Correspondence
Mitochondrial Disease in Patients with Exercise Intolerance
N Engl J Med 2000; 342:438-440February 10, 2000
- Article
To the Editor:
The report by Andreu et al. (Sept. 30 issue)1 describes a sporadically occurring mitochondrial myopathy in patients with exercise intolerance that is caused by somatic mutations in the cytochrome b gene of mitochondrial DNA. We performed a retrospective analysis of patients with exercise intolerance whose muscle-biopsy specimens were sent to our laboratory for diagnosis. Patients at high risk for the cytochrome b defect were those with deficiencies of complexes I–III, II–III, or both and those with idiopathic mitochondrial myopathy with weakness, fatigue, and evidence of increased mitochondrial content in muscle. Plasma lactate levels were measured too infrequently to be contributory.
Of 1250 patients who were evaluated for metabolic muscle disease, 160 reported exercise intolerance. Fifty-five of these 160 patients had glycogen storage diseases or defects in lipid or purine metabolism, and 12 had respiratory-chain defects. Five of these 12 patients had deficiencies of complexes I–III, II–III, or both. Of these five patients (age range, 13 to 57 years), only three had either “ragged-red fibers” or increased succinate dehydrogenase and cytochrome c oxidase activities. Plasma lactate was not measured. An additional 11 patients (age range, 6 to 52 years) with idiopathic mitochondrial myopathies were also candidates for the cytochrome b defect, and plasma lactate levels were abnormal in 2 of 5 such patients.
Several of the variables associated with a high risk of cytochrome b defects are relatively common among patients with respiratory-chain defects. In our experience, 61 percent of such adults have muscle weakness, 31 percent have pain on exertion, and 33 percent have increased numbers of mitochondria in muscle. Only 37 percent of these patients underwent electromyography, yet the results were abnormal for 73 percent. Only 11 percent had plasma lactate measured, and levels were abnormal in 50 percent of these patients. Elevated succinate dehydrogenase and cytochrome c oxidase activities were only found in 11 percent of patients with respiratory-chain defects and may therefore be the primary discriminator in any consideration of a cytochrome b defect. The results of screening for mutations in the cytochrome b gene in our high-risk patients may support the view of Andreu et al.1 that the disorder is underdiagnosed.
1 ReferencesGeorgirene D. Vladutiu, Ph.D.
Elizabeth Tabone
State University of New York at Buffalo, Buffalo, NY 142091
Andreu AL ,Hanna MG ,Reichmann H , et al. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Engl J Med 1999;341:1037-1044
Full Text | Web of Science | Medline
To the Editor:
Andreu et al. described five patients with a sporadic form of mitochondrial myopathy who had a deficiency of complex III of the electron-transport chain as a result of pathogenic mutations of mitochondrial DNA encoding cytochrome b. In the accompanying editorial, Griggs and Karpati1 voice concern about the real incidence of complex III defects in patients with exercise intolerance, since the patients described by Andreu et al. were from referral centers around the world.
To estimate the incidence of a dysfunction in the electron-transport chain as a cause of exercise intolerance, we reviewed all muscle biopsies performed over a five-year period (1994 through 1998) at a single institution (size of referral area, 500,000 persons) in patients with undiagnosed long-term exercise intolerance, cramps, or isolated, elevated creatine kinase levels. Muscle-biopsy specimens are routinely processed for histologic studies, and Gomori's trichrome staining and cytochrome c oxidase and succinate dehydrogenase reactions are used to detect mitochondrial abnormalities. When present, the enzyme activities of complexes of the electron-transport chain are also assayed in muscle homogenate.2
We evaluated 51 patients (mean age, 34±12 years; 33 percent women): 36 (71 percent) reported exercise intolerance, 15 (29 percent) objective weakness, 8 (16 percent) postexercise myalgia or cramps, and 10 (20 percent) myoglobinuria. Serum creatine kinase levels were elevated in 28 patients (55 percent). A specific diagnosis was made in the case of six patients (two had myophosphorylase deficiency, two had phosphofructokinase deficiency, one had carnitine palmitoyltransferase deficiency, and one had adult-onset nemaline myopathy). Three additional patients had a nonspecific myopathy with massive lipid storage. Among the remaining 42 patients, only 2 (5 percent) had histologic evidence of mitochondrial dysfunction. Biochemical analyses in these two patients revealed deficient enzyme activities in the case of complexes III and IV. However, after correction for citrate synthase activity (in order to normalize mitochondrial content), the analyses showed that only one had a true complex III deficiency.
