Mitochondrial diseases are a heterogeneous group of disorders. Abnormal mitochondria may be seen to have altered histological characteristics with the use of light microscopy or at the ultrastructural level, abnormal DNA sequences, alterations in the levels and function of enzymes, or a combination of these abnormalities12,17.
In mitochondrial myopathies, symptoms often are limited to muscle; patients usually have slowly progressive weakness and, frequently, ophthalmoplegia. Weakness generally begins between birth and the age of ten months and is transiently exacerbated by exercise16. The weakness usually is in the proximal portion of the limb but can be in the distal area11. Occasionally, weakness does not appear until adulthood1,2,5,8-10,13,18,19,23.
We report on a patient who had lumbar disc disease and previously undiagnosed mitochondrial myopathy, resulting in long-standing weakness of the muscles of the lower extremities and radicular pain. A decompressive procedure was done for a bulging disc at the fifth lumbar-first sacral interspace, and the radicular pain resolved but the weakness persisted. Additional evaluation, including muscle biopsy, revealed the characteristic features of mitochondrial myopathy. We believe that the coexistence of lumbar disc disease and mitochondrial myopathy in our patient was a unique finding.
*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.
†Department of Pathology, University of Oklahoma Health Sciences Center, BMSB-451,940 Stanton L. Young Boulevard, Oklahoma City, Oklahoma 73104.
‡Southwest Medical Center, 1016 S.W. 44th Street, Suite 500, Oklahoma City, Oklahoma 73109.
A seventy-six-year-old man had had intermittent low-back pain for approximately fifty years, which he related to the lifting of very heavy objects. He was evaluated five years after the first episode for low-back pain that radiated into the right lower extremity; he had weakness of both lower extremities and paresthesia in the right lower extremity. The diagnosis was a compression fracture of the fifth lumbar vertebra, and the patient was managed with analgesics, vitamins, and testosterone.
Although the symptoms persisted intermittently, the patient had no medical evaluation until myelography and computed tomography were done (not at our institution) when he was seventy-four years old. These studies revealed diffuse bulging of the disc at the fifth lumbar-first sacral interspace, with impingement on both first sacral nerve roots, but this was not definitively treated. Two years later, the patient was seen by one of us (G.D.C.) because of low-back pain that radiated into both lower extremities. The pain was more severe on the right than on the left, and there was numbness and weakness in the right lower extremity. Physical examination revealed sensory loss in the second lumbar to first sacral dermatomes involving all modalities in both lower extremities, which was worse on the right; weakness of both lower extremities, which was most pronounced proximally in the iliopsoas and quadriceps but was also present in the muscles in the anterior and posterior compartments of the thighs; absence of all reflexes in the lower extremities; positive straight-leg-raising tests at 30 degrees on the right and at 45 degrees on the left; and no abnormal findings in the upper extremities.
Magnetic resonance imaging of the lumbar spine confirmed a diffuse bulging of the disc at the fifth lumbar-first sacral interspace, which impinged on the nerve roots bilaterally in the neural foramina. Percutaneous laser-assisted decompression of the disc was done.
Postoperatively, the patient had relief of pain but continued to have weakness in both lower extremities, most pronounced in the quadriceps, and he had intolerance to exercise. Additionally, he continued to have sensory loss involving all modalities in a stocking distribution in both lower extremities and normal sensation in both upper extremities. The stocking distribution suggested a non-radicular neurogenic etiology for the sensory loss. Electromyography revealed a decreased number of motor units as well as decreased insertional activity in the intrinsic muscles of the foot; evidence of acute denervation in muscles innervated by the fifth lumbar root, including the tibialis anterior, peronei, and tibialis posterior muscles; and increased insertional activity with occasional positive waves in the quadriceps and gluteus medius. The findings in the upper extremities were normal.
The patient had two open biopsies of the right quadriceps muscle, which revealed changes consistent with mitochondrial myopathy (Figs. 1-A and 1-B), including ragged-red fibers with clumped staining by reduced nicotinamide-adenine dinucleotide, succinate dehydrogenase, and cytochrome oxidase. The variation in the size of fibers was increased, and occasional dark angulated fibers, consistent with denervation, stained positively for esterase. Electron microscopy revealed collections of enlarged and abnormally shaped mitochondria that contained cristae with abnormal morphology, dense osmiophilic inclusions, and lipid droplets (Figs. 1-C and 1-D). Biochemical analysis revealed a deficiency of multiple enzymes, suggestive of a large deletion of mitochondrial DNA. The muscle mitochondria had decreased activity of cytochrome-c oxidase (0.23 micromole per minute per gram; normal, 2.28 to 3.32 micromoles per minute per gram), succinate cytochrome-c reductase (0.20 micromole per minute per gram; normal, 0.47 to 0.93 micromole per minute per gram), rotenone-sensitive nicotinamide-adenine dinucleotide cytochrome-c reductase (0.54 micromole per minute per gram; normal, 0.64 to 1.40 micromoles per minute per gram), reduced nicotinamide-adenine dinucleotide dehydrogenase (8.30 micromoles per minute per gram; normal, 28.41 to 42.55 micromoles per minute per gram), and citrate synthase (1.53 micromoles per minute per gram; normal, 7.33 to 12.53 micromoles per minute per gram). Succinate dehydrogenase activity was normal (1.53 micromoles per minute per gram; normal, 0.47 to 1.53 micromoles per minute per gram). After the biopsy, the resting level of serum lactate was elevated (3.0 millimoles per liter; normal, less than 2.2 millimoles per liter); this was additional evidence that mitochondrial myopathy was the cause of the weakness. Subsequently, empirical therapy was started with a daily regimen of forty milligrams of vitamin K3 (menadione), four grams of vitamin C (ascorbate), ten milligrams of coenzyme Q (ubiquinone), and one megavitamin. This treatment resulted in subjective improvement—the patient said that he was able to be more active—but not in objective improvement. One year later, the patient died of cardiac disease, and permission for an autopsy was not obtained.