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MECP2 mutation in a boy with severe apnea and sick sinus syndrome
Brain & Development xxx (2018) xxx–xxx www.elsevier.com/locate/braindev
Case Report
MECP2 mutation in a boy with severe apnea and sick sinus syndrome Tsutomu Shioda a,⇑, Satoru Takahashi b, Tadashi Kaname c, Toyohiro Yamauchi d, Tetsuya Fukuoka a a
Department of Pediatrics, Shizuoka Saiseikai General Hospital, Shizuoka, Japan b Department of Pediatrics, Asahikawa Medical University, Hokkaido, Japan c Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan d Department of General Pediatrics, Shizuoka Children’s Hospital, Shizuoka, Japan Received 10 January 2018; received in revised form 19 March 2018; accepted 24 March 2018
Abstract Rett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene, which encodes methyl-CpG-binding protein 2 (MECP2). It almost exclusively affects the female sex and is considered lethal in the male sex. However, an increasing number of male patients with MECP2 mutations have been reported, including patients who suddenly died of unknown causes. We report a case of MECP2 mutation in a male patient who exhibited neonatal encephalopathy. He developed severe apnea, epilepsy, and psychomotor developmental delay and died suddenly of sick sinus syndrome at 17 months of age. Severe bradycardia had been noticed since 16 months of age. His older brother followed a similar clinical course and died at 30 months of age. The brother had also experienced severe bradycardia. This familial case might help to clarify the causes of sudden death in cases of MECP2 mutations. Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: MECP2; Male; Neonatal encephalopathy; Apnea; Sick sinus syndrome
1. Introduction Rett syndrome (RTT, MIM 312750) is a neurodevelopmental disorder that is clinically characterized by the regression of acquired motor and language skills, ataxia, and stereotypic hand movements. It is caused by mutations in the MECP2 gene encoding methyl-CpG-binding protein 2 (MECP2), which is mapped on chromosome Xq28. RTT is an X-linked disorder that almost exclusively affects the female sex. It is considered lethal in the male sex, but recently an increasing number of cases ⇑ Corresponding author at: Department of Pediatrics, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-ku, Shizuoka-shi, Shizuoka 422-8021, Japan. E-mail address: [email protected] (T. Shioda).
in male patients have been reported. MECP2 mutations in the male sex can be classified into: (1) severe neonatal encephalopathy that usually results in death in early childhood, (2) RTT with Klinefelter syndrome (47, XXY karyotype) or somatic mosaicism, and (3) mental retardation [1], indicating the very broad clinical phenotypic spectrum of MECP2 mutations in the male sex. The various complications in male patients with MECP2 mutations are not fully understood; thus, it is necessary to accumulate clinical evidence of such cases. Here, we describe the case of a male patient with an MECP2 mutation. The patient presented with severe apnea, epilepsy, stereotypic movements, and bradycardia and died suddenly of sick sinus syndrome at 17 months of age.
https://doi.org/10.1016/j.braindev.2018.03.008 0387-7604/Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Shioda T et al. MECP2 mutation in a boy with severe apnea and sick sinus syndrome. Brain Dev (2018), https://doi. org/10.1016/j.braindev.2018.03.008
2
T. Shioda et al. / Brain & Development xxx (2018) xxx–xxx
2. Case report The patient was born by emergency caesarean section because of severe variable deceleration at 38 weeks’ gestation (birth weight, 2438 g; height, 46.0 cm; head circumference, 33.0 cm). The Apgar scores were 6 at 5 min and 10 at 10 min. Soon after birth, he frequently presented with apnea and desaturation. Therefore, he was admitted to the Neonatal Intensive Care Unit (NICU) and was started on heated, humidified, highflow nasal cannula therapy. However, the severe apnea and bradypnea (respiratory rate less than 20 breaths per minute) remained. Complete blood cell count, blood biochemistry, basic metabolic workup, brain computed tomography scan, and brain magnetic resonance imaging were normal. Electroencephalography revealed an abnormal pattern of background activity and multifocal spikes. Carbamazepine was initiated. Upper gastrointestinal examination revealed gastroesophageal reflux. Neurological examination revealed muscle hypotonia and profoundly delayed psychomotor development. The patient had no eye contact and was unable to control his head. He was discharged