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1. Clinical characteristics of SARS-CoV-2-associated encephalopathy in children: Nationwide epidemiological study

Author

Akamine, Satoshi, Chong, Pin Fee, Ema, Tatsuya, Enomoto, Sayaka, Fukatsu, Ryohei, Hanaoka, Yoshiyuki, Igarashi, Ayuko, Ikeda, Tae, Ishida, Kouhei, Ishikawa, Nobutsune, Itamura, Shinji, Iwayama, Hideyuki, Kawata, Nanako, Kawano, Go, Kikuchi, Kenjiro, Kobayashi, Osamu, Kondo, Hidehito, Korematsu, Seigo, Matsuoka, Tsuyoshi, Minamisawa, Yuki, Mitani, Osamu, Mizuma, Kanako, Mori, Tatsuo, Morichi, Shinichiro, Moriyama, Yoko, Motobayashi, Mitsuo, Motoi, Hirotaka, Muramatsu, Kazuhiro, Nakamura, Kazuyuki, Nakazawa, Tomoyuki, Negishi, Yutaka, Nishizawa, Yuka, Okada, Hiroshi, Okanari, Kazuo, Oki, Keisuke, Okumura, Yoshinori, Omata, Taku, Saeki, Saki, Sano, Fumikazu, Sano, Kentaro, Sato, Tatsuharu, Shiihara, Takashi, Shimoda, Konomi, Suzuki, Motomasa, Tanaka, Ryuta, Tokorodani, Chiho, Uematsu, Mitsugu, Yamada, Hiroyuki, Yamamoto, Naohiro, Yamamoto, Tatsuya, Yokoyama, Haruna, Kasai, Mariko, Sakuma, Hiroshi, Abe, Yuichi, Kuki, Ichiro, Maegaki, Yoshihiro, Murayama, Kei, Murofushi, Yuka, Nagase, Hiroaki, Nishiyama, Masahiro, Okumura, Akihisa, Sakai, Yasunari, Tada, Hiroko, Mizuguchi, Masashi, and Takanashi, Jun-ichi

Published
2024
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7. Painless thyroiditis in a dupilumab-treated patient

Author

Daramjav Narantsatsral, Takagi Junko, Iwayama Hideyuki, Inukai Daisuke, Takama Hiroyuki, Nomura Yuka, Hirase Syo, Morita Hiroyuki, Otake Kazuo, Ogawa Tetsuya, and Takami Akiyoshi

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Dupilumab an inhibitor of the interleukin (IL)-4R-alpha subunit is used for the treatment of allergic diseases. The patient was a 49-year-old man who received dupilumab for the treatment of severe atopic dermatitis. He presented hyperthyroidism with elevated thyroglobulin and anti-thyroid antibody negativity at 4 months after the initiation of therapy. On scintigraphy, the thyroid radioiodine uptake was low. Ultrasonography showed a diffuse hypoechoic area in the thyroid gland. A pathological study revealed lymphocytic infiltration. The administration of dupilumab was continued because of his atopic dermatitis that showed an excellent response. The patient`s hyperthyroidism changed to hypothyroidism 3 weeks later. Six months later his thyroid function normalized without any treatment. We herein describe the case of a patient with atopic dermatitis who developed painless thyroiditis under treatment with dupilumab. To the best of our knowledge, this is the first report of this event in the literature.

