A CASE OF SEVERE HYPERMETABOLISM OF NONTHYROID ORIGIN WITH A DEFECT IN THE MAINTENANCE OF MITOCHONDRIAL RESPIRATORY CONTROL: A CORRELATED CLINICAL, BIOCHEMICAL, AND MORPHOLOGICAL STUDY

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Abstract
The case of a 33 year old woman with severe hypermetabolism (BMR usually between +150 and +200%) since the age of seven, or probably even longer, is described. The clinical picture is characterized by profuse perspiration, polydipsia without polyuria, thinness despite polyphagia, and progressing asthenia. In addition, there is muscular wasting and weakness, a pathological electromyogram and creatinuria. Thyroid function is normal, and measures that normally depress thyroid hormone production (subtotal thyroidectomy and administration of iodine and thiouracil) have no or only moderate effect on the BMR. None of the known extra-thyroidal causes of hypermetabolism can be demonstrated. The findings are not consistent with any of the known muscular diseases. Biochemical studies with isolated skeletal muscle mitochondria reveal a loosely-coupled state of the oxidative phosphorylation in the patient''s mitochondria, characterized by a nearly maximal rate of respiration in the absence of PO4 acceptor, parallel to an essentially normal extent of phosphorylation when PO4 acceptor is present. The sensitivity of the respiration to oligomycin is only partial. The mitochondria exhibit a high Mg++-dependent ATPase activity, which is only slightly stimulated by dinitrophenol. Complete centrifugal fractionation of the muscle homogenate reveals the presence of a three- to fourfold increase in total mitochondrial protein, together with an increased cytochrome oxidase activity per unit of mitochondrial protein. Electron microscopic examination of the patient''s skeletal muscle reveals an increased amount of mitochondria in the perinuclear areas of the fibers. The mitochondria are of extremely variable size and contain a vast amount of densely packed cristae. Also other structural changes of the mitochondria are observed, such as tubular inner structures instead of cristae, lack of opaque bodies, presence of dense, regularly layered cores, and occurrence of cylindrical mitochondria surrounded by concentric sheaths. It is concluded that the hypermetabolic state of the patient is caused by a defect in the mitochondrial enzyme organization, resulting in a severely lowered capacity for respiratory control. The present case appears to represent the first clinical instance of an endogenous defect at this level of biological organization.