on day 44 and home oxygen therapy was initiated. Because of swallowing difficulties, a nasogastric tube was placed from 8 months of age. He had a small occipitofrontal circumference (below the 3rd percentile). Stereotypic movement (shaking of the head) developed at 11 months of age. At 13 months of age, his chronic hypercapnic respiratory failure deteriorated and noninvasive positive pressure ventilation via a nasal mask was initiated. At 15 months of age, the both sides of his mandible were broken due to compression by the nasal mask band and pronounced shaking of the head. At 16 months of age, he experienced severe bradycardia (heart rate of approximately 40 beats per minute). Electrocardiography did not show long QT intervals. Holter electrocardiography indicated many episodes of sinus pauses for longest 6.0 s 45 times
a day (Fig. 1). Therefore, we diagnosed sick sinus syndrome and considered whether to implant a pacemaker. While discussing the possibility of surgery with the parents, the patient died suddenly at 17 months of age, which we considered had resulted from the sick sinus syndrome. Fig. 2 shows the pedigree of the patient’s family. The clinical course of the affected brother was very similar to that of the proband (Table 1). The brother was born at 40 weeks’ gestation (birth weight, 3128 g; height, 51.0 cm; head circumference, 34.0 cm). The Apgar scores were 5 both at 5 and 10 min. Soon after birth, the brother also presented with the frequent episodes of apnea that repeatedly appeared thereafter. At 7 months of age, he experienced respiratory syncytial virus bronchiolitis and treatment with noninvasive positive pressure ventilation was initiated. Electroencephalography showed an abnormal pattern and he was administered antiepileptics. Stereotypic movements including head shaking, oral munching, and arm waving, appeared at 8 months of age. At 10 months old, he underwent tracheotomy. At 23 months of age, severe bradycardia (heart rate less than 40 beats per minute) developed. Holter electrocardiography recorded sinus pauses for 2.6 s but not long QT intervals. His parents did not agree to pacemaker implantation, and he was treated with cilostazol to increase the pulse rate. Unfortunately, he died of an unknown cause at 30 months of age. The postmortem autopsy of the patient was not performed. We have summarized the results identifying the etiology of the proband. The karyotype from cultured blood lymphocytes revealed 46,XY. Screening test results for Prader-Willi syndrome, Pompe disease, and mitochondrial diseases were negative. The result for a PHOX2B mutation, which is a cause of congenital central hypoventilation syndrome, was also negative. Therefore, we examined the possibility of neonatal encephalopathy associated with MECP2 mutations. Mutation analysis
Fig. 1. Holter electrocardiogram demonstrating a 6.0 s pause (at 17 months of age).
Please cite this article in press as: Shioda T et al. MECP2 mutation in a boy with severe apnea and sick sinus syndrome. Brain Dev (2018), https://doi. org/10.1016/j.braindev.2018.03.008
T. Shioda et al. / Brain & Development xxx (2018) xxx–xxx
3
I
1
2
II
1
2
III 1
2
3
4
Fig. 2. Pedigree of the family. The proband (III-4) presented with severe neonatal encephalopathy and died at 17 months of age. His older brother (III-2) died suddenly of unknown cause at 30 months of age. Their asymptomatic mother (II-2) may have had germline mosaicism for the MECP2 mutation.
Table 1 Clinical summary of the two affected boys.
Sex Gestational age Birth weight Apgar score at 5 min Apgar score at 10 min Neonatal encephalopathy Severe apnea Home mechanical ventilation Tracheotomy Seizures Severe mental retardation Stereotypic movements Gastroesophageal reflux Bradycardia Long QT syndrome Pacemaker implantation Age at death Abbreviations: +, yes;
Older brother (III-2)
Proband (III-4)
Male 40 weeks 3128 g 5 5 + + + + + + + + +
Male 38 weeks 2438 g 6 10 + + +
30 months
17 months
+ + + + +
, no.
using DNA extracted from peripheral blood leukocytes revealed that the proband had a hemizygous missense mutation within the methyl-CpG binding domain of MECP2, which has been reported in female RTT patients (Fig. 3). This missense mutation was not detected in the peripheral blood lymphocytes of the patients’ parents (Fig. 3). Considering that the clinical course of the affected brother was similar to that of the proband, the mother most likely had germline mosaic. Except for this MECP2 variant, whole exome sequencing did not indicate pathogenic variations in genes associated with sick sinus syndrome.
