Yu Kobayashi1, Jun Tohyama2, Yukitoshi Takahashi3, Tomohide Goto4, Kazuhiro Haginoya5, Takeshi Inoue6, Masaya Kubota7, Hiroshi Fujita8, Ryoko Honda9, Masahiro Ito10, Kanako Kishimoto11, Kazuyuki Nakamura12, Yasunari Sakai13, Jun-Ichi Takanashi14, Manabu Tanaka15, Koichi Tanda16, Koji Tominaga17, Seiichiro Yoshioka18, Mitsuhiro Kato19, Mitsuko Nakashima20, Hirotomo Saitsu20, Naomichi Matsumoto21. 1. Department of Child Neurology, NHO Nishiniigata Chuo Hospital, Niigata, Japan. Electronic address: kobayashi.yu.gw@mail.hosp.go.jp. 2. Department of Child Neurology, NHO Nishiniigata Chuo Hospital, Niigata, Japan. 3. National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan. 4. Division of Neurology, Kanagawa Children's Medical Center, Yokohama, Japan. 5. Department of Pediatric Neurology, Miyagi Children's Hospital, Sendai, Japan. 6. Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan. 7. Division of Neurology, National Center for Child Health and Development, Tokyo, Japan. 8. Department of Pediatrics, NHO Aomori Hospital, Aomori, Japan. 9. Department of Pediatrics, National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan. 10. Department of Pediatrics, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan. 11. Department of Pediatrics, Osaka Hospital, Japan Community Healthcare Organization (JCHO), Osaka, Japan. 12. Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan. 13. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 14. Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan. 15. Division of General Pediatrics, Saitama Children's Medical Center, Saitama, Japan. 16. Department of Pediatrics, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan. 17. Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan. 18. Ritto Yoshioka Children's Clinic, Ritto, Japan. 19. Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan. 20. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan. 21. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Abstract
OBJECTIVE: Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments. METHODS: We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information. RESULTS: We identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI. CONCLUSION: Our patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.
OBJECTIVE:Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments. METHODS: We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information. RESULTS: We identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI. CONCLUSION: Our patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.
Authors: William Hong; Isabel Haviland; Elia Pestana-Knight; Judith L Weisenberg; Scott Demarest; Eric D Marsh; Heather E Olson Journal: CNS Drugs Date: 2022-05-28 Impact factor: 6.497
Authors: Jacinta Saldaris; Helen Leonard; Peter Jacoby; Eric D Marsh; Tim A Benke; Scott Demarest; Jenny Downs Journal: J Child Neurol Date: 2022-04-14 Impact factor: 2.363