- Email: [email protected]
Clinical heterogeneity in Andersen-Tawil syndrome
Accepted Manuscript Title: Clinical heterogeneity in andersen-tawil syndrome Author: Armando Totomoch-Serra, Manlio F. Márquez, David E. CervantesBarragan PII: DOI: Reference:
S0960-8966(17)30497-2 http://dx.doi.org/doi: 10.1016/j.nmd.2017.09.001 NMD 3442
To appear in:
Neuromuscular Disorders
Please cite this article as: Armando Totomoch-Serra, Manlio F. Márquez, David E. CervantesBarragan, Clinical heterogeneity in andersen-tawil syndrome, Neuromuscular Disorders (2017), http://dx.doi.org/doi: 10.1016/j.nmd.2017.09.001. 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.
1
CLINICAL HETEROGENEITY IN ANDERSEN-TAWIL SYNDROME
Armando Totomoch-Serra1, Manlio F Márquez2*, David E. Cervantes-Barragan3
Authors affiliation 1
Department of Genetics and Molecular Biology, CINVESTAV, Mexico City, Mexico. Department of Electrophysiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico
2
City, Mexico. 3
Department of Genetics, Hospital Central Sur de Alta Especialidad PEMEX, Mexico City,
Mexico.
Corresponding author: Manlio F. Márquez* Department of Electrophysiology. Instituto Nacional de Cardiología “Ignacio Chávez”. Juan Badiano 1, Sección XVI. Tlalpan 14010. Mexico City. Mexico. Fax: (5255) 5573-0994. Phone: (5255) 5513-3740. E-mail: [email protected]
Key Words: Andersen-Tawil, p.Arg218Trp, Long Test-Protocol, Subtle Phenotypes, Clinical Heterogeneity, and Mexico.
Page 1 of 5
2
Letters to the Editor Dear Editor, We read with great interest the article of Ardissone et al. stressing the presence of intrafamilial phenotypic variability in Andersen-Tawil syndrome (ATS) [1]. Their observation is consonant with previous reports of the cardiac phenotype of ATS [2]. We want to emphasize some particular characteristics for the specific familial case with c.652C>T (p.Arg218Trp) mutation reported by the authors. Like the authors point out, p.Arg218Trp mutation is a hotspot with an increasing number of patients informed in literature [3]. With a frequency of 1:500 000, ATS is an ultrarare disease according to The European Commission [4]. We agree about avoiding unnecessary exam as muscle biopsy and a better study of dysmorphic characteristics in the suspected cases especially in heterozygous patients carrying the pArg218Trp mutation. From here, we would like to address 3 points: 1. The need to improve clinical diagnostic abilities during training in neurology, cardiology, and rehabilitation specialists with a focus in rare and ultra-rare diseases. As ATS is commonly unexpected to these specialists, the diagnosis is usually delayed. Proper training could help to increase the opportunity for a better treatment. Additionally, it is also important to take into account the interaction with a clinical geneticist specifically trained to identify subtle phenotypic differences that can be easily unnoticed by other specialists. Complementary to this point, ATS screening through long exercise protocol [5,6] could help the clinician to identify ATS patients. Tan et al. [7] described 11 individuals, 82% were positives for the long-exercise protocol. Unfortunately, due to different circumstances, this protocol is seldom used in standard clinical practice. This approach could help to avoid unnecessary biopsies in these patients.
Page 2 of 5
3
2. In the report by Ardissone et al., it is somewhat difficult to appreciate the welldescribed facial features of individuals in the family photo. However, it is interesting to note that in all reports in which the skeletal phenotype is shown, the facies of the affected subjects are so similar that they could well pass through members of the same family. This is even more noticeable if we take into account ATS patients from non-Caucasian populations such as Mexico [8,9]. 3.
Reports of p.Arg218Trp mutation will probably increase worldwide with NGS
technologies, and maybe we will discover subtle phenotypes even without cardiac disease. What remains to be elucidated is the difference between some severe phenotypes and those that present with a “benign” behavior, even in subjects with the same mutation. A search for modulating genetic factors in ATS is urgently needed. In the next years with the improvements in CRISPR/Cas9 technology [10] and induced pluripotent stem cell models [11], we will have better in vitro and in vivo models, and possibly new therapeutic approaches for this disease. As Ardissone et al. [1] pointed out, the diagnosis of ATS is challenging and their findings are particularly relevant due to the great variability in the phenotype for p.Arg218Trp mutation. We encourage the clinician to work side by side with the Cardiology, Clinical Genetics, Neurology, and Physical Rehabilitation Departments to search for the characteristic phenotype clearly described by the authors.
Page 3 of 5
4
Reference [1]
Ardissone A, Sansone V, Colleoni L, Bernasconi P, Moroni I. Intrafamilial phenotypic variability in Andersen–Tawil syndrome: A diagnostic challenge in a potentially treatable condition. Neuromuscul Disord. 2017;27:294-7.
