The second category can be subdivided on the basis of pathophysiology into three groups that are useful for diagnosis. Group 1. Diseases that disturb the synthesis or catabolism of complex molecules (lysosomal and peroxisomal disorders; disturbances of intracellular trafficking and secretory protein processing). Clinical symptoms are permanent, progressive, independent of intercurrent events, and unrelated to food intake. Group 2. Inborn errors of intermediary metabolism that lead to acute or progressive intoxication caused by accumulation of toxic compounds proximal to the metabolic block. The group includes aminoacidopathies, most organic acidurias, congenital urea cycle defects, and sugar intolerances. In these conditions, a symptom-free interval is followed by clinical signs of acute or chronic intoxication and by recurrent metabolic disturbances. Clinical expression is often late in onset and intermittent. Diagnosis is easy, relying mainly on chromatography of plasma and urine amino acids or organic acids. Treatment involves removing the toxin. Group 3. “Energy deficiency” disorders, in which symptoms are caused at least partly by a deficiency in energy production or utilization resulting from an inborn error of intermediary metabolism in liver, myocardium, muscle, or brain. This group includes glycogenosis, gluconeogenesis defects, congenital lactic acidemias, fatty acid oxidation defects, and mitochondrial respiratory chain disorders. These diseases present an overlapping clinical spectrum, and manifestations sometimes result from accumulation of toxic compounds as well as from the deficiency in energy production. Common symptoms include hypoglycemia, hyperlactacidemia, severe generalized hypotonia, myopathy, cardiomyopathy, failure to thrive, cardiac failure, circulatory collapse, sudden infant death syndrome, and congenital malformations, the last suggesting that the abnormal process affected fetal energy pathways.