3. Discussion An increasing number of male patients with MECP2 mutations have been identified in families with female RTT patients. However, male patients without such a family history have rarely been reported [2–4]. The severity of the clinical symptoms in MECP2 mutations is relatively wide, ranging from congenital encephalopathy to mental retardation. Thus, it is difficult to determine in which patients MECP2 mutation should be suspected. Kankirawatana et al. proposed that screening for MECP2 mutation should be considered for male
Please cite this article in press as: Shioda T et al. MECP2 mutation in a boy with severe apnea and sick sinus syndrome. Brain Dev (2018), https://doi. org/10.1016/j.braindev.2018.03.008
4
T. Shioda et al. / Brain & Development xxx (2018) xxx–xxx
Fig. 3. The MECP2 mutation in the proband. Automated DNA sequencing with the polymerase chain reaction product from the proband showed a hemizygous missense mutation at nucleotide 316 (NM_004992.3:c.316C > T) in MECP2, which resulted in an arginineto-tryptophan substitution at amino acid position 106 (NP_004983.1:p. (Arg106Trp)). This missense mutation was not found in his unaffected parents.
patients with two or more of the following: neonatal encephalopathy, unexplained central hypoventilation or respiratory insufficiency, abnormal movements, seizures, and abnormal muscle tone [2]. However, many diseases present with apnea, hypercapnic respiratory failure, and hypotonia, such as congenital myopathy, spinal muscular atrophy, Prader-Willi syndrome, and congenital central hypoventilation syndrome [5]. If screening results for these diseases are negative, screening for MECP2 mutation should be conducted in male patients, especially in cases involving apnea, respiratory failure, and hypotonia [5]. Moreover, the morbidity of breath-holding is reportedly high in RTT patients with p.Arg106Trp mutation [6]. The features of this case are consistent with the results of earlier RTT reports. Another crucial point in this case is the sudden death of the RTT patient. Incidence of sudden death in RTT
(mostly in the female sex) is 0.3% per year, which is higher than that in the general population [7]. Among the reported deaths from Rett syndrome, 26% were sudden and unexpected [7], which were suspected to have a cardiac origin. Female RTT patients have lower heart rate variability and longer correlated QT intervals [8]. It was revealed that the prevalence of the long QT syndrome is high in RTT girls [9] and male MeCP2-null mice [10]. In our case, electrocardiography did not show long QT intervals; however it did show sick sinus syndrome. A case report noted the occurrence of severe sinus bradycardia in a female RTT patient [11]. Several studies have suggested that cardiac dysautonomia is linked to immaturity of medullary cardiorespiratory neurons [12] or reduced serotonin plasma levels [13]. In a study using embryonic stem cell model, MECP2 was involved in maintaining normal cardiac gene expression and cardiomyocyte structure [14]. Spontaneous cardiac rhythm abnormalities, including bradycardic events or sinus pauses, were observed in MeCP2-null animals [15]. Results from the pharmacological manipulation of MeCP2-null animals suggested that the underlying cause of the decreased heart rate might be due to increased parasympathetic input to the heart, and is not a function of the heart itself [15]. Severe bradycardia could be a critical complication of male patients with MECP2 mutation. More case reports and research are required to identify the causes of sudden death in male patients with congenital encephalopathy and MECP2 mutation. 4. Conclusions We reported on a male patient with neonatal encephalopathy associated with MECP2 mutation. The patient was suddenly died of sick sinus syndrome. This case suggests that elucidation of the etiology of bradycardia is important to prevent sudden death in cases with MECP2 mutations. 5. Competing interests The authors declare that they have no competing interests. 6. Funding None. 7. Ethical considerations We obtained written informed consent for this report from the patient’s parents and the Institutional Review Board of Shizuoka Saiseikai Hospital approved this case report (No.29-05-02).
