Glutaric acidemia I results from a deficiency at the end of thelysine catabolic pathway. It is an autosomal recessive diseaseproduced by deficiency of glutaryl-CoA dehydrogenase activity (Fig. 54-3). Clinical manifestations include macrocephaly, which may be present at birth, with fever and metabolic distress. Before the advent of newborn screening, more than70% of children had metabolic stroke-like episodes associated with infarction of the basal ganglia and dystonia, which characteristically develops after an episode of intercurrent illness, although it may reflect birth stress or prenatal insults. Treatment includes a protein-restricted diet accompanied by amedical food deficient in lysine and aggressive management of intercurrent illness. Despite this treatment as many as onethird of children still develop neurologic symptoms.
Biotin is a ubiquitous vitamin that is covalently linked to many carboxylases and cannot be recycled from its attachment to
Figure 54-3 Scheme of flavoprotein metabolism with reference to glutaric aciduria types I and II. (1) Glutaryl-CoA dehydrogenase (deficient in glutaric aciduria type1), (2) fatty acyl-CoA dehydrogenases, (3) other flavoprotein dehydrogenases, (4) ETF (deficiency results in glutaric aciduria type II), (5) ETF-ubiquinone oxidoreductase (deficiency results in glutaric aciduria type II). CoA, Coenzyme A; ETF, electron transfer flavoprotein.
the carboxylases. Thus, inherited biotinidase deficiency greatly increases the dietary requirement for biotin. Affected individuals become biotin deficient while consuming normal diets. Clinical disease can appear in the neonatal period or be delayed until later infancy, depending on the degree of deficiency.
Clinical manifestations of biotin deficiency vary greatly (seizures, hypotonia, sensory neural deafness, alopecia, skin rash, metabolic acidosis, immune deficits) and depend on which enzymes in which tissues have the most biotin depletion. Carboxylation is a crucial reaction in the metabolism of organic acids; most patients with biotinidase deficiency excrete abnormal amounts of several organic acids, among which β-methyl-crