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Peter Freisinger, MD; Nancy Fütterer, MD; Erwin Lankes, MD; Klaus Gempel, MD; Thomas M. Berger, MD; Johannes Spalinger, MD; Alexandra Hoerbe, MD; Claudia Schwantes, MD; Martin Lindner, MD; René Santer, MD; Martin Burdelski, MD; Hansjörg Schaefer, MD; Bernhard Setzer, PhD; Ulrich A. Walker, MD; Rita Horváth, MD

Arch Neurol. 2006;63:1129-1134.

Background  Autosomal recessive mutations in deoxyguanosine kinase (DGUOK) have been identified in the hepatocerebral form of mitochondrial DNA (mtDNA) depletion syndrome.

Objectives  To describe the clinical spectrum of DGUOK-related mtDNA depletion syndrome in 6 children and to summarize the literature.

Results  We identified pathogenic mutations in DGUOK in 6 children with the hepatocerebral form of mtDNA depletion syndrome. We describe the clinical, neuroradiologic, histologic, and genetic features in these children. All children showed severe hepatopathy, while involvement of other organs (skeletal muscle and brain) was variable. We identified 5 novel mutations (1 of them in 2 children) and 2 previously described mutations. Three different mutations affected the initial methionine, suggesting a mutational hot spot. One of our patients underwent liver transplantation; pathologic findings revealed (in addition to diffuse hepatopathy) a hepatocellular carcinoma, implying a possible link between mtDNA depletion syndrome and tumorigenesis.

Conclusion  We studied 12 children with infantile hepatoencephalopathies and mtDNA depletion syndrome and found pathogenic DGUOK mutations in 6, suggesting that this gene defect is a frequent but not an exclusive cause of the hepatic form of mtDNA depletion syndrome.

Author Affiliations: Metabolic Disease Center Munich-Schwabing (Drs Freisinger, Fütterer, Lankes, Gempel, and Horváth); Institutes of Clinical Chemistry, Molecular Diagnostics, and Mitochondrial Genetics, Academic Hospital Schwabing (Drs Gempel and Horváth); and Children's Hospital and Institute of Medical Genetics, Technical University Munich (Drs Freisinger, Fütterer and Lankes); Munich; Pediatric Clinic, Hospital of the City of Cologne, Cologne (Drs Hoerbe and Schwantes); Pediatric Clinic, University of Heidelberg, Heidelberg (Dr Lindner); Institute of Pathology, University of Hamburg, Hamburg (Drs Santer, Burdelski, and Schaefer); and Department of Rheumatology, Freiburg University Hospital, Freiburg (Drs Setzer and Walker), Germany; and Pediatric Clinic Kinderspital Luzern, Luzern, Switzerland (Drs Berger and Spalinger).

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