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Right arrow Genetics & Dysmorphology

PEDIATRICS Vol. 111 No. 3 March 2003, pp. e262-e268

ELECTRONIC ARTICLE

A Mutation in Mitochondrial DNA-Encoded Cytochrome c Oxidase II Gene in a Child With Alpers-Huttenlocher-Like Disease

Johanna Uusimaa, MD*,{ddagger},¶, Saara Finnilä, MD{ddagger},§,¶, Leena Vainionpää, MD*, Mikko Kärppä, MD{ddagger},§,¶, Riitta Herva, MD||, Heikki Rantala, MD*, Ilmo E. Hassinen, MD{ddagger} and Kari Majamaa, MD{ddagger},§,¶

* Departments of *Pediatrics
{ddagger} Medical Biochemistry and Molecular Biology
§ Neurology
|| Pathology
Biocenter, University of Oulu, Oulu, Finland

--> Objective. Cytochrome c oxidase (COX) deficiency has been demonstrated in some patients with Alpers-Huttenlocher disease, but no genetic background has been identified. Our objective was to determine the molecular defect underlying the mitochondrial respiratory chain deficiency in a child with Alpers-Huttenlocher-like progressive cerebrohepatic disease.

Methods. The entire coding region of mitochondrial DNA was analyzed by conformation-sensitive gel electrophoresis and sequencing. Biochemical and morphologic investigations were performed on tissue biopsy material, including oximetric and spectrophotometric analyses of oxidative phosphorylation, histochemistry, and electron microscopy.

Results. Postmortem histologic examination revealed a marked loss of neurons in the olivary nuclei and a spongy change in the calcarine cortex, fatty infiltration and micronodular cirrhosis of the liver, and atrophic ovaries. A novel heteroplasmic 7706G>A mutation was found in the COX II gene. The median degree of the mutant heteroplasmy was 90% in 5 tissues examined but was lower in the blood of asymptomatic maternal relatives. The distribution of the mutant heteroplasmy was skewed to the left in single muscle fibers of the proband and her mother. The 7706G>A mutation converts a hydrophobic alanine in a conserved transmembrane segment to hydrophilic threonine.

Conclusions. The 7706G>A mutation is pathogenic and may lead to impaired dioxygen transfer to the active site of COX. The clinical phenotype of this patient resembled that in Alpers-Huttenlocher disease, suggesting that analysis of mitochondrial DNA is worthwhile in patients with a progressive cerebrohepatic disease.

Key Words: mitochondria • mitochondrial DNA • genetics • energy metabolism • pathology • cerebrohepatic disease

Abbreviations: COX, cytochrome c oxidase • mtDNA, mitochondrial DNA • CSGE, conformation-sensitive gel electrophoresis • PCR, polymerase chain reaction

Received for publication Jul 16, 2002; Accepted Nov 6, 2002.




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