Please cite this article in press as: Shioda T et al. MECP2 mutation in a boy with severe apnea and sick sinus syndrome. Brain Dev (2018), https://doi. org/10.1016/j.braindev.2018.03.008
T. Shioda et al. / Brain & Development xxx (2018) xxx–xxx
Acknowledgments The authors thank Dr. Ayako Sasaki, Department of Pediatrics, Yamagata University School of Medicine, for performing the test for PHOX2B mutations. The authors greatly appreciate all the pediatricians at Shizuoka Saiseikai General Hospital and Dr. Jun Yoshimoto, Department of Cardiology, Shizuoka Children’s Hospital, for their cooperation during the medical treatment of the patient and for their constructive comments on the case conference. References [1] Psoni S, Sofocleous C, Traeger-Synodinos J, Kitsiou-Tzeli S, Kanavakis E, Fryssira-Kanioura H. Phenotypic and genotypic variability in four males with MECP2 gene sequence aberrations including a novel deletion. Pediatr Res 2010;67:551–6. [2] Kankirawatana P, Leonard H, Ellaway C, Scurlock J, Mansour A, Makris CM, et al. Early progressive encephalopathy in boys and MECP2 mutations. Neurology 2006;67:164–6. [3] Schu¨le B, Armstrong DD, Vogel H, Oviedo A, Francke U. Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure. Clin Genet 2008;74:116–26. [4] RettBASE: RettSyndrome.org Variation Databasse. http:// mecp2.chw.edu.au [accessed 01.11.17]. [5] Falsaperla R, Pavone L, Fichera M, Striano P, Pavone P. Apneic crises: a clue for MECP2 testing in severe neonatal hypotoniarespiratory failure. Eur J Paediatr Neurol 2012;16:744–8. [6] Cardoza B, Clarke A, Wilcox J, Gibbon F, Smith PE, Archer H, et al. Epilepsy in Rett syndrome: association between phenotype
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
5
and genotype, and implications for practice. Seizure 2011;20:646–9. Kerr AM, Armstrong DD, Prescott RJ, Doyle D, Kearney DL. Rett syndrome: analysis of deaths in the British survey. Eur Child Adolesc Psychiatry 1997;6:71–4. Guideri F, Acampa M, Hayek G, Zappella M, Di Perri T. Reduced heart rate variability in patients affected with Rett syndrome. A possible explanation for sudden death. Neuropediatrics 1999;30:146–8. Acampa M, Guideri F. Cardiac disease and Rett syndrome. Arch Dis Child 2006;91:440–3. McCauley MD, Wang T, Mike E, Herrera J, Beavers DL, Haung TW, et al. Pathogenesis of lethal cardiac arrythmias in Mecp2 mutant mice: implication for therapy in Rett syndrome. Sci Transl Med 2011;3:113ra125. Madan N, Levine M, Pourmoghadam K, Sokoloski M. Severe sinus bradycardia in a patient with Rett syndrome: a new cause for a pause? Pediatr Cardiol 2004;25:53–5. Julu PO, Kerr AM, Hansen S, Apartopoulos F, Jamal GA. Immaturity of medullary cardiorespiratory neurones leading to inappropriate autonomic reactions as a likely cause of sudden death in Rett’s syndrome. Arch Dis Child 1997;77:464–5. Guideri F, Acampa M, Blardi P, de Lalla A, Zappella M, Hayek Y. Cardiac dysautonomia and serotonin plasma levels in Rett syndrome. Neuropediatrics 2004;35:36–8. Hara M, Takahashi T, Mitsumasu C, Igata S, Takano M, Minami T, et al. Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrythmias. Sci Rep 2015;5:11204. Herrera JA, Ward CS, Wehrens XH, Neul JL. Methyl-CpG binding-protein 2 function in cholinergic neurons mediates cardiac arrhythmogenesis. Hum Mol Genet 2016;25:4983–95.
Please cite this article in press as: Shioda T et al. MECP2 mutation in a boy with severe apnea and sick sinus syndrome. Brain Dev (2018), https://doi. org/10.1016/j.braindev.2018.03.008
Case Report
MECP2 mutation in a boy with severe apnea and sick sinus syndrome Tsutomu Shioda a,⇑, Satoru Takahashi b, Tadashi Kaname c, Toyohiro Yamauchi d, Tetsuya Fukuoka a a
Department of Pediatrics, Shizuoka Saiseikai General Hospital, Shizuoka, Japan b Department of Pediatrics, Asahikawa Medical University, Hokkaido, Japan c Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan d Department of General Pediatrics, Shizuoka Children’s Hospital, Shizuoka, Japan Received 10 January 2018; received in revised form 19 March 2018; accepted 24 March 2018
Abstract Rett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene, which encodes methyl-CpG-binding protein 2 (MECP2). It almost exclusively affects the female sex and is considered lethal in the male sex. However, an increasing number of male patients with MECP2 mutations have been reported, including patients who suddenly died of unknown causes. We report a case of MECP2 mutation in a male patient who exhibited neonatal encephalopathy. He developed severe apnea, epilepsy, and psychomotor developmental delay and died suddenly of sick sinus syndrome at 17 months of age. Severe bradycardia had been noticed since 16 months of age. His older brother followed a similar clinical course and died at 30 months of age. The brother had also experienced severe bradycardia. This familial case might help to clarify the causes of sudden death in cases of MECP2 mutations. Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: MECP2; Male; Neonatal encephalopathy; Apnea; Sick sinus syndrome
1. Introduction Rett syndrome (RTT, MIM 312750) is a neurodevelopmental disorder that is clinically characterized by the regression of acquired motor and language skills, ataxia, and stereotypic hand movements. It is caused by mutations in the MECP2 gene encoding methyl-CpG-binding protein 2 (MECP2), which is mapped on chromosome Xq28. RTT is an X-linked disorder that almost exclusively affects the female sex. It is considered lethal in the male sex, but recently an increasing number of cases ⇑ Corresponding author at: Department of Pediatrics, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Suruga-ku, Shizuoka-shi, Shizuoka 422-8021, Japan. E-mail address: [email protected] (T. Shioda).
