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Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood

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Abstract

Cerebellar and/or vermis atrophy is recognized in various types of childhood disorders with clinical and genetic heterogeneity. Although careful evaluation of clinical features and neuroimaging can lead to correct diagnosis of disorders, their diagnosis is sometimes difficult because clinical features can overlap with each other. In this study, we performed family-based whole exome sequencing of 23 families including 25 patients with cerebellar and/or vermis atrophy in childhood, who were unable to be diagnosed solely by clinical examination. Pathological mutations of seven genes were found in ten patients from nine families (9/23, 39.1 %): compound heterozygous mutations in FOLR1, C5orf42, POLG, TPP1, PEX16, and de novo mutations in CACNA1A, and ITPR1. Patient 1A with FOLR1 mutations showed extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid and serum, and Patient 6 with TPP1 mutations demonstrated markedly lowered tripeptidyl peptidase 1 activity in leukocytes. Furthermore, Patient 8 with PEX16 mutations presented a mild increase of very long chain fatty acids in the serum as supportive data for genetic diagnosis. The main clinical features of these ten patients were nonspecific and mixed, and included developmental delay, intellectual disability, ataxia, hypotonia, and epilepsy. Brain MRI revealed both cerebellar and vermis atrophy in eight patients (8/10, 80 %), vermis atrophy/hypoplasia in two patients (2/10, 20 %), and brainstem atrophy in one patient (1/10, 10 %). Our data clearly demonstrate the utility of whole exome sequencing for genetic diagnosis of childhood cerebellar and/or vermis atrophy.

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Acknowledgments

We would like to thank all patients and their families for their participation in this study. We also thank Aya Narita and Nobuko Watanabe for technical assistance. This work was supported by the Ministry of Health, Labour, and Welfare of Japan; the Japan Society for the Promotion of Science (a Grant-in-Aid for Scientific Research (B) from (25293085, 25293235), a Grant-in-Aid for Scientific Research (A) (13313587)); the Takeda Science Foundation; the Japan Science and Technology Agency; the Strategic Research Program for Brain Sciences (11105137); and a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (12024421).

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Authors and Affiliations

  1. Department of Human Genetics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan

    Chihiro Ohba, Kiyomi Nishiyama, Yoshinori Tsurusaki, Mitsuko Nakashima, Noriko Miyake, Naomichi Matsumoto & Hirotomo Saitsu

  2. Department of Clinical Neurology and Stroke Medicine, Yokohama City University, Yokohama, 236-0004, Japan

    Chihiro Ohba, Yume Suzuki, Hiroshi Doi, Atsuko Tomita-Katsumoto & Fumiaki Tanaka

  3. Division of Neurology, Kanagawa Children’s Medical Center, Clinical Research Institute, Yokohama, 232-0066, Japan

    Hitoshi Osaka, Mizue Iai & Sumimasa Yamashita

  4. Division of Radiology, Kanagawa Children’s Medical Center, Clinical Research Institute, Yokohama, 232-0066, Japan

    Noriko Aida

  5. Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, 501-1193, Japan

    Nobuyuki Shimozawa

  6. Department of Genetics and Genome Science, Tokyo Jikei University School of Medicine, Tokyo, 105-8461, Japan

    Ayumi Takamura & Yoshikatsu Eto

  7. Advanced Clinical Research Center, Institute of Neurological Disorders, Kawasaki, 215-0026, Japan

    Ayumi Takamura & Yoshikatsu Eto

Authors
  1. Chihiro Ohba
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  2. Hitoshi Osaka
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  3. Mizue Iai
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  4. Sumimasa Yamashita
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  5. Yume Suzuki
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  6. Noriko Aida
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  7. Nobuyuki Shimozawa
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  8. Ayumi Takamura
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  9. Hiroshi Doi
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  10. Atsuko Tomita-Katsumoto
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  11. Kiyomi Nishiyama
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  12. Yoshinori Tsurusaki
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  13. Mitsuko Nakashima
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  14. Noriko Miyake
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  15. Yoshikatsu Eto
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  16. Fumiaki Tanaka
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  17. Naomichi Matsumoto
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  18. Hirotomo Saitsu
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Correspondence to Naomichi Matsumoto or Hirotomo Saitsu.

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Ohba, C., Osaka, H., Iai, M. et al. Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood. Neurogenetics 14, 225–232 (2013). https://doi.org/10.1007/s10048-013-0375-8

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  • DOI: https://doi.org/10.1007/s10048-013-0375-8

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