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Nationwide survey of Alexander disease in Japan and proposed new guidelines for diagnosis

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Abstract

Alexander disease (AxD) is a rare neurodegenerative disorder characterized by white matter degeneration and formation of cytoplasmic inclusions. Glial fibrillary acidic protein (GFAP) mutations have been reported in various forms of AxD since 2001. However, a definitive diagnosis remains difficult because of uncertain prevalence, and different clinical features seen in infantile AxD and adult AxD may lead to confusion and misdiagnosis. Here we report an epidemiological study conducted in Japan. Two nationwide questionnaire-based surveys were conducted using tentative diagnostic criteria. We gathered information regarding prevalence, neurological findings, magnetic resonance imaging (MRI) findings, electrophysiological findings, genetic information, and the results of therapeutic interventions and home care. Prevalence of various forms of AxD was determined as 27.3% (infantile), 24.2% (juvenile), and 48.5% (adult). Prevalence of AxD in Japan was estimated to be approximately 1 case per 2.7 million individuals. The main characteristics of infantile and juvenile AxD include delayed psychomotor development or mental retardation, convulsions, macrocephaly, and predominant cerebral white matter abnormalities in the frontal lobe on brain MRI. The main characteristics of adult AxD include bulbar signs, muscle weakness with hyperreflexia, and signal abnormalities and/or atrophy of medulla oblongata and cervical spinal cord on MRI. To ensure correct diagnosis of AxD, the physician should understand the importance of the process of GFAP genetic testing, which provides definitive diagnosis. Therefore, we propose new clinical guidelines for diagnosing AxD based on simplified classifications: cerebral AxD (type 1), bulbospinal AxD (type 2), and intermediate form (type 3).

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Abbreviations

AxD:

Alexander disease

GFAP:

Glial fibrillary acidic protein

EEG:

Electroencephalogram

ABR:

Auditory brainstem response

TRH:

Thyroid-releasing hormone

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Acknowledgments

This work was supported by Alexander disease research grants received from the Intractable Disease Research Grants, from the Ministry of Health, Labor, and Welfare of the Government of Japan, and a Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant number 22790825).

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Correspondence to Tomokatsu Yoshida.

Appendix

Appendix

The Alexander Disease Study Group in Japan: Manami Akasaka, MD (Iwate Medical University); Nobutaka Sakae, MD (Kyusyu University); Hitoshi Yamamoto, MD (St. Marianna University of Medicine); Toshiro Okazaki, MD (Oita University); Yasuhiro Takeshima, MD (Kobe University); Keiji Senda, MD (National Hospital Organization Iwate Hospital); Nobuyuki Murakami, MD (Dokkyo Medical University Koshigaya Hospital); Takayoshi Shimohata, MD (Niigata University); Ryutarou Kohira, MD (Nihon University Itabashi Hospital); Tomoaki Yuhi, MD (University of Occupational and Environmental Health); Akira Sudo, MD (Sapporo City General Hospital); Ikuko Aiba, MD (National Hospital Organization Higashi Nagoya Hospital); Keiko Ishigaki, MD (Tokyo Woman’s Medical University, School of Medicine); Hisato Nakamura, MD (Iwao Hospital); Hiroko Tsukamoto, MD (Sumitomo Hospital); Hideki Houzen, MD (Obihiro General Hospital); Koki Nikaido, MD (Sapporo Medical University); Yoshihiro Suzuki, MD (Nihonkai General Hospital); Hitoshi Kawato, MD (Asahi Hospital); Yasushi Kita, MD (Hyogo Brain and Heart Center); Hitoshi Osaka, MD (Kanagawa Children’s Medical Center); Toru Yamamoto, MD (Osaka Saiseikai Nakatsu Hospital); Atsushi Imamura, MD (Gifu Prefectural General Medical Center); Hideaki Kishikawa, MD (Kahan Hospital); Muneaki Matsuo, MD (Saga University); Rei Masuda, MD (Kitasato University School of Medicine); Mitsugu Uematsu, MD (Tohoku University); Hasegawa Kazuko, MD (National Hospital Organization Sagamihara); Tadataka Hoshika, MD (Tottori Prefectural General Medical Center); Hiroaki Shii, MD (Kokura Memorial Hospital); Takashi Shiihar, MD (Gunma Children’s Medical Center); Michio Kobayashi, MD (National Hospital Organization Akita Hospital); Kazuhiro Takamatsu, MD (Oota Memorial Hospital); Takahiro Yokoyama, MD (Yotsuya Medical Mall); Yasuyuki Okuma, MD (Juntendo University Shizuoka Hospital); Kazuhide Ochi, MD (Hiroshima University); Kazuma Kaneko, MD (Shinsyu University).

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Yoshida, T., Sasaki, M., Yoshida, M. et al. Nationwide survey of Alexander disease in Japan and proposed new guidelines for diagnosis. J Neurol 258, 1998–2008 (2011). https://doi.org/10.1007/s00415-011-6056-3

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  • DOI: https://doi.org/10.1007/s00415-011-6056-3

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