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Brain Advance Access first published online on February 2, 2005
This version published online on February 16, 2005
Brain, doi:10.1093/brain/awh410
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© The Author (2005). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received October 11, 2004
Revised December 27, 2004
Accepted January 4, 2005

Article

Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-{gamma}A

Gianfrancesco Ferrari 1, Eleonora Lamantea 1, Alice Donati 2, Massimiliano Filosto 3, Egill Briem 1, Franco Carrara 1, Rossella Parini 4, Alessandro Simonati 3, René Santer 5, and Massimo Zeviani 1*

1 Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, National Institute of Neurology, Milano, Italy
2 Unit of Child Neurology, ‘Meyer’ Children's Hospital (Florence), Italy
3 Institute of Neurology, University of Verona, Verona, Italy
4 Unit of Pediatrics, Pierfranco and Luisa Mariani Center for the Study of Children's Metabolic Disorders, University Hospital, Monza, Italy
5 University Children's Hospital, Hamburg, Germany

* To whom correspondence should be addressed.
Massimo Zeviani, E-mail: zeviani{at}instituto-besta.it


  Abstract

Summary We studied nine infant patients with a combination of progressive neurological and hepatic failure. Eight children, including two sibling pairs and four singletons, were affected by Alpers' hepatopathic poliodystrophy. A ninth baby patient suffered of a severe floppy infant syndrome associated with liver failure. Analysis of POLG1, the gene encoding the catalytic subunit of mitochondrial DNA polymerase, revealed that all the patients carried different allelic mutations in this gene. POLG1 is a major disease gene in mitochondrial disorders. Mutations in this gene can be associated with multiple deletions, depletion or point mutations of mitochondrial DNA (mtDNA). In turn, these different molecular phenotypes dictate an extremely heterogeneous spectrum of clinical outcomes, ranging from adult-onset progressive ophthalmoplegia to juvenile ataxic syndromes with epilepsy, to rapidly fatal hepatocerebral presentations, including Alpers' syndrome.

Keywords: POLG; mitochondrial DNA polymerase; Alpers' hepatopathic poliodystrophy; valproate toxicity; mtDNA depletion.
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