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THE JOURNAL OF THE JAPAN PEDIATRIC SOCIETY
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Vol.126, No.3, March 2022
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Review
Title
New Era in Treatment of Spinal Muscular Atrophy: Adeno-Associated Virus-Based Gene Therapy
Author
Hiroyuki Awano1) Yoshinori Nambu1) Masakazu Shinohara2) Kentaro Okamoto3) Toshio Saito4) Yasuhiro Takeshima5) and Hisahide Nishio6)
1)Department of Pediatrics, Kobe University Graduate School of Medicine
2)Department of Community Medicine and Social Health Care, Kobe University Graduate School of Medicine
3)Department of Pediatrics, Ehime Prefectural Imabari Hospital
4)Division of Child Neurology, Department of Neurology, National Hospital Organization Osaka Toneyama Medical Center
5)Department of Pediatrics, Hyogo College of Medicine
6)Department of Occupational Therapy, Faculty of Rehabilitation, Kobe Gakuin University
Abstract
Spinal muscular atrophy (SMA) is an inherited neuromuscular disease, and its severe form (Werdnig-Hoffmann disease) is the most common genetic cause of infant deaths. Recently, several effective drugs have been developed, providing hope to SMA patients and their families. One of the newly developed SMA drugs, Onasemnogene Abeparvovec (OA), is an adeno-associated viral (AAV)-based drug carrying human SMN cDNA. The drug received regulatory approval in the U.S., Japan, EU countries and Brazil consecutively, and now SMA is considered to be a target disease for such gene therapy. In this paper, we will sketch the history of SMA research and OA development, and describe the clinical trials and adverse effects of OA, and discuss its indication and cost-effectiveness. In addition, we will give some comments on the newborn screening for SMA.
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Original Article
Title
Delayed Onset and the Mode of Transmission of Exanthem Subitum in Japan
Author
Sadayoshi Torigoe1) Masahiro Watanabe2) Hikaru Namba3) and Masao Yamada3)
1)Aquair Medical Station
2)Suzuka Pediatrics
3)Department of Virology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Abstract
Exanthem subitum (ES) is caused by human herpesviruses 6B (HHV-6B) and 7 (HHV-7). We surveyed the onset age of ES for 27 years in Japan. Delayed onset of ES was common, and morbidity rates of ES by age decreased over time. We also monitored HHV-6B and -7 DNA loads in saliva during the acute and convalescent phases of ES. HHV-6B DNA loads were small during the acute phase. Thereafter, DNA loads and the frequency of excretion increased and remained at high levels for months. The positivity rates of HHV-6B and -7 DNA were 50% and 20% in 3- to 5-year-old children, and 4.3% and 56.5% in adults, respectively. Analysis of salivary secretion showed that negative-to-positive HHV-6B DNA conversion rates were 56.7% during the first 6 months in children at day care centers and 28.6% in those receiving home care. In the initial samples, the positivity rates of HHV-6B DNA were 31.7% in children who had elder siblings and 14.0% in those who did not. These results suggest that HHV-6B is transmitted mainly in day care centers and by elder siblings, while HHV-7 is transmitted mainly by adults.
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Case Report
Title
Congenital Aortic Aneurysm Diagnosed in a Fetus
Author
Yusuke Watanabe1)2) Hiroshi Ono1) Yui Ozawa1) Koichi Takamizawa1) Yosuke Ogawa1) Taiyu Hayashi1) Takahiro Shindo1) Yasushi Misaki1) and Hitoshi Kato1)
1)Division of Cardiology, National Center for Child Health and Development
2)Division of Pediatrics and Adolescent Medicine, Tokyo Medical University Hospital
Abstract
A fetus showed signs of having an aortic malformation in the 20th week of gestation, and was referred to the National Center for Child Health and Development. Fetal ultrasonography displayed an ascending aortic aneurysm of about 10 mm, but no problems occurred during the pregnancy. The patient was born by vacuum extraction at 39 weeks and 4 days of gestation. At birth, he was diagnosed as having congenital absence of skin from above the umbilicus to the xiphoid process, accompanied with diastasis recti, and echocardiography displayed an ascending aortic aneurysm, which was the same size as that during the fetal period. Other than the above findings, no abnormalities were observed. We regularly evaluated his aortic aneurysm by echocardiography, and treatment with a β-blocker was started on day 7 after birth. As enlargement of the aortic aneurysm was not observed, he was discharged on day 11. Congenital aortic aneurysm is a rare pathology, which has been reported to be associated with connective tissue disease, congenital heart disease, Takayasu's arteritis, and PHACE syndrome. However, the cause of the aortic aneurysm in this patient has not been identified to date. The patient is continuing treatment of only β-blocker therapy, and no enlargement of the aortic aneurysm has been observed up to the age of 11 months.
