Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus

Authors

  • Johanna Uusimaa,

    1. Department of Pediatrics, University of Oulu, Oulu, Finland
    2. Clinical Research Center, Oulu University Hospital, Oulu, Finland
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  • Reetta Hinttala,

    1. Clinical Research Center, Oulu University Hospital, Oulu, Finland
    2. Department of Neurology, University of Oulu, Oulu, Finland
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  • Heikki Rantala,

    1. Department of Pediatrics, University of Oulu, Oulu, Finland
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  • Markku Päivärinta,

    1. Department of Neurology, University of Turku, Turku, Finland
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  • Riitta Herva,

    1. Department of Pathology, University of Oulu, Oulu, Finland
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  • Matias Röyttä,

    1. Department of Pathology, University of Turku, Turku, Finland
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  • Heidi Soini,

    1. Clinical Research Center, Oulu University Hospital, Oulu, Finland
    2. Department of Neurology, University of Oulu, Oulu, Finland
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  • Jukka S. Moilanen,

    1. Clinical Research Center, Oulu University Hospital, Oulu, Finland
    2. Department of Clinical Genetics, University of Oulu, Oulu, Finland
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  • Anne M. Remes,

    1. Clinical Research Center, Oulu University Hospital, Oulu, Finland
    2. Department of Neurology, University of Oulu, Oulu, Finland
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  • Ilmo E. Hassinen,

    1. Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland
      [Correction added after online publication Feb. 20, 2008: The affiliation: Jukka S. Moilanen, †Clinical Research Center, Oulu University Hospital, Oulu, Finland; **Department of Clinical Genetics, University of Turku, Turku, Finland has been changed to: Jukka S. Moilanen, †Clinical Research Center, Oulu University Hospital, Oulu, Finland; **Department of Clinical Genetics, University of Oulu, Oulu, Finland]
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  • Kari Majamaa

    1. Clinical Research Center, Oulu University Hospital, Oulu, Finland
    2. Department of Neurology, University of Oulu, Oulu, Finland
    3. Department of Neurology, University of Turku, Turku, Finland
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Address correspondence to Dr. Kari Majamaa, M.D., University of Turku, Department of Neurology, FIN-20014 Turku, Finland. E-mail: kari.majamaa@utu.fi

Summary

Purpose: Polymerase gamma (POLG) is the sole enzyme in the replication of mitochondrial DNA (mtDNA). Numerous mutations in the POLG1 gene have been detected recently in patients with various phenotypes including a classic infantile-onset Alpers-Huttenlocher syndrome (AHS). Here we studied the molecular etiology of juvenile-onset AHS manifesting with status epilepticus and liver disease in three teenagers.

Patients and Methods: We examined 14- and 17-year-old female siblings (patients 1 and 2) and an unrelated 15-year-old girl (patient 3) with juvenile-onset AHS, sequenced POLG1, and the entire mtDNA, examined mtDNA deletions by amplification of the full-length mtDNA with the long PCR method and used real-time PCR to quantify mtDNA in the tissue samples.

Results: The initial manifestations were migraine-like headache and epilepsy, and the terminal manifestations status epilepticus and hepatic failure. A homozygous W748S mutation in POLG1 was detected in the three patients. No deletions or pathogenic point mutations were found in mtDNA, but all three patients had mtDNA depletion.

Conclusions: POLG mutations should be considered in cases of teenagers and young adults with a sudden onset of intractable seizures or status epilepticus, and acute liver failure. The W748S POLG1 mutation seems to lead to tissue-specific, partial mtDNA depletion in patients with juvenile-onset Alpers syndrome. Valproic acid should be avoided in the treatment of epileptic seizures in these patients.

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