in male patients have been reported. MECP2 mutations in the male sex can be classified into: (1) severe neonatal encephalopathy that usually results in death in early childhood, (2) RTT with Klinefelter syndrome (47, XXY karyotype) or somatic mosaicism, and (3) mental retardation [1], indicating the very broad clinical phenotypic spectrum of MECP2 mutations in the male sex. The various complications in male patients with MECP2 mutations are not fully understood; thus, it is necessary to accumulate clinical evidence of such cases. Here, we describe the case of a male patient with an MECP2 mutation. The patient presented with severe apnea, epilepsy, stereotypic movements, and bradycardia and died suddenly of sick sinus syndrome at 17 months of age.
https://doi.org/10.1016/j.braindev.2018.03.008 0387-7604/Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Shioda T et al. MECP2 mutation in a boy with severe apnea and sick sinus syndrome. Brain Dev (2018), https://doi. org/10.1016/j.braindev.2018.03.008
2
T. Shioda et al. / Brain & Development xxx (2018) xxx–xxx
2. Case report The patient was born by emergency caesarean section because of severe variable deceleration at 38 weeks’ gestation (birth weight, 2438 g; height, 46.0 cm; head circumference, 33.0 cm). The Apgar scores were 6 at 5 min and 10 at 10 min. Soon after birth, he frequently presented with apnea and desaturation. Therefore, he was admitted to the Neonatal Intensive Care Unit (NICU) and was started on heated, humidified, highflow nasal cannula therapy. However, the severe apnea and bradypnea (respiratory rate less than 20 breaths per minute) remained. Complete blood cell count, blood biochemistry, basic metabolic workup, brain computed tomography scan, and brain magnetic resonance imaging were normal. Electroencephalography revealed an abnormal pattern of background activity and multifocal spikes. Carbamazepine was initiated. Upper gastrointestinal examination revealed gastroesophageal reflux. Neurological examination revealed muscle hypotonia and profoundly delayed psychomotor development. The patient had no eye contact and was unable to control his head. He was discharged on day 44 and home oxygen therapy was initiated. Because of swallowing difficulties, a nasogastric tube was placed from 8 months of age. He had a small occipitofrontal circumference (below the 3rd percentile). Stereotypic movement (shaking of the head) developed at 11 months of age. At 13 months of age, his chronic hypercapnic respiratory failure deteriorated and noninvasive positive pressure ventilation via a nasal mask was initiated. At 15 months of age, the both sides of his mandible were broken due to compression by the nasal mask band and pronounced shaking of the head. At 16 months of age, he experienced severe bradycardia (heart rate of approximately 40 beats per minute). Electrocardiography did not show long QT intervals. Holter electrocardiography indicated many episodes of sinus pauses for longest 6.0 s 45 times
a day (Fig. 1). Therefore, we diagnosed sick sinus syndrome and considered whether to implant a pacemaker. While discussing the possibility of surgery with the parents, the patient died suddenly at 17 months of age, which we considered had resulted from the sick sinus syndrome. Fig. 2 shows the pedigree of the patient’s family. The clinical course of the affected brother was very similar to that of the proband (Table 1). The brother was born at 40 weeks’ gestation (birth weight, 3128 g; height, 51.0 cm; head circumference, 34.0 cm). The Apgar scores were 5 both at 5 and 10 min. Soon after birth, the brother also presented with the frequent episodes of apnea that repeatedly appeared thereafter. At 7 months of age, he experienced respiratory syncytial virus bronchiolitis and treatment with noninvasive positive pressure ventilation was initiated. Electroencephalography showed an abnormal pattern and he was administered antiepileptics. Stereotypic movements including head shaking, oral munching, and arm waving, appeared at 8 months of age. At 10 months old, he underwent tracheotomy. At 23 months of age, severe bradycardia (heart rate less than 40 beats per minute) developed. Holter electrocardiography recorded sinus pauses for 2.6 s but not long QT intervals. His parents did not agree to pacemaker implantation, and he was treated with cilostazol to increase the pulse rate. Unfortunately, he died of an unknown cause at 30 months of age. The postmortem autopsy of the patient was not performed. We have summarized the results identifying the etiology of the proband. The karyotype from cultured blood lymphocytes revealed 46,XY. Screening test results for Prader-Willi syndrome, Pompe disease, and mitochondrial diseases were negative. The result for a PHOX2B mutation, which is a cause of congenital central hypoventilation syndrome, was also negative. Therefore, we examined the possibility of neonatal encephalopathy associated with MECP2 mutations. Mutation analysis
Fig. 1. Holter electrocardiogram demonstrating a 6.0 s pause (at 17 months of age).