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Case Report
Title
Use of RB1 Genetic Test for Successful Diagnosis of Bilateral Retinoblastoma
Author
Naoko Nakatani1) Atsuro Saito1) Daisuke Katayama1) Takayuki Ichikawa1) Jun Noguchi1) Sayaka Nakamura1) Akihiro Tamura1) Aiko Kozaki1) Kenji Kishimoto1) Toshiaki Ishida1) Takeshi Mori1) Naoya Morisada2) Makiko Yoshida3) Koji Nomura4) Daiichiro Hasegawa1) and Yoshiyuki Kosaka1)
1)Department of Hematology and Oncology, Hyogo Prefectural Kobe Children's Hospital
2)Department of Clinical Genetics, Hyogo Prefectural Kobe Children's Hospital
3)Department of Pathology, Hyogo Prefectural Kobe Children's Hospital
4)Department of Ophthalmology, Hyogo Prefectural Kobe Children's Hospital
Abstract
The patient was a 2-month-old female infant who presented with left leukocoria. Ophthalmoscopic examination revealed the presence of two white bulging lesions that were characteristic of retinoblastoma (RBL) in the right eye. Further observation of the left eye was not possible due to total retinal detachment. It was also challenging to determine on imaging whether the lesion in the left eye was a large tumor or congenital abnormality. Assuming bilateral RBL, chemotherapy was initiated to aid in the diagnosis. While the treatment was successful in reducing the lesion in the right eye, it was still difficult to properly assess the lesion in the left eye. Since approximately 70% of hereditary RBL is bilateral, a genetic test for the RB1 gene was performed in order to determine treatment plans. A germline mutation was identified, indicating that the patient had bilateral RBL. As the vision was unlikely to be preserved, we performed enucleation of the left eye to ensure patient survival. Pathological examinations led to the definitive diagnosis of RBL. We demonstrated that genetic testing for RBL can also be used effectively in cases where clinical diagnosis is challenging.
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Case Report
Title
Skin Abscess Caused by Staphylococcus aureus and Prevotella bivia: A Case Report
Author
Kyoko Hinata Hiroki Kitaoka Hayato Chikai Hiroto Ida Keiko Watanabe Ayako Masui and Tadayuki Kumagai
Department of Pediatrics, Yaizu City Hospital
Abstract
Skin abscess is a sign of infection caused by disruption of the skin barrier secondary to injury or immunodeficiency. Prevotella spp. are indigenous anaerobes of the oral cavity, intestinal tract, and vagina that are not known to cause skin abscesses in infants. Herein, we report a case of subcutaneous abscess caused by mixed infection with Staphylococcus aureus and Prevotella bivia. A 9-month-old infant with atopic dermatitis presented with a two-day history of high-grade fever and right lower leg swelling. The patient was diagnosed with cellulitis, which then prompted treatment with intravenous cefazolin. However, fever and right lower leg swelling persisted. Ultrasonography performed four days after onset revealed subcutaneous abscess on the right lower leg. Incision and drainage of the abscess were then performed. The antibiotic treatment was switched to vancomycin and piperacillin/tazobactam. On the fifth day, fever and leg swelling resolved. However, abscess cultures revealed the presence of S. aureus and P. bivia. The antibiotics were then switched based on the antibiotic susceptibility findings and were continued until the 19th day. Although Prevotella spp. rarely cause subcutaneous infections, P. bivia caused skin abscess in our patient. Atypical pathogens may cause infections in infants owing to behaviors such as finger sucking. This study highlights that physicians should consider infections caused by atypical pathogens (e.g., Prevotella spp.) as differential diagnoses in infants with subcutaneous abscesses. Ultrasonography may be useful for early diagnosis of skin abscesses.
