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

Authors: Uusimaa, Johanna; Hinttala, Reetta; Rantala, Heikki¹; Päivärinta, Markku²; Herva, Riitta³; Röyttä, Matias⁴; Soini, Heidi; Moilanen, Jukka S.; Remes, Anne M.; Hassinen, Ilmo E.⁵; Majamaa, Kari

Source: Epilepsia, Volume 49, Number 6, June 2008 , pp. 1038-1045(8)

Publisher: Blackwell Publishing

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Abstract:

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.

Keywords: Status epilepticus; Metabolic diseases; Mitochondrial diseases; Genetic diseases

Document Type: Research article

DOI: 10.1111/j.1528-1167.2008.01544.x

Affiliations: 1: Department of Pediatrics, University of Oulu, Oulu, Finland 2: Department of Neurology, University of Turku, Turku, Finland 3: Department of Pathology, University of Oulu, Oulu, Finland 4: Department of Pathology, University of Turku, Turku, Finland 5: 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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