Published
2020
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11. Clinical characteristics of SARS-CoV-2-associated encephalopathy in children: Nationwide epidemiological study

Author

Kasai, Mariko, primary, Sakuma, Hiroshi, additional, Abe, Yuichi, additional, Kuki, Ichiro, additional, Maegaki, Yoshihiro, additional, Murayama, Kei, additional, Murofushi, Yuka, additional, Nagase, Hiroaki, additional, Nishiyama, Masahiro, additional, Okumura, Akihisa, additional, Sakai, Yasunari, additional, Tada, Hiroko, additional, Mizuguchi, Masashi, additional, Takanashi, Jun-ichi, additional, Akamine, Satoshi, additional, Chong, Pin Fee, additional, Ema, Tatsuya, additional, Enomoto, Sayaka, additional, Fukatsu, Ryohei, additional, Hanaoka, Yoshiyuki, additional, Igarashi, Ayuko, additional, Ikeda, Tae, additional, Ishida, Kouhei, additional, Ishikawa, Nobutsune, additional, Itamura, Shinji, additional, Iwayama, Hideyuki, additional, Kawata, Nanako, additional, Kawano, Go, additional, Kikuchi, Kenjiro, additional, Kobayashi, Osamu, additional, Kondo, Hidehito, additional, Korematsu, Seigo, additional, Matsuoka, Tsuyoshi, additional, Minamisawa, Yuki, additional, Mitani, Osamu, additional, Mizuma, Kanako, additional, Mori, Tatsuo, additional, Morichi, Shinichiro, additional, Moriyama, Yoko, additional, Motobayashi, Mitsuo, additional, Motoi, Hirotaka, additional, Muramatsu, Kazuhiro, additional, Nakamura, Kazuyuki, additional, Nakazawa, Tomoyuki, additional, Negishi, Yutaka, additional, Nishizawa, Yuka, additional, Okada, Hiroshi, additional, Okanari, Kazuo, additional, Oki, Keisuke, additional, Okumura, Yoshinori, additional, Omata, Taku, additional, Saeki, Saki, additional, Sano, Fumikazu, additional, Sano, Kentaro, additional, Sato, Tatsuharu, additional, Shiihara, Takashi, additional, Shimoda, Konomi, additional, Suzuki, Motomasa, additional, Tanaka, Ryuta, additional, Tokorodani, Chiho, additional, Uematsu, Mitsugu, additional, Yamada, Hiroyuki, additional, Yamamoto, Naohiro, additional, Yamamoto, Tatsuya, additional, and Yokoyama, Haruna, additional

Published
2024
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15. Long-term efficacy of nusinersen and its evaluation in adolescent and adult patients with spinal muscular atrophy types 1 and 2

Author

Iwayama, Hideyuki, primary, Kawahara, Kohei, additional, Takagi, Mizuki, additional, Numoto, Shingo, additional, Azuma, Yoshiteru, additional, Kurahashi, Hirokazu, additional, Yasue, Yumiko, additional, Kawajiri, Hiroyuki, additional, Yanase, Atsushi, additional, Ito, Teruyoshi, additional, Kimura, Shinya, additional, Kumagai, Toshiyuki, additional, and Okumura, Akihisa, additional

Published
2023
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19. Early immunological responses to the mRNA SARS-CoV-2 vaccine in patients with neuromuscular disorders

Author

Iwayama, Hideyuki, primary, Ishihara, Naoko, additional, Kawahara, Kohei, additional, Madokoro, Yuta, additional, Togawa, Yasuko, additional, Muramatsu, Kanji, additional, Murakami, Ayuka, additional, Kuru, Satoshi, additional, Kumagai, Toshiyuki, additional, Ohashi, Wataru, additional, Nanya, Kengo, additional, Hasegawa, Shinji, additional, Katsuno, Masahisa, additional, and Okumura, Akihisa, additional

Published
2022
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23. Serum free carnitine levels in children with Kawasaki disease

Author

Muto, Taichiro, primary, Nakamura, Nami, additional, Masuda, Yu, additional, Numoto, Shingo, additional, Kodama, Shunsuke, additional, Miyamoto, Ryosuke, additional, Hayakawa, Tomohito, additional, Mori, Hiromitsu, additional, Iwayama, Hideyuki, additional, Kurahashi, Hirokazu, additional, Agata, Hiroatsu, additional, and Okumura, Akihisa, additional

