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Background: Patients with isolated complex I deficiency (CID) in skeletal muscle mitochondria often present with exercise intolerance as their major clinical symptom. Objective: To study the in vivo bioenergetics in patients with complex I deficiency in skeletal muscle mitochondria. Methods: In vivo bioenergetics were studied in three of these patients by measuring oxygen uptake at rest and during maximal exercise, together with forearm ADP concentrations ([ADP]) at rest. Whole-body oxygen consumption at rest (Vo(2)) was measured with respiratory calorimetry. Maximal oxygen uptake (Vo(2)max) was measured during maximal exercise on a cycle ergometer. Resting [ADP] was estimated from in vivo P-31 MRS measurements of inorganic phosphate, phosphocreatine, and ATP content of forearm muscle. Results: Resting Vo(2) was significantly increased in all three patients: 128 +/- 14% (SD) of values in healthy control subjects. Vo(2)max in patients was on average 2.8 times their Vo(2) at rest and was only 28% of Vo(2)max in control subjects. Resting [ADP] in forearm muscle was significantly increased compared with healthy control subjects (patients 26 +/- 2 muM, healthy controls 9 +/- 2 muM). Conclusion: In patients with CID, the increased whole-body oxygen consumption rate at rest reflects increased electron transport through the respiratory chain, driven by a decreased phosphorylation potential, The increased electron transport rate may compensate for the decreased efficiency of oxidative phosphorylation (phosphorylation potential).

Background: Patients with isolated complex I deficiency (CID) in skeletal muscle mitochondria often present with exercise intolerance as their major clinical symptom. Objective: To study the in vivo bioenergetics in patients with complex I deficiency in skeletal muscle mitochondria. Methods: In vivo bioenergetics were studied in three of these patients by measuring oxygen uptake at rest and during maximal exercise, together with forearm ADP concentrations ([ADP]) at rest. Whole-body oxygen consumption at rest (Vo(2)) was measured with respiratory calorimetry. Maximal oxygen uptake (Vo(2)max) was measured during maximal exercise on a cycle ergometer. Resting [ADP] was estimated from in vivo P-31 MRS measurements of inorganic phosphate, phosphocreatine, and ATP content of forearm muscle. Results: Resting Vo(2) was significantly increased in all three patients: 128 +/- 14% (SD) of values in healthy control subjects. Vo(2)max in patients was on average 2.8 times their Vo(2) at rest and was only 28% of Vo(2)max in control subjects. Resting [ADP] in forearm muscle was significantly increased compared with healthy control subjects (patients 26 +/- 2 muM, healthy controls 9 +/- 2 muM). Conclusion: In patients with CID, the increased whole-body oxygen consumption rate at rest reflects increased electron transport through the respiratory chain, driven by a decreased phosphorylation potential, The increased electron transport rate may compensate for the decreased efficiency of oxidative phosphorylation (phosphorylation potential).

We identified nine children with a leukoencephalopathy of similar type according to clinical and MRI findings. The patients included three affected sibling pairs. The age range was 3 to 19 years. The onset of the disease was in childhood; the course was both chronic-progressive and episodic. There were episodes of deterioration following infections and minor head traumas, and these could result in unexplained coma. In eight patients with advanced disease, MRI revealed a diffuse cerebral hemispheric leukoencephalopathy, in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In one patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter, which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate, compatible with the presence of mainly CSF and little brain tissue. Spectra of the cortex were much better preserved. However, in addition to the normal resonances, there were signals representing lactate and glucose. MRS of the white matter in the patient whose disease was at an early stage was much less abnormal. Autopsy in one patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. Typical involvement of pontine tegmental white matter was suggested by MRI and confirmed by autopsy. The disease probably has an autosomal recessive mode of inheritance, but the basic metabolic defect is not known.

We identified nine children with a leukoencephalopathy of similar type according to clinical and MRI findings. The patients included three affected sibling pairs. The age range was 3 to 19 years. The onset of the disease was in childhood; the course was both chronic-progressive and episodic. There were episodes of deterioration following infections and minor head traumas, and these could result in unexplained coma. In eight patients with advanced disease, MRI revealed a diffuse cerebral hemispheric leukoencephalopathy, in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In one patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter, which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate, compatible with the presence of mainly CSF and little brain tissue. Spectra of the cortex were much better preserved. However, in addition to the normal resonances, there were signals representing lactate and glucose. MRS of the white matter in the patient whose disease was at an early stage was much less abnormal. Autopsy in one patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. Typical involvement of pontine tegmental white matter was suggested by MRI and confirmed by autopsy. The disease probably has an autosomal recessive mode of inheritance, but the basic metabolic defect is not known.

We performed a short-term, double-blind, placebo-controlled, crossover trial of sodium dichloroacetate (DCA) therapy in 11 patients affected by various primary mitochondrial disorders. Independent measures of oxidative metabolism (venous blood metabolites, exercise testing, phosphorus magnetic resonance [MR] spectroscopy of muscle, and proton MR spectroscopy of brain) were used in order to monitor metabolic responses to the drug. One week of DCA treatment produced significant decreases (p0.05) in blood lactate, pyruvate, and alanine at rest and after bicycle exercise. Proton MR spectra collected from a supraventricular volume of interest in brain of seven of 11 patients also showed significant changes. Brain lactate/creatine ratio decreased by 42% during DCA treatment (p0.05). Brain choline/creatine ratio (which is low in patients with myelinopathies) increased by 18% (p0.01) after therapy. N-Acetylaspartate/creatine ratio (an index of neuronal damage or loss) increased by 8% after treatment (p0.05). Proton MR spectra collected in two of 11 patients from a volume of interest including the basal ganglia showed similar results (decrease of 36.6% in lactate/creatine; increases of 16% in choline/creatine and 4.5% in N-acetylaspartate/creatine). Phosphorus MR spectroscopy of muscle and self-assessed clinical disability were unchanged. Our study indicates that short-term DCA treatment not only lowers blood lactate but also improves indices of both brain oxidative metabolism and neuronal and glial density or function.