Correspondence

Mitochondrial Diseases

N Engl J Med 2003; 349:1293-1294September 25, 2003

Article

To the Editor:

The timely review article by DiMauro and Schon (June 26 issue)1 does not highlight the opportunities for the development of diagnostic, preventive, and therapeutic interventions presented by the study of diseases caused by homoplasmic mutations in mitochondrial DNA (mtDNA). In patients with such diseases, the pathogenic mutation is expressed ubiquitously, yet the diseases tend to be tissue-specific and have highly variable clinical expression.2 In most cases, the different phenotypes are attributable to nuclear-encoded modifier genes with complex patterns of inheritance.3 Positional cloning and candidate-gene approaches, as well as the existence of a mouse model,4 make it likely that at least some of these modifiers will be identified in the near term. Their functional characterization may provide targets for pharmacologic modification and since many of the modifiers seem to operate in a tissue-specific manner, these pharmacologic interventions could have a favorable safety profile. Since identical heteroplasmic mtDNA mutations can cause entirely different diseases,1,5 the same or similar modifiers may also be responsible for these different phenotypic expressions. We owe it to our patients to explore these opportunities in an expedited fashion.

Nathan Fischel-Ghodsian, M.D.
Cedars–Sinai Medical Center, Los Angeles, CA 90048
nathan.fischel@cshs.org

5 References

1. 1

   DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 2003;348:2656-2668
   Full Text | Web of Science | Medline

2. 2

   Fischel-Ghodsian N. Mitochondrial mutations and hearing loss: paradigm for mitochondrial genetics. Am J Hum Genet 1998;62:15-19
   CrossRef | Web of Science | Medline

3. 3

   Bykhovskaya Y, Yang H, Taylor K, et al. Modifier locus for mitochondrial DNA disease: linkage and linkage disequilibrium mapping of a nuclear modifier gene for maternally inherited deafness. Genet Med 2001;3:177-180
   CrossRef | Web of Science | Medline

4. 4

   Johnson KR, Zheng QY, Bykhovskaya Y, Spirina O, Fischel-Ghodsian N. A nuclear-mitochondrial DNA interaction affecting hearing impairment in mice. Nat Genet 2001;27:191-194
   CrossRef | Web of Science | Medline

5. 5

   Fischel-Ghodsian N. Mitochondrial DNA mutations and diabetes: another step toward individualized medicine. Ann Intern Med 2001;134:777-779
   Web of Science | Medline

Author/Editor Response

Dr. Fischel-Ghodsian is correct. His comment emphasizes the complexity of mitochondrial genetics and highlights one of the many nuances of mitochondrial diseases that we were unable to cover in a general review.

Salvatore DiMauro, M.D.
Eric A. Schon, Ph.D.
Columbia University College of Physicians and Surgeons, New York, NY 10032
sd12@columbia.edu