Published
2022
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26. Measurement of Reverse Triiodothyronine Level and the Triiodothyronine to Reverse Triiodothyronine Ratio in Dried Blood Spot Samples at Birth May Facilitate Early Detection of Monocarboxylate Transporter 8 Deficiency

Author

Iwayama, Hideyuki, primary, Kakita, Hiroki, additional, Iwasa, Masumi, additional, Adachi, Shinsuke, additional, Takano, Kyoko, additional, Kikuchi, Masahiro, additional, Fujisawa, Yasuko, additional, Osaka, Hitoshi, additional, Yamada, Yasumasa, additional, Okumura, Akihisa, additional, Hirani, Khemraj, additional, Weiss, Roy E., additional, and Refetoff, Samuel, additional

Published
2021
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29. Usefulness of Q-probe PCR in Children with Mycoplasma pneumniae infection

Author

Muto, Taichiro, primary, Nakamura, Nami, additional, Masuda, Yu, additional, Numoto, Shingo, additional, Kodama, Shunsuke, additional, Miyamoto, Ryosuke, additional, Hayakawa, Tomohito, additional, Mori, Hiromitsu, additional, Iwayama, Hideyuki, additional, Kurahashi, Hirokazu, additional, Agata, Hiroatsu, additional, and Okumura, Akihisa, additional

Published
2021
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30. Diagnostic accuracy of insulin-like growth factor-1 for screening growth hormone deficiency: a prospective, single-center, diagnostic accuracy study

Author

Iwayama, Hideyuki, primary, Kitagawa, Sachiko, additional, Sada, Jyun, additional, Miyamoto, Ryosuke, additional, Hayakawa, Tomohito, additional, Kuroyanagi, Yoshiyuki, additional, Muto, Taichiro, additional, Kurahashi, Hirokazu, additional, Ohashi, Wataru, additional, Takagi, Junko, additional, and Okumura, Akihisa, additional

Published
2021
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31. Reverse T3 Level and T3 to Reverse T3 Ratio in Dried Blood Spot Samples at Birth May Facilitate Early Diagnosis of MCT8 Deficiency

Author

Iwayama, Hideyuki, primary, Kakita, Hiroki, additional, Iwasa, Masumi, additional, Adachi, Shinsuke, additional, Takano, Kyoko, additional, Kikuchi, Masahiro, additional, Fujisawa, Yasuko, additional, Osaka, Hitoshi, additional, Yamada, Yasumasa, additional, Okumura, Akihisa, additional, and Refetoff, Samuel, additional

Published
2021
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32. Painless thyroiditis in a dupilumab-treated patient

Author

Iwayama Hideyuki, Ogawa Tetsuya, Nomura Yuka, Takami Akiyoshi, Daramjav Narantsatsral, Takama Hiroyuki, Morita Hiroyuki, Takagi Junko, Inukai Daisuke, Hirase Syo, and Otake Kazuo

Subjects
Male, Thyroiditis, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Biopsy, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Hyperthyroidism, 0302 clinical medicine, Japan, Tachycardia, Eosinophilia, FT3, FT4, Fatigue, Thyroid, Goitre, TSH, Atopic dermatitis, Dupilumab, Anti-thyroid autoantibodies, medicine.anatomical_structure, Thyroid antibodies, 030220 oncology & carcinogenesis, Hypertension, Thyroid function, medicine.symptom, Adult, medicine.medical_specialty, endocrine system, Thyroxine (T4), 030209 endocrinology & metabolism, Dermatology, Thyroglobulin, C-reactive protein, 03 medical and health sciences, Neck pain/discomfort, Hypothyroidism, Internal Medicine, medicine, Unusual Effects of Medical Treatment, Thyroid scintigraphy, June, lcsh:RC648-665, business.industry, Asian - Japanese, medicine.disease, body regions, Oedema, Thyroid ultrasonography, Immunoglobulin G4, business
Abstract

