Patti L. Peterson

The treatment of mitochondrial myopathies and encephalomyopathies.

This paper briefly summarizes the results of a long-term, open pharmacotherapy trial in 16 patients with well-characterized mitochondrial disease. Outcome measures included repeated clinical evaluation, 31P-NMR spectroscopy and near-infrared spectroscopy. Treated patients appeared to survive longer with less functional disability and medical complications than typically seen in clinical practice.

In vitro effects of glucocorticoid on mitochondrial energy metabolism

A systematic study of the effects of the synthetic glucocorticoid, methylprednisolone (MP), on respiration and energy coupling in tightly-coupled mitochondria isolated from rat tissues has been initiated. In intact rat skeletal muscle, liver and heart mitochondria, incubation, in vitro, with greater than or equal to 0.1 mM MP caused inhibition of the state 3 respiratory rates with succinate and NAD-linked substrates. In skeletal muscle and heart mitochondria, the oxidation of succinate was significantly more sensitive to MP than was that of the NAD-linked substrates. No effects were seen at low concentrations (less than 0.02 mM) of MP. In all three tissues, these data together with analysis of the partial reactions of the electron transport chain and steady-state kinetic analysis of cytochrome reduction indicated that in isolated mitochondria high concentrations of MP: (a) inhibit the oxidation of NAD-linked substrates at the level of the respiratory chain between the primary NADH dehydrogenase flavoprotein and coenzyme Q, most likely at the iron-sulfur centers or coenzyme Q-binding proteins of complex I; and (b) inhibit succinate oxidation in intact (but not disrupted) mitochondria, not by inhibiting electron transfer along the respiratory chain, but possibly at the level of succinate transport into the mitochondria. The results of these studies suggest that the therapeutic effects of MP in mitochondrial disease result from indirect effects rather than direct effects on the mitochondrial membrane. More importantly, the absence of an effect at low MP concentrations provides the baseline information needed for further studies to be carried out in vivo.

The treatment of Friedreich's ataxia with amantadine hydrochloride

Amantadine hydrochloride (AH) was orally administered to 16 patients with Friedreichs ataxia. We evaluated patient response with the functional ataxia scoring scale and calculated a total disability score. The mean percent improvement of the total disability score was 29.5%; for ambulatory patients alone it was 45.5%. No significant side effects were encountered. AH appears to be a safe and effective symptomatic treatment of Friedreichs ataxia.

The pathophysiology of brain injury: understanding innovative drug therapies.

The advancement of acute care for persons with brain injury is predicated on the further clarification of the mechanical and biochemical processes that are begun at the time of the injury. Attempts to enhance survival and functional outcome have led to cerebral perfusion and intracranial pressure management techniques. In addition, novel neuroprotective pharmacotherapeutic strategies have been borne from an ever growing knowledge of the degradative biochemical injury that occurs subsequent to the initial insult. The link between the acute and rehabilitation phases of care continues to grow closer, thus compelling the rehabilitationist to be aware of the potential effect these processes and treatments have on outcome.

Alterations in cerebral energy metabolism induced by traumatic brain injury.

Abstract Energy metabolism of the brain is unique, possessing high aerobic metabolism with no significant capacity for anaerobic glycolysis and limited tissue stores of glucose. A steady supply of oxygen and glucose is essential in order to maintain cerebral function and integrity. Extensive research in experimental and human head injury has been conducted regarding the delivery of oxygen and outcome. This research has provided evidence which indicates that in addition to the availability of oxygen and glucose, other factors, such as perturbation of mitochondrial energy transducing processes which also follow head trauma, play significant roles. In this paper, the salient findings from biochemical studies of experimental and clinical brain injury are summarized and indicate that the mitochondrial respiratory chain-linked oxidative phosphorylation and calcium transport are compromised by trauma-induced brain injury and support the idea that oxidative stress and perturbation of cellular calcium homeostasis play significant roles in traumatic brain injury. [Neurol Res 2001; 23: 129-138]

Heteroplasmy in Chronic External Ophthalmoplegia: Clinical and Molecular Observations

ABSTRACT: Chronic progressive external ophthalmoplegia (CPEO) describes a recognizable clinical syndrome frequently associated with variable dysfunction in other organ systems. Histochemical and biochemical studies suggested primary dysfunction of oxidative phosphorylation. This has recently been confirmed by demonstration of partially deleted as well as normal mitochondrial DNA—heteroplasmy—in some of these patients, most of them sporadic. In the six heteroplasmic CPEO patients that we have examined to date, the partially deleted species has been detected in all tissues tested, albeit in vastly different proportions. We report here detection of physiologically significant proportions of partially deleted mitochondrial DNA in several organs taken at autopsy from a CPEO patient with severe multisystem disease. We discuss the relationship of CPEO to several other clinical phenotypes associated with mitochondrial dysfunction, and discuss the possible implications of heteroplasmy for the development of variable phenotypes.

Impaired NADH-CoQ reductase activity in a child with moyamoya syndrome

A 33-month-old boy with recurrent stroke-like episodes had angiographic features characteristic of moyamoya syndrome. Mitochondrial encephalomyopathy was suspected because of lactic acidosis and ptosis. Studies of oxidative metabolism on isolated skeletal muscle mitochondria revealed impairment of NADH-coenzyme Q reductase activity. Mitochondrial metabolic disorders may cause moyamoya syndrome when other known associated factors are absent.

Partial cytochrome b deficiency and generalized dystonia

An 18-year-old female had clinical features of idiopathic torsion dystonia with bilateral hypodense putaminal lesions on computed tomography. Mitochondrial encephalomyopathy was suspected because of persistent lactic acidemia and myopathy. Studies of oxidative metabolism on isolated skeletal muscle mitochondria revealed partial cytochrome b deficiency indicating a defect in the cytochrome b- c1 complex. This finding represents a unique, multisystem syndrome of progressive dystonia, putaminal degeneration, myopathy, and mitochondrial cytochrome b deficiency. Mitochondrial metabolic disorders may be a cause of torsion dystonia when other known associated factors are absent.

Elevated Cerebrospinal Fluid Lactic Acid Levels in Creutzfeldt-Jakob Disease

The concentration of cerebrospinal fluid (CSF) lactic acid was determined in three patients with biopsy proven Creutzfeldt-Jacob disease (CJD). When compared with twenty demented patients diagnosed as having either Alzheimers disease or multi-infarct dementia, the CSF lactic acid values of the CJD patients were significantly elevated (p less than .001). Elevated CSF lactic acid levels may be an important biochemical marker of CJD and useful in the differential diagnosis of dementia.

Cytochrome Oxidase and Neuromuscular Diseases

The pioneer work of Luft, Ernster and associates more than 2 decades ago on a patient with hypermetabolism of non-thyroid origin has clearly illustrated the critical role of mitochondrial respiratory control in the energy metabolism of living organisms1. Since then there have been a growing, though not very large, number of reports of mitochondrial deficiencies identified by direct investigation of biopsied tissue. These advances have stemmed partly from an increasing awareness of the clinical and metabolic consequences of impaired oxidative metabolism in humans, and partly from the introduction of improved methods for assessing the functional integrity of these pathways in intact and disrupted cells, and in isolated mitochondrial preparations. A number of biochemical defects have been identified which have recently been reviewed by DiMauro2 and Morgan-Hughes3. Based on biochemical characteristics, Morgan-Hughes has classified the defects into the following A major groups: (A). defects of mitochondrial substrate transport; (B). defects of substrate utilization; (C). defects of the respiratory chain components; and (D). defects of energy conservation and transduction3.