Clinical Information

Mitochondrial metabolites occur as physiologic intermediates in a variety of metabolic pathways. Mitochondrial diseases, organic acidurias, and ketone disorders are groups of disorders in which one or more of these pathways are blocked, resulting in a deficiency of normal products and an abnormal accumulation of intermediate metabolites in the body. In some conditions, these excess metabolites are observed in abnormal plasma concentrations.

Mitochondrial disorders vary widely in both clinical presentation and age of onset. Patients commonly present with neurologic and myopathic features. In addition, patients may experience involvement of multiple organ systems with features such as myopathy, ophthalmoplegia, ptosis, cardiomyopathy, sensorineural hearing loss, optic atrophy, pigmentary retinopathy, diabetes mellitus, encephalomyopathy, seizures, and stroke-like episodes.

Organic acidurias typically present with either an acute life-threatening illness in early infancy or unexplained developmental delay with intercurrent episodes of metabolic decompensations in later childhood. Organic acidurias should be considered when patients present with severe and persistent metabolic acidosis of unexplained origin, elevated anion gap, and severe neurologic manifestations, such as seizures. Other findings, especially during acute episodes of metabolic decompensations, may include elevated ketones in urine or plasma, hyperammonemia, hypoglycemia, and lactic acidemia.

Ketone disorders include disorders of impaired ketone body metabolism and disorders of ketogenesis. Ketones are converted as an energy source when either carbohydrate reserves are depleted or excessive fatty acids are present. Clinical symptoms of ketone body metabolism disorders include episodes of ketoacidosis, vomiting, dehydration, and lethargy with increased risk of symptoms during periods of illness or fasting. Patients with disorders of ketogenesis experience hypoketotic hypoglycemic episodes that may result in long-term sequelae including seizure disorders, intellectual disability, and white matter changes in the brain. Treatment for ketone disorders involves avoidance of fasting and management of acute symptoms.

A diagnostic workup for mitochondrial disorders, organic acidurias, and ketone body disorders includes analysis of urine organic acids (OAU / Organic Acids Screen, Random, Urine), plasma amino acids (AAQP / Amino Acids, Quantitative, Plasma) and plasma acylcarnitines (ACRN / Acylcarnitines, Quantitative, Plasma) as recommended first-tier tests for assessment. While the mitochondrial metabolites panel complements this work up and provides additional context, this test should not be used in isolation for diagnostic purposes.