Summary Dupilumab an inhibitor of the interleukin (IL)-4R-alpha subunit is used for the treatment of allergic diseases. The patient was a 49-year-old man who received dupilumab for the treatment of severe atopic dermatitis. He presented hyperthyroidism with elevated thyroglobulin and anti-thyroid antibody negativity at 4 months after the initiation of therapy. On scintigraphy, the thyroid radioiodine uptake was low. Ultrasonography showed a diffuse hypoechoic area in the thyroid gland. A pathological study revealed lymphocytic infiltration. The administration of dupilumab was continued because of his atopic dermatitis that showed an excellent response. The patient`s hyperthyroidism changed to hypothyroidism 3 weeks later. Six months later his thyroid function normalized without any treatment. We herein describe the case of a patient with atopic dermatitis who developed painless thyroiditis under treatment with dupilumab. To the best of our knowledge, this is the first report of this event in the literature. Learning points: Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has been shown to be effective in the treatment atopic dermatitis and asthma with eosinophilia. Painless thyroiditis is characterized by transient hyperthyroidism and hypothyroidism and recovery without anti-thyroid treatment. This is the first report of painless thyroiditis as an adverse effect of dupilumab, although conjunctivitis and nasopharyngitis are the main adverse effects of dupilumab.

Published
2020

34. Diagnostic accuracy of IGF-1 for screening growth hormone deficiency: a prospective, single-center, diagnostic accuracy study

Author

Iwayama, Hideyuki, primary, Kitagawa, Sachiko, additional, Sada, Jyun, additional, Miyamoto, Ryosuke, additional, Hayakawa, Tomohito, additional, Kuroyanagi, Yoshiyuki, additional, Muto, Taichiro, additional, Kurahashi, Hirokazu, additional, Ohashi, Wataru, additional, Takagi, Junko, additional, and Okumura, Akihisa, additional

Published
2021
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40. Elevated Serum Free Carnitine Levels in Children with Kawasaki Disease and Their Relation to Unresponsiveness to Intravenous Immunoglobulin: retrospective study

Author

Muto, Taichiro, primary, Nakamura, Nami, additional, Masuda, Yu, additional, Numoto, Shingo, additional, Kodama, Shunsuke, additional, Miyamoto, Ryosuke, additional, Miyata, Kenji, additional, Hayakawa, Tomohito, additional, Mori, Hiromitsu, additional, Kuroyanagi, Yoshiyuki, additional, Akaihata, Mitsuko, additional, Iwayama, Hideyuki, additional, Kurahashi, Hirokazu, additional, Shimomura, Yasuhito, additional, Nagai, Takuhito, additional, Hori, Toshinori, additional, Agata, Hiroatsu, additional, and Okumura, Akihisa, additional

Published
2020
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42. Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism

