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Hypoalbuminemia in early onset dentatorubral−pallidoluysian atrophy due to leakage of albumin in multiple organs

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Abstract

We delineate a complication of hypoalbuminemia in dentatorubral−pallidoluysian atrophy (DRPLA), which we have found to be common in this disorder. In addition, we explored the pathogenesis of this phenomenon through clinical and histological examinations. Clinical course and laboratory findings of nine patients with childhood-onset DRPLA (aged 6–49 years; CAG repeat length 62–93) were retrospectively reviewed. Autopsied specimens from three patients were examined by histopathological and immunohistochemical analyses. Eight DRPLA patients showed hypoalbuminemia <3.5 g/dl in the initial stages of the disease (age, 2–32 years), which correlated with the CAG repeat length in each patient. Disease worsened in six patients, often triggered by febrile infections and accompanied by increased urinary protein excretion. One patient showed increased fecal α1-antitripsin while another showed accumulation of radioactive albumin in the urinary and gastrointestinal tracts after intravenous infusion. Immunohistochemistry revealed albumin-containing monocytes and astrocytes in the perivascular areas of the cerebral white matter. Fluid collection in the glomerular capillaries was noted. Immunolabeling using antibodies against the expanded polyglutamine (polyQ) polypeptide was positive in cerebral cortical neurons, hepatocytes, renal collecting ducts, and glomerular podocytes, which act as filtration barrier against serum proteins. Serum albumin appears to easily leak from blood vessels in certain visceral organs in DRPLA during later stages of the illness, particularly in the kidneys of patients with largely expanded CAG repeats. We hypothesize that the accumulation of the DRPLA gene product with expanded polyQ sequences in the podocytes results in the dysfunction of the glomerular filtration barrier.

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Abbreviations

DRPLA:

Dentatorubral–pallidoluysian atrophy

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Acknowledgments

Each author contributed to this article as stated below. Study concept and design: Saito Yo, Sasaki, Ito S, Matsuoka; Management of each patient and data acquisition: Nagai, Saito Yo, Endo, Saito T, Sugai, Ishiyama, Komaki, Nakagawa, Sasaki; Histological examination of autopsied specimen: Saito Yo, Saito Yu, Sukigara, Ito M, Ito S, Matsuoka; Preparation, execution, and data processing for albumin scintigraphy: Nagai, Ito K; Drafting the manuscript: Nagai, Saito Yo; Critical revision of the manuscript: and Sasaki, Matsuoka K; Obtaining research grant for investigation: Saito Yo. Drs. Saito Yo and Sasaki obtained a Research Grant (24-7) for Nervous and Mental Disorders from the Ministry of Health, Labor, and Welfare of Japan for conducting this study.

Conflicts of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan

    Shigehiro Nagai, Yoshiaki Saito, Yukari Endo, Takashi Saito, Kenji Sugai, Akihiko Ishiyama, Hirofumi Komaki, Eiji Nakagawa & Masayuki Sasaki

  2. Department of Radiology, NCNP, Tokyo, Japan

    Kimiteru Ito

  3. Department of Clinical Laboratory Medicine, NCNP, Tokyo, Japan

    Yuko Saito

  4. Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, NCNP, Tokyo, Japan

    Sayuri Sukigara, Masayuki Ito & Yu-ichi Goto

  5. Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan

    Shuichi Ito

  6. Department of Pathology, National Center for Child Health and Development, Tokyo, Japan

    Kentaro Matsuoka

Authors
  1. Shigehiro Nagai
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  2. Yoshiaki Saito
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  3. Yukari Endo
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  4. Takashi Saito
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  5. Kenji Sugai
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  6. Akihiko Ishiyama
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  7. Hirofumi Komaki
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  8. Eiji Nakagawa
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  9. Masayuki Sasaki
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  10. Kimiteru Ito
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  11. Yuko Saito
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  12. Sayuri Sukigara
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  13. Masayuki Ito
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  14. Yu-ichi Goto
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  15. Shuichi Ito
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  16. Kentaro Matsuoka
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Corresponding author

Correspondence to Yoshiaki Saito.

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Nagai, S., Saito, Y., Endo, Y. et al. Hypoalbuminemia in early onset dentatorubral−pallidoluysian atrophy due to leakage of albumin in multiple organs. J Neurol 260, 1263–1271 (2013). https://doi.org/10.1007/s00415-012-6787-9

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  • DOI: https://doi.org/10.1007/s00415-012-6787-9

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