Please cite this article in press as: Shioda T et al. MECP2 mutation in a boy with severe apnea and sick sinus syndrome. Brain Dev (2018), https://doi. org/10.1016/j.braindev.2018.03.008
T. Shioda et al. / Brain & Development xxx (2018) xxx–xxx
3
I
1
2
II
1
2
III 1
2
3
4
Fig. 2. Pedigree of the family. The proband (III-4) presented with severe neonatal encephalopathy and died at 17 months of age. His older brother (III-2) died suddenly of unknown cause at 30 months of age. Their asymptomatic mother (II-2) may have had germline mosaicism for the MECP2 mutation.
Table 1 Clinical summary of the two affected boys.
Sex Gestational age Birth weight Apgar score at 5 min Apgar score at 10 min Neonatal encephalopathy Severe apnea Home mechanical ventilation Tracheotomy Seizures Severe mental retardation Stereotypic movements Gastroesophageal reflux Bradycardia Long QT syndrome Pacemaker implantation Age at death Abbreviations: +, yes;
Older brother (III-2)
Proband (III-4)
Male 40 weeks 3128 g 5 5 + + + + + + + + +
Male 38 weeks 2438 g 6 10 + + +
30 months
17 months
+ + + + +
, no.
using DNA extracted from peripheral blood leukocytes revealed that the proband had a hemizygous missense mutation within the methyl-CpG binding domain of MECP2, which has been reported in female RTT patients (Fig. 3). This missense mutation was not detected in the peripheral blood lymphocytes of the patients’ parents (Fig. 3). Considering that the clinical course of the affected brother was similar to that of the proband, the mother most likely had germline mosaic. Except for this MECP2 variant, whole exome sequencing did not indicate pathogenic variations in genes associated with sick sinus syndrome.
3. Discussion An increasing number of male patients with MECP2 mutations have been identified in families with female RTT patients. However, male patients without such a family history have rarely been reported [2–4]. The severity of the clinical symptoms in MECP2 mutations is relatively wide, ranging from congenital encephalopathy to mental retardation. Thus, it is difficult to determine in which patients MECP2 mutation should be suspected. Kankirawatana et al. proposed that screening for MECP2 mutation should be considered for male
Please cite this article in press as: Shioda T et al. MECP2 mutation in a boy with severe apnea and sick sinus syndrome. Brain Dev (2018), https://doi. org/10.1016/j.braindev.2018.03.008
4
T. Shioda et al. / Brain & Development xxx (2018) xxx–xxx
Fig. 3. The MECP2 mutation in the proband. Automated DNA sequencing with the polymerase chain reaction product from the proband showed a hemizygous missense mutation at nucleotide 316 (NM_004992.3:c.316C > T) in MECP2, which resulted in an arginineto-tryptophan substitution at amino acid position 106 (NP_004983.1:p. (Arg106Trp)). This missense mutation was not found in his unaffected parents.