Author

Cangul, Hakan, Liao, Xiao-Hui, Schoenmakers, Erik, Kero, Jukka, Barone, Sharon, Srichomkwun, Panudda, Iwayama, Hideyuki, Serra, Eva G, Saglam, Halil, Eren, Erdal, Tarim, Omer, Nicholas, Adeline K, Zvetkova, Ilona, Anderson, Carl A, Frankl, Fiona E Karet, Boelaert, Kristien, Ojaniemi, Marja, Jääskeläinen, Jarmo, Patyra, Konrad, Löf, Christoffer, Williams, E Dillwyn, UK10K Consortium, Soleimani, Manoocher, Barrett, Timothy, Maher, Eamonn R, Chatterjee, V Krishna, Refetoff, Samuel, Schoenmakers, Nadia, Cangul, Hakan Istanbul Medipol Univ, Dept Med Genet, Int Sch Med, Istanbul, Turkey, Liao, Xiao-Hui, Srichomkwun, Panudda, Iwayama, Hideyuki, Refetoff, Samuel Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA, Schoenmakers, Erik, Nicholas, Adeline K., Zvetkova, Ilona, Chatterjee, V. Krishna, Schoenmakers, Nadia Univ Cambridge, Metabol Res Labs, Wellcome Trust Med Res Council, Inst Metab Sci,Addenbrookes Hosp, Level 4,Box 289,Hills Rd, Cambridge CB2 0QQ, England, Kero, Jukka, Patyra, Konrad, Lof, Christoffer Univ Turku, Res Ctr Integrat Physiol & Pharmacol, Inst Biomed, Turku, Finland, Kero, Jukka Turku Univ Hosp, Dept Paediat, Turku, Finland, Barone, Sharon, Soleimani, Manoocher Univ Cincinnati, Cincinnati, OH USA, Soleimani, Manoocher Vet Adm Hosp, Cincinnati, OH USA, Serra, Eva G., Anderson, Carl A. Wellcome Trust Sanger Inst, Dept Human Genet, Cambridge, England, Saglam, Halil, Eren, Erdal, Tarim, Omer Uludag Univ, Sch Med, Dept Paediat Endocrinol, Bursa, Turkey, Frankl, Fiona E. Karet Univ Cambridge, Dept Med Genet, Cambridge, England, Frankl, Fiona E. Karet Univ Cambridge, Div Renal Med, Cambridge, England, Boelaert, Kristien Univ Birmingham, Inst Metab & Syst Res, Birmingham, W Midlands, England, Boelaert, Kristien Birmingham Hlth Partners, Ctr Endocrinol Diabet & Metab, Birmingham, W Midlands, England, Ojaniemi, Marja Univ Oulu, PEDEGO Res Ctr, Oulu, Finland, Ojaniemi, Marja Univ Oulu, MRC Oulu, Oulu, Finland, Ojaniemi, Marja Oulu Univ Hosp, Dept Children & Adolescents, Oulu, Finland, Jaaskelainen, Jarmo Univ Eastern Finland, Dept Pediat, Kuopio, Finland, Jaaskelainen, Jarmo Kuopio Univ Hosp, Kuopio, Finland, Williams, E. Dillwyn Univ Cambridge, Thyroid Carcinogenesis Grp, Strangeways Res Lab, Cambridge, England, Consortium, Ukk Univ Birmingham, Consortium Detailed Supplemental Acknowledgments, Birmingham, W Midlands, England, Barrett, Timothy Univ Birmingham, Inst Canc & Genom Sci, Coll Med & Dent Sci, Birmingham, W Midlands, England, Barrett, Timothy Birmingham Childrens Hosp, Dept Endocrinol, Birmingham, W Midlands, England, Maher, Eamonn R. Univ Cambridge, Dept Med Genet, Cambridge, England, Maher, Eamonn R. NIHR Cambridge Biomed Res Ctr, Cambridge, England, Refetoff, Samuel Univ Chicago, Dept Pediat, Chicago, IL 60637 USA, Refetoff, Samuel Univ Chicago, Comm Genet, Chicago, IL USA, Barrett, Timothy -- 0000-0002-6873-0750, MAHER, EAMONN R -- 0000-0002-6226-6918, Schoenmakers, Nadia -- 0000-0002-0847-2884, Eren, Erdal -- 0000-0002-1684-1053, Kelly, Kirsten -- 0000-0003-4234-543X, kero, jukka -- 0000-0001-8767-7222, Anderson, Carl -- 0000-0003-1719-7009, Schoenmakers, Erik [0000-0003-0674-8282], Karet, Fiona [0000-0002-2457-2869], Maher, Eamonn [0000-0002-6226-6918], Chatterjee, Krishna [0000-0002-2654-8854], Schoenmakers, Nadia [0000-0002-0847-2884], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, endocrine system, endocrine system diseases, DNA Mutational Analysis, Thyroid Gland, Antiporters, Vestibular Aqueduct, Monogenic diseases, Mice, Endocrinology, Exome Sequencing, Genetics, Congenital Hypothyroidism, otorhinolaryngologic diseases, Animals, Humans, Molecular genetics, Hearing Loss, Child, Mice, Knockout, Goiter, Homozygote, Middle Aged, Thyroid disease, Pedigree, HEK293 Cells, Codon, Nonsense, Sulfate Transporters, FOS: Biological sciences, Child, Preschool, Female, Aqueduct EVA
Abstract