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Case Report
Title
An Adult Patient with Intellectual Disability Diagnosed as Adult-onset Type II Citrullinemia
Author
Atsushi Yanai1) Mitsuji Moriya1) Takuya Miyamori1) Takanobu Ito1) Toshinari Takahashi1) Sou Niitsuma1) Hirohito Shima1) Megumi Nitta1) Atsuo Kikuchi2) Taro Kitamura1) Ikuma Fujiwara1) Toshihiro Ohura1) and Shigeo Kure2)
1)Department of Pediatrics, Sendai City Hospital
2)Department of Pediatrics, Tohoku University Hospital
Abstract
Adult-onset type II citrullinemia (CTLN2) is a congenital metabolic disorder that causes hypercitrullinemia and hyperammonemia due to abnormalities in the aspartate/glutamate membrane transporter protein (citrin) present in the mitochondrial membrane. We diagnosed a patient with intellectual disability as CTLN2, as she showed consciousness disorder and had peculiar eating habits. She often preferred high-protein and high-fat foods such as peanuts, meat, and dairy products, and she disliked sugar since her infancy. It is presumed that the change in eating habits centered on carbohydrates caused disturbance of consciousness after she started living in a group home half a year before admission. Analysis of the melting temperature curve by real-time PCR method revealed that she had high-frequent compound heterozygous mutations in the causative gene SLC25A13, that confirmed the diagnosis of CTLN2. Symptoms were alleviated by dieting mainly on low-carbohydrate diets and effective use of MCT oil. Currently, the symptoms have not recurred due to dietary guidance given to members of the family and the group home. CTLN2 is an urgent and fatal disease that is difficult to properly diagnose and treat. In particular, diagnosis of CTLN2 is difficult in patients with intellectual disability, therefore we must rely heavily on medical interviews on eating habits. It is important to consider CTLN2 to differentiate in cases of unexplained consciousness disturbance.
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Case Report
Title
Improvement in Migraine after Treatment of Sleep Disorder Secondary to Periodic Limb Movement Disorder: A Report of Two Cases
Author
Asami Sekine Toshiki Inumaru Yuya Saito Yukiko Osawa and Toshimasa Obonai
Department of Pediatrics, Tama-Hokubu Medical Center
Abstract
Headaches are a common complaint encountered in pediatric practice. However, accurate diagnosis of the cause is challenging in busy outpatient settings in view of the wide range of conditions that need to be considered in the differential diagnosis. We describe two patients in whom treatment of sleep disorder (periodic limb movement disorder [PLMD]) led to significant improvement in headache.
A 14-year-old female adolescent (Case 1) and a 10-year-old boy (Case 2) were diagnosed with PLMD based on polysomnography evaluation. Blood test results showed a decrease in the serum ferritin level, which was considered to contribute to PLMD. Initiation of supplementary iron therapy resulted in improvement in headache and PLMD. Headache recurred in the patient described in Case 2, following a decrease in blood ferritin levels; however, this symptom disappeared with improved ferritin levels.
Currently, the association between sleep disorders and headaches is not investigated in Japan. Therefore, accurate diagnosis may be delayed, even for years in some cases. However, accurate diagnosis and prompt treatment aid with significant improvement in headache and other autonomic symptoms. A comprehensive patient interview that includes careful history taking regarding sleep disorders is important for accurate diagnosis of this condition. Owing to widespread lifestyle changes, sleep disorders are increasingly being observed in younger patients in recent years. Therefore, sleep disorders should be considered in the differential diagnosis of headaches.
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