED MANUSCRIPT
RI PT
Policlinico Umberto I Viale Regina Elena 324 00161 Rome, Italy E-mail address: [email protected]
SC
References
[1] Giordano C, Perli E, Orlandi M, et al. Cardiomyopathies due to homoplasmic mitochondrial
NU
tRNA mutations: morphologic and molecular features. HUM PATHOL 2013;44:1262–70.
MA
[2] Perli E, Giordano C, Tuppen HA, et al. Isoleucyl-tRNA synthetase levels modulate the penetrance of a homoplasmic m.4277T/C mitochondrial tRNA(Ile) mutation causing
PT ED
hypertrophic cardiomyopathy. Hum Mol Genet 2012;21:85–100. [3] Taylor RW, Giordano C, Davidson MM, et al. A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. J
CE
Am Coll Cardiol 2003;41:1786–96.
[4] Rapezzi C, Arbustini E, Caforio AL, et al. Diagnostic work-up in cardiomyopathies: bridging
AC
the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013;34:1448–58. [5] Caselli S, Autore C, Serdoz A, et al. Three-dimensional echocardiographic characterization of patients with left ventricular noncompaction. J Am Soc Echocardiogr 2012;25:203–9. [6] Petersen SE, Selvanayagam JB, Wiesmann F, et al. Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging. J Am Coll Cardiol 2005;46:101–5. [7] Burke A, Mont E, Kutys R, Virmani R. Left ventricular noncompaction: a pathological study of 14 cases. HUM PATHOL 2005;36:403–11.
ACCEPTED MANUSCRIPT [8] Elliott PM, Kholi SK, Pantazis AA, Sharma S. No re-appraisal of non-compaction diagnostic criteria without considering neurological co-morbidity and genetic heterogeneity: reply. Eur
AC
CE
PT ED
MA
NU
SC
RI PT
Heart J 2008;29:951–2.
S0046-8177(14)00190-7 doi: 10.1016/j.humpath.2014.01.024 YHUPA 3304
To appear in:
Human Pathology
Received date: Accepted date:
9 January 2014 16 January 2014
Please cite this article as: Giordano Carla, Autore Camillo, d’Amati Giulia, I Policlinico Umberto, Mitochondrial tRNA mutations manifest not only as hypertrophic cardiomyopathy but also as noncompaction—reply, Human Pathology (2014), doi: 10.1016/j.humpath.2014.01.024
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—reply Dear Editor,
RI PT
We welcome the opportunity to respond to the comments of Drs Finsterer and ZarroukMahjoub and thank these investigators for their interest in our report. We are well aware that hypertrophic cardiomyopathy is not the sole feature of cardiac involvement in mitochondrial disease, and we take this opportunity to address and clarify the important issues they have
SC
raised.
First, we never claimed that hypertrophic cardiomyopathy was the sole clinical
NU
manifestation of mitochondrial disease in all patients. In fact, as reported in our paper [1], patient 3 also showed progressive hearing impairment from the age of 2 years. A more
MA
detailed clinical history of this patient was previously reported by Perli et al [2]. Briefly, the patient was diagnosed with hypertrophic cardiomyopathy at the age of 12. There was no family history of hypertrophic cardiomyopathy or premature sudden death. Besides the
PT ED
finding of hearing loss, general neurological examination was normal. He had no evidence of ptosis or external ophthalmoplegia. Based on the association of hypertrophic cardiomyopathy and hearing loss, a skeletal muscle biopsy was performed and confirmed our suspicion of mitochondrial disease. There was only a mild increase in serum creatine kinase levels (324
CE
IU/L, normal range 22–269 IU/L). The patient, along with his unaffected mother and brother, is currently followed at our institution. Regarding patients 1 and 2, they belong to a large
AC
kindred, previously described in detail by members of our group [3]. All family members underwent both cardiologic and neurologic screening. The latter excluded a coexisting neuropathology or myopathy. There were no dysmorphisms. Out of 38 family members screened, 14 showed hypertrophic cardiomyopathy as the sole clinical manifestation of mitochondrial disease. In addition to the two patients with transplants considered in the present study, one family member died of congestive heart failure at 28 years of age, after information about the family was published. Several members of this large kindred are currently followed at our institution for their cardiomyopathy, and it is our common practice to perform clinical assessment with a multidisciplinary approach, with a close interface between the cardiologist and other medical specialties. Regarding the specific question about an MRI of the brain, this study was not performed in the index cases and their relatives, since neurologic examination was unremarkable. Second, we agree with the observation that “a ‘symmetric pattern of hypertrophy in
ACCEPTED MANUSCRIPT the absence of left ventricular outflow obstruction’ does not necessarily implicate MID.” In fact, in our paper we never stated that the echocardiographic pattern of symmetric left ventricular hypertrophy is sufficient to make a diagnosis of mitochondrial etiology [1].