WOS: 000447709700003 PubMed ID: 30333321 Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear. Wellcome Trust; NIDDK NIH HHS [R37 DK015070, R01 DK015070]; Medical Research Council [MC_UU_12012/5, G0600717, G0502115]

Published
2018

45. White Blood Cell and Neutrophil Counts and Response to Intravenous Immunoglobulin in Kawasaki Disease

Author

Muto, Taichiro, primary, Masuda, Yu, additional, Numoto, Shingo, additional, Kodama, Shunsuke, additional, Yamakawa, Kiyoshi, additional, Takasu, Michihiko, additional, Hayakawa, Tomohito, additional, Miyata, Kenji, additional, Miyamoto, Ryosuke, additional, Akaihata, Mitsuko, additional, Iwayama, Hideyuki, additional, Kitagawa, Yoshiro, additional, Kurahashi, Hirokazu, additional, Shimomura, Yasuto, additional, Hori, Toshinori, additional, Okuda, Masumi, additional, Agata, Hiroatsu, additional, and Okumura, Akihisa, additional

Published
2019
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46. A nationwide questionnaire survey on accidental magnet ingestion in children in Japan.

Author

Miyamoto, Ryosuke, Okuda, Masumi, Kikuchi, Shogo, Iwayama, Hideyuki, Hataya, Hiroshi, and Okumura, Akihisa

Subjects
INGESTION, GASTROINTESTINAL system injuries, MAGNETS, SURVEYS, PEDIATRIC surgery
Abstract

Aim: The aim is to investigate the actual situation of accidental ingestion of magnets in children in Japan and the clinical features of the resulting gastrointestinal damage. Methods: We developed a questionnaire and sent it to 496 board‐certified training hospitals nationwide. Information was collected on the number of children with accidental magnet intake from 2015 to 2017, witnesses of magnet intake, number and type of magnets, presence or absence of gastrointestinal injury, treatment, etc Results: The number of cases of accidental ingestion of magnets within the study period was 104, with a median age of 2 years. About half of the incidents were unwitnessed. There were 33 cases of accidental ingestion of multiple magnets. Among them, oesophagogastroduodenoscopy was performed in 4 children and surgery in 10, and significantly invasive treatment was required in comparison with single‐magnet ingestion. Gastrointestinal injury was observed in 11 cases, 10 of which were caused by multiple‐magnet ingestion. All 10 of these patients underwent surgical treatment. There was no mortality. Conclusion: The incidence of accidental magnet ingestion in Japan is estimated to be 50‐70 per year. Unwitnessed cases are not uncommon. Multiple magnet ingestion often causes gastrointestinal injury. Many cases of gastrointestinal injury are caused by ingestion of magnetic toys. [ABSTRACT FROM AUTHOR]

Published
2021
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47. Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism

Author

Cangul, Hakan, primary, Liao, Xiao-Hui, additional, Schoenmakers, Erik, additional, Kero, Jukka, additional, Barone, Sharon, additional, Srichomkwun, Panudda, additional, Iwayama, Hideyuki, additional, Serra, Eva G., additional, Saglam, Halil, additional, Eren, Erdal, additional, Tarim, Omer, additional, Nicholas, Adeline K., additional, Zvetkova, Ilona, additional, Anderson, Carl A., additional, Frankl, Fiona E. Karet, additional, Boelaert, Kristien, additional, Ojaniemi, Marja, additional, Jääskeläinen, Jarmo, additional, Patyra, Konrad, additional, Löf, Christoffer, additional, Williams, E. Dillwyn, additional, Soleimani, Manoocher, additional, Barrett, Timothy, additional, Maher, Eamonn R., additional, Chatterjee, V. Krishna, additional, Refetoff, Samuel, additional, and Schoenmakers, Nadia, additional