[2]
Márquez MF, Totomoch-Serra A, Burgoa JA, Méndez A, Gómez-Flores JR, Nava S, et al. Abnormal electroencephalogram, epileptic seizures, structural congenital heart disease and aborted sudden cardiac death in Andersen–Tawil syndrome. Int J Cardiol. 2015;180:206-9.
[3]
Márquez MF, Totomoch-Serra A, Vargas-Alarcón G, Cruz-Robles D, Pellizzon OA, Cárdenas M. Andersen-Tawil syndrome: a review of its clinical and genetic diagnosis with emphasis on cardiac manifestations. Arch Cardiol Mex. 2014;84:278-85.
[4]
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, text with EEA relevance [document on the Internet]. European Parliament, Council of the European Union; 2014 [updated 2014 April 16; cited 2017 Jun 16]. Available from: http://eur-lex.europa.eu/legalcontent/EN/TXT/?qid=1497588923340&uri=CELEX:32014R0536
[5]
Kuntzer T, Flocard F, Vial C, Kohler A, Magistris M, Labarre-Vila A, et al. Exercise test in muscle channelopathies and other muscle disorders. Muscle Nerve. 2000;23:1089-94.
Page 4 of 5
5
[6]
Fournier E, Arzel M, Sternberg D, Vicart S, Laforet P, Eymard B, et al. Electromyography
guides
toward
subgroups
of
mutations
in
muscle
channelopathies. Ann Neurol. 2004;56:650-61. [7]
Tan SV, Matthews E, Barber M, Burge JA, Rajakulendran S, Fialho D, et al. Refined
exercise
testing
can
aid
DNA-based
diagnosis
in
muscle
channelopathies.Ann Neurol. 2011;69:328-40. [8]
Canún S, Pérez N, Beirana LG. Andersen syndrome autosomal dominant in three generations. Am J Med Genet. 1999;85:147-56.
[9]
Yoon G, Oberoi S, Tristani-Firouzi M, Etheridge SP, Quitania L, Kramer JH, et al. Andersen-Tawil syndrome: prospective cohort analysis and expansion of the phenotype. Am J Med Genet A. 2006;140:312-21.
[10]
Xie C, Zhang YP, Song L, Luo J, Qi W, Hu J, et al. Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome. Cell Res. 2016;26:1099-111.
[11]
Meijer van Putten RM, Mengarelli I, Guan K, Zegers JG, van Ginneken AC, Verkerk AO1, et al. Ion channelopathies in human induced pluripotent stem cell derived cardiomyocytes: a dynamic clamp study with virtual IK1. Front Physiol. 2015;6:7.
Page 5 of 5
S0960-8966(17)30497-2 http://dx.doi.org/doi: 10.1016/j.nmd.2017.09.001 NMD 3442
To appear in:
Neuromuscular Disorders
Please cite this article as: Armando Totomoch-Serra, Manlio F. Márquez, David E. CervantesBarragan, Clinical heterogeneity in andersen-tawil syndrome, Neuromuscular Disorders (2017), http://dx.doi.org/doi: 10.1016/j.nmd.2017.09.001. 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.
1
CLINICAL HETEROGENEITY IN ANDERSEN-TAWIL SYNDROME
Armando Totomoch-Serra1, Manlio F Márquez2*, David E. Cervantes-Barragan3
Authors affiliation 1
Department of Genetics and Molecular Biology, CINVESTAV, Mexico City, Mexico. Department of Electrophysiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico
2
City, Mexico. 3
Department of Genetics, Hospital Central Sur de Alta Especialidad PEMEX, Mexico City,
Mexico.
Corresponding author: Manlio F. Márquez* Department of Electrophysiology. Instituto Nacional de Cardiología “Ignacio Chávez”. Juan Badiano 1, Sección XVI. Tlalpan 14010. Mexico City. Mexico. Fax: (5255) 5573-0994. Phone: (5255) 5513-3740. E-mail: [email protected]
Key Words: Andersen-Tawil, p.Arg218Trp, Long Test-Protocol, Subtle Phenotypes, Clinical Heterogeneity, and Mexico.
Page 1 of 5
2
Letters to the Editor Dear Editor, We read with great interest the article of Ardissone et al. stressing the presence of intrafamilial phenotypic variability in Andersen-Tawil syndrome (ATS) [1]. Their observation is consonant with previous reports of the cardiac phenotype of ATS [2]. We want to emphasize some particular characteristics for the specific familial case with c.652C>T (p.Arg218Trp) mutation reported by the authors. Like the authors point out, p.Arg218Trp mutation is a hotspot with an increasing number of patients informed in literature [3]. With a frequency of 1:500 000, ATS is an ultrarare disease according to The European Commission [4]. We agree about avoiding unnecessary exam as muscle biopsy and a better study of dysmorphic characteristics in the suspected cases especially in heterozygous patients carrying the pArg218Trp mutation. From here, we would like to address 3 points: 1. The need to improve clinical diagnostic abilities during training in neurology, cardiology, and rehabilitation specialists with a focus in rare and ultra-rare diseases. As ATS is commonly unexpected to these specialists, the diagnosis is usually delayed. Proper training could help to increase the opportunity for a better treatment. Additionally, it is also important to take into account the interaction with a clinical geneticist specifically trained to identify subtle phenotypic differences that can be easily unnoticed by other specialists. Complementary to this point, ATS screening through long exercise protocol [5,6] could help the clinician to identify ATS patients. Tan et al. [7] described 11 individuals, 82% were positives for the long-exercise protocol. Unfortunately, due to different circumstances, this protocol is seldom used in standard clinical practice. This approach could help to avoid unnecessary biopsies in these patients.