Therefore, although complex III deficiency must be added to the causes of exercise intolerance or muscular symptoms in otherwise healthy people, it has to be considered a rare (rather than frequent) cause of this syndrome.
2 ReferencesÒscar Miró, M.D.
Josep Maria Grav, M.D.
Jordi Casademont, M.D.
University of Barcelona, 08036 Barcelona, Spain1
Griggs RC ,Karpati G . Muscle pain, fatigue, and mitochondriopathies. N Engl J Med 1999;341:1077-1078
Full Text | Web of Science | Medline2
Miro O ,Casademont J ,Grau JM ,Jarreta D ,Urbano-Marquez A ,Cardellach F . Histological and biochemical assessment of mitochondrial function in dermatomyositis. Br J Rheumatol 1998;37:1047-1053
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Author/Editor Response
The authors reply:
To the Editor: As described in our article, we learned of the association between exercise intolerance and a non–maternally inherited mutation in the cytochrome b gene of muscle mitochondrial DNA from a report by Dumoulin et al.1 When we found that two patients referred to us for exercise intolerance had distinct mutations in the cytochrome b gene,2,3 we reviewed our files, as well as the literature, looking for patients with exercise intolerance and complex III deficiency. In short order, we identified the five patients described in our paper. This led us to the not unreasonable conclusion that somatic (i.e., non–maternally inherited) mutations in the mitochondrial cytochrome b gene were probably underdiagnosed as causes of exercise intolerance. After reviewing their files, Dr. Vladutiu and Ms. Tabone apparently came to the same conclusion, although their data have to be confirmed by molecular genetic analysis.
It is becoming apparent that defects of respiratory-chain enzymes, often a result of somatic mutations in mitochondrial DNA genes coding for proteins, have been neglected in the differential diagnosis of exercise intolerance with or without myoglobinuria. Witness the reports of two patients, one with a complex I deficiency and a nonsense mutation in the NADH dehydrogenase subunit 4 gene (ND4)4 and the other with a cytochrome c oxidase deficiency and a microdeletion in the cytochrome c oxidase subunit III gene (COX III).5 Although the exact frequency of this group of disorders remains to be established, the medical community should be aware of their existence.
5 ReferencesAntoni Andreu, M.D.
Hospitals Vall d'Hebron, 08035 Barcelona, SpainSalvatore DiMauro, M.D.
Columbia University College of Physicians and Surgeons, New York, NY 100321
Dumoulin R ,Sagnol I ,Ferlin T ,Bozon D ,Stepien G ,Mousson B . A novel gly290asp mitochondrial cytochrome b mutation linked to a complex III deficiency in progressive exercise intolerance. Mol Cell Probes 1996;10:389-391
CrossRef | Web of Science | Medline2
Andreu AL ,Bruno C ,Shanske S , et al. Missense mutation in the mtDNA cytochrome b gene in a patient with myopathy. Neurology 1998;51:1444-1447
Web of Science | Medline3
Andreu AL ,Bruno C ,Dunne TC , et al. A nonsense mutation (G15059A) in the cytochrome b gene in a patient with exercise intolerance and myoglobinuria. Ann Neurol 1999;45:127-130
CrossRef | Web of Science | Medline4
Andreu AL ,Tanji K ,Bruno C , et al. Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene. Ann Neurol 1999;45:820-823
CrossRef | Web of Science | Medline5
Keightley JA ,Hoffbuhr KC ,Burton MD , et al. A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria. Nat Genet 1996;12:410-416
CrossRef | Web of Science | Medline
Author/Editor Response
In our editorial we noted that although Andreu et al. found five patients with symptoms resulting from mutations in the cytochrome b gene, it remained to be determined whether this disorder is a common cause of exercise intolerance. The information provided by Miró et al. suggests that this mitochondriopathy is a relatively uncommon cause of these symptoms in their referral practice. However, the use of microscopical criteria alone to diagnose mitochondrial myopathy is generally insufficient. This point may, in part, explain the low incidence of mitochondrial disorders reported by Miró et al. Furthermore, mitochondrial disorders could be more common in other populations and might well be more common in areas with different referral practices. Moreover, finding a cause of these common symptoms, even if it is infrequent, provides patients with an explanation for symptoms that were once unexplained and allows further study of their mechanism and treatment.
Robert C. Griggs, M.D.
University of Rochester Medical Center, Rochester, NY 14642George Karpati, M.D.
Montreal Neurological Institute, Montreal, QC H3A 2B4, Canada- Citing Articles (2)