Published
2018
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48. Adeno associated virus 9-based gene therapy delivers a functional MCT8 which improves thyroid hormone availability to brain of Mct8 deficient mice

Author

Iwayama, Hideyuki, Liao, Xiao-Hui, Braun, Lyndsey, Bárez-López, Soledad, Kaspar, Brian, Weiss, Roy E., Dumitrescu, Alexandra M., Guadaño-Ferraz, Ana, and Refetoff, Samuel

Abstract

Resumen del trabajo presentado al MCT8 Symposium, celebrado en Los Angeles (California-USA) del 4 al 6 de enero de 2017., [Background]: MCT8 gene mutations produce thyroid hormone (TH) deficiency in the brain, causing severe neuropsychomotor abnormalities not correctable by treatment with TH. In this proof of concept study, we examined whether transfer of human MCT8 (hMCT8) cDNA using adeno-associated virus 9 (AAV9) could correct the brain defects of Mct8 knockout mice (Mct8KO). [Methods]: AAV9 vectors delivering long and/or short hMCT8 protein isoforms or an empty vector were injected intravenously (IV) and/or intracerebroventricularly (ICV) into postnatal day 1 Mct8KO and wild type (Wt) mice. T3 was given daily for 4 days before post-natal day 28, at which time brains were collected after perfusion to assess increase in T3 content and effect on the T3-responsive transcription factor, Hairless. [Results]: Increased pup mortality was observed after IV injection of the AAV9-long hMCT8 isoform, but not after injection of AAV9-short hMCT8 isoform. Compared to IV, ICV delivery produced more hMCT8 mRNA and protein relative to the viral dose, which was present in various brain regions and localized to the cell membranes. Despite production of abundant hMCT8 mRNA and protein with ICV delivery, only IV delivered AAV9-hMCT8 targeted the choroid plexus and significantly increased brain T3 content and expression of Hairless. [Conclusions]: These results indicate that MCT8 delivery to brain barriers by IV but not ICV injection is crucial for its proper function. MCT8 has no constitutive activity but acts through an increase in T3 entering brain tissue. Increasing MCT8 expression on brain cells membranes, including neurons, is insufficient to produce an effect without increase in brain T3 content. The correct hMCT8 isoform along with an optimized delivery method are critical for an effective gene therapy to provide functional MCT8 in the brain of patients with MCT8 mutations.

Published
2017

49. Adeno Associated Virus 9–Based Gene Therapy Delivers a Functional Monocarboxylate Transporter 8, Improving Thyroid Hormone Availability to the Brain of Mct8-Deficient Mice

Author

Iwayama, Hideyuki, Liao, Xiao-Hui, Braun, Lyndsey, Bárez-López, Soledad, Kaspar, Brian, Weiss, Roy E., Dumitrescu, Alexandra M., Guadaño-Ferraz, Ana, Refetoff, Samuel, Iwayama, Hideyuki, Liao, Xiao-Hui, Braun, Lyndsey, Bárez-López, Soledad, Kaspar, Brian, Weiss, Roy E., Dumitrescu, Alexandra M., Guadaño-Ferraz, Ana, and Refetoff, Samuel

Published
2016

50. Adeno Associated Virus 9–Based Gene Therapy Delivers a Functional Monocarboxylate Transporter 8, Improving Thyroid Hormone Availability to the Brain of Mct8-Deficient Mice

Author

Iwayama, Hideyuki, primary, Liao, Xiao-Hui, additional, Braun, Lyndsey, additional, Bárez-López, Soledad, additional, Kaspar, Brian, additional, Weiss, Roy E., additional, Dumitrescu, Alexandra M., additional, Guadaño-Ferraz, Ana, additional, and Refetoff, Samuel, additional

Published
2016
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