patients with two or more of the following: neonatal encephalopathy, unexplained central hypoventilation or respiratory insufficiency, abnormal movements, seizures, and abnormal muscle tone [2]. However, many diseases present with apnea, hypercapnic respiratory failure, and hypotonia, such as congenital myopathy, spinal muscular atrophy, Prader-Willi syndrome, and congenital central hypoventilation syndrome [5]. If screening results for these diseases are negative, screening for MECP2 mutation should be conducted in male patients, especially in cases involving apnea, respiratory failure, and hypotonia [5]. Moreover, the morbidity of breath-holding is reportedly high in RTT patients with p.Arg106Trp mutation [6]. The features of this case are consistent with the results of earlier RTT reports. Another crucial point in this case is the sudden death of the RTT patient. Incidence of sudden death in RTT
(mostly in the female sex) is 0.3% per year, which is higher than that in the general population [7]. Among the reported deaths from Rett syndrome, 26% were sudden and unexpected [7], which were suspected to have a cardiac origin. Female RTT patients have lower heart rate variability and longer correlated QT intervals [8]. It was revealed that the prevalence of the long QT syndrome is high in RTT girls [9] and male MeCP2-null mice [10]. In our case, electrocardiography did not show long QT intervals; however it did show sick sinus syndrome. A case report noted the occurrence of severe sinus bradycardia in a female RTT patient [11]. Several studies have suggested that cardiac dysautonomia is linked to immaturity of medullary cardiorespiratory neurons [12] or reduced serotonin plasma levels [13]. In a study using embryonic stem cell model, MECP2 was involved in maintaining normal cardiac gene expression and cardiomyocyte structure [14]. Spontaneous cardiac rhythm abnormalities, including bradycardic events or sinus pauses, were observed in MeCP2-null animals [15]. Results from the pharmacological manipulation of MeCP2-null animals suggested that the underlying cause of the decreased heart rate might be due to increased parasympathetic input to the heart, and is not a function of the heart itself [15]. Severe bradycardia could be a critical complication of male patients with MECP2 mutation. More case reports and research are required to identify the causes of sudden death in male patients with congenital encephalopathy and MECP2 mutation. 4. Conclusions We reported on a male patient with neonatal encephalopathy associated with MECP2 mutation. The patient was suddenly died of sick sinus syndrome. This case suggests that elucidation of the etiology of bradycardia is important to prevent sudden death in cases with MECP2 mutations. 5. Competing interests The authors declare that they have no competing interests. 6. Funding None. 7. Ethical considerations We obtained written informed consent for this report from the patient’s parents and the Institutional Review Board of Shizuoka Saiseikai Hospital approved this case report (No.29-05-02).
Please cite this article in press as: Shioda T et al. MECP2 mutation in a boy with severe apnea and sick sinus syndrome. Brain Dev (2018), https://doi. org/10.1016/j.braindev.2018.03.008
T. Shioda et al. / Brain & Development xxx (2018) xxx–xxx
Acknowledgments The authors thank Dr. Ayako Sasaki, Department of Pediatrics, Yamagata University School of Medicine, for performing the test for PHOX2B mutations. The authors greatly appreciate all the pediatricians at Shizuoka Saiseikai General Hospital and Dr. Jun Yoshimoto, Department of Cardiology, Shizuoka Children’s Hospital, for their cooperation during the medical treatment of the patient and for their constructive comments on the case conference. References [1] Psoni S, Sofocleous C, Traeger-Synodinos J, Kitsiou-Tzeli S, Kanavakis E, Fryssira-Kanioura H. Phenotypic and genotypic variability in four males with MECP2 gene sequence aberrations including a novel deletion. Pediatr Res 2010;67:551–6. [2] Kankirawatana P, Leonard H, Ellaway C, Scurlock J, Mansour A, Makris CM, et al. Early progressive encephalopathy in boys and MECP2 mutations. Neurology 2006;67:164–6. [3] Schu¨le B, Armstrong DD, Vogel H, Oviedo A, Francke U. Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure. Clin Genet 2008;74:116–26. [4] RettBASE: RettSyndrome.org Variation Databasse. http:// mecp2.chw.edu.au [accessed 01.11.17]. [5] Falsaperla R, Pavone L, Fichera M, Striano P, Pavone P. Apneic crises: a clue for MECP2 testing in severe neonatal hypotoniarespiratory failure. Eur J Paediatr Neurol 2012;16:744–8. [6] Cardoza B, Clarke A, Wilcox J, Gibbon F, Smith PE, Archer H, et al. Epilepsy in Rett syndrome: association between phenotype
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
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Please cite this article in press as: Shioda T et al. MECP2 mutation in a boy with severe apnea and sick sinus syndrome. Brain Dev (2018), https://doi. org/10.1016/j.braindev.2018.03.008