Page 2 of 5
3
2. In the report by Ardissone et al., it is somewhat difficult to appreciate the welldescribed facial features of individuals in the family photo. However, it is interesting to note that in all reports in which the skeletal phenotype is shown, the facies of the affected subjects are so similar that they could well pass through members of the same family. This is even more noticeable if we take into account ATS patients from non-Caucasian populations such as Mexico [8,9]. 3.
Reports of p.Arg218Trp mutation will probably increase worldwide with NGS
technologies, and maybe we will discover subtle phenotypes even without cardiac disease. What remains to be elucidated is the difference between some severe phenotypes and those that present with a “benign” behavior, even in subjects with the same mutation. A search for modulating genetic factors in ATS is urgently needed. In the next years with the improvements in CRISPR/Cas9 technology [10] and induced pluripotent stem cell models [11], we will have better in vitro and in vivo models, and possibly new therapeutic approaches for this disease. As Ardissone et al. [1] pointed out, the diagnosis of ATS is challenging and their findings are particularly relevant due to the great variability in the phenotype for p.Arg218Trp mutation. We encourage the clinician to work side by side with the Cardiology, Clinical Genetics, Neurology, and Physical Rehabilitation Departments to search for the characteristic phenotype clearly described by the authors.
Page 3 of 5
4
Reference [1]
Ardissone A, Sansone V, Colleoni L, Bernasconi P, Moroni I. Intrafamilial phenotypic variability in Andersen–Tawil syndrome: A diagnostic challenge in a potentially treatable condition. Neuromuscul Disord. 2017;27:294-7.
[2]
Márquez MF, Totomoch-Serra A, Burgoa JA, Méndez A, Gómez-Flores JR, Nava S, et al. Abnormal electroencephalogram, epileptic seizures, structural congenital heart disease and aborted sudden cardiac death in Andersen–Tawil syndrome. Int J Cardiol. 2015;180:206-9.
[3]
Márquez MF, Totomoch-Serra A, Vargas-Alarcón G, Cruz-Robles D, Pellizzon OA, Cárdenas M. Andersen-Tawil syndrome: a review of its clinical and genetic diagnosis with emphasis on cardiac manifestations. Arch Cardiol Mex. 2014;84:278-85.
[4]
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, text with EEA relevance [document on the Internet]. European Parliament, Council of the European Union; 2014 [updated 2014 April 16; cited 2017 Jun 16]. Available from: http://eur-lex.europa.eu/legalcontent/EN/TXT/?qid=1497588923340&uri=CELEX:32014R0536
[5]
Kuntzer T, Flocard F, Vial C, Kohler A, Magistris M, Labarre-Vila A, et al. Exercise test in muscle channelopathies and other muscle disorders. Muscle Nerve. 2000;23:1089-94.
Page 4 of 5
5
[6]
Fournier E, Arzel M, Sternberg D, Vicart S, Laforet P, Eymard B, et al. Electromyography
guides
toward
subgroups
of
mutations
in
muscle
channelopathies. Ann Neurol. 2004;56:650-61. [7]
Tan SV, Matthews E, Barber M, Burge JA, Rajakulendran S, Fialho D, et al. Refined
exercise
testing
can
aid
DNA-based
diagnosis
in
muscle
channelopathies.Ann Neurol. 2011;69:328-40. [8]
Canún S, Pérez N, Beirana LG. Andersen syndrome autosomal dominant in three generations. Am J Med Genet. 1999;85:147-56.
[9]
Yoon G, Oberoi S, Tristani-Firouzi M, Etheridge SP, Quitania L, Kramer JH, et al. Andersen-Tawil syndrome: prospective cohort analysis and expansion of the phenotype. Am J Med Genet A. 2006;140:312-21.
[10]
Xie C, Zhang YP, Song L, Luo J, Qi W, Hu J, et al. Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome. Cell Res. 2016;26:1099-111.
[11]
Meijer van Putten RM, Mengarelli I, Guan K, Zegers JG, van Ginneken AC, Verkerk AO1, et al. Ion channelopathies in human induced pluripotent stem cell derived cardiomyocytes: a dynamic clamp study with virtual IK1. Front Physiol. 2015;6:7.
Page 5 of 5