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Tina D. Jeppesen, MD; Marianne Schwartz, PhD; Anja L. Frederiksen, MD; Flemming Wibrand, PhD; David B. Olsen, MD; John Vissing, MD, PhD

Arch Neurol. 2006;63:1701-1706.

Background  Mitochondrial disorders are generally not associated with a clear phenotype-genotype relationship, which complicates the understanding of the disease and genetic counseling.

Objective  To investigate the relationship between the muscle and blood mitochondrial DNA mutation load and phenotype.

Design  Survey.

Setting  The Neuromuscular Research Unit, Rigshospitalet, Copenhagen, Denmark.

Participants  Fifty-one persons with the 3243A>G point mutation of mitochondrial DNA, and 20 healthy control subjects.

Methods  We recorded the maximal oxygen uptake (O₂max), maximal workload, resting and peak-exercise plasma lactate levels, muscle and blood mutation load, muscle morphology, and presence of diabetes mellitus and hearing impairment in all subjects.

Results  Muscle mutation load (mean ± SE, 50% ± 5%; range, 2%-95%) correlated with O₂max and resting plasma lactate level (P<.001; R0.64). All persons except 5 with a muscle mutation load above 50% had abnormal O₂max and morphology on muscle biopsy findings. Persons with hearing impairment and diabetes mellitus had a muscle mutation load above 65%. The mutation load in blood (mean ± SE, 18% ± 3%; range, 0%-61%) did not correlate with O₂max, resting plasma lactate levels, or presence of hearing impairment or diabetes mellitus.

Conclusions  This study demonstrates a close relationship between the muscle mutation load and phenotype in persons carrying the 3243A>G mutation. The lack of correlation between the mutation load in blood and symptoms from other tissues emphasizes the importance of assessing phenotype-genotype correlations in the same tissue in mitochondrial disease. The results indicate that the threshold of muscle mutation load at which oxidative impairment occurs can be as low as 50%, which is as much as 40% lower than that suggested by in vitro studies.

Author Affiliations: Copenhagen Muscle Research Center (Drs Jeppesen, Olsen, and Vissing), Department of Neurology and Neuromuscular Research Unit (Drs Jeppesen, Olsen, and Vissing), and Department of Clinical Genetics (Dr Schwartz), National University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Endocrinology, Ribe County Hospital, Esbjerg, Denmark (Dr Frederiksen); and J. F. Kennedy Institute, Glostrup, Denmark (Dr Wibrand).

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