RI PT
However, concentric hypertrophy is common in metabolic, storage, infiltrative, and mitochondrial disorders. Thus, a mitochondrial cardiomyopathy with a hypertrophic phenotype must be considered in the diagnostic flow chart of unexplained cardiac hypertrophy when the more frequent familial hypertrophic "sarcomeric" cardiomyopathy has
SC
been excluded. Other “red flags” must be accurately searched for, including maternal inheritance, increased serum levels of CK, and other signs, such as hearing loss, ptosis, etc [4],
NU
as is current practice at our institution.
Third, Finsterer et al state that the morphological aspects of the left ventricle in Fig. 1D
MA
of patient 3 suggest a diagnosis of left ventricular noncompaction (LVNC) and that the diagnosis was missed by the authors of the original article by Giordano et al [1]. We definitely disagree with this observation. In fact, LVNC was excluded by serial echocardiographic
PT ED
examinations performed before transplantation by a cardiologist (C. A.) with a specific expertise in cardiomyopathies, including LVNC [5]. Cardiac magnetic resonance confirmed the anatomical and functional features of the echocardiogram, in absence of morphological features fulfilling the diagnostic criteria for LVNC [6]. More importantly, we had the
CE
opportunity to thoroughly examine the explanted heart, both at gross and microscopic level, and we recorded only a slight increase in left ventricular trabeculation, with well-formed
AC
papillary muscles and in absence of deep intertrabecular recesses lined by endothelium [7], thus confirming the echocardiographic findings. The presence of increased left ventricular trabeculation in our case is not surprising since, as suggested by Elliott et al [8], it is possible that normal left ventricular trabeculations may become more prominent in certain disease states, such as left ventricular hypertrophy. Carla Giordano Department of Radiological, Oncological and Pathological Sciences Sapienza University of Rome Camillo Autore Department of Clinical and Molecular Medicine Sapienza University of Rome Giulia d’Amati Department of Radiological, Oncological and Pathological Sciences Sapienza University of Rome
ACCEPTED MANUSCRIPT
RI PT
Policlinico Umberto I Viale Regina Elena 324 00161 Rome, Italy E-mail address: [email protected]
SC
References
[1] Giordano C, Perli E, Orlandi M, et al. Cardiomyopathies due to homoplasmic mitochondrial
NU
tRNA mutations: morphologic and molecular features. HUM PATHOL 2013;44:1262–70.
MA
[2] Perli E, Giordano C, Tuppen HA, et al. Isoleucyl-tRNA synthetase levels modulate the penetrance of a homoplasmic m.4277T/C mitochondrial tRNA(Ile) mutation causing
PT ED
hypertrophic cardiomyopathy. Hum Mol Genet 2012;21:85–100. [3] Taylor RW, Giordano C, Davidson MM, et al. A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. J
CE
Am Coll Cardiol 2003;41:1786–96.
[4] Rapezzi C, Arbustini E, Caforio AL, et al. Diagnostic work-up in cardiomyopathies: bridging
AC
the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013;34:1448–58. [5] Caselli S, Autore C, Serdoz A, et al. Three-dimensional echocardiographic characterization of patients with left ventricular noncompaction. J Am Soc Echocardiogr 2012;25:203–9. [6] Petersen SE, Selvanayagam JB, Wiesmann F, et al. Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging. J Am Coll Cardiol 2005;46:101–5. [7] Burke A, Mont E, Kutys R, Virmani R. Left ventricular noncompaction: a pathological study of 14 cases. HUM PATHOL 2005;36:403–11.
ACCEPTED MANUSCRIPT [8] Elliott PM, Kholi SK, Pantazis AA, Sharma S. No re-appraisal of non-compaction diagnostic criteria without considering neurological co-morbidity and genetic heterogeneity: reply. Eur
AC
CE
PT ED
MA
NU
SC
RI PT
Heart J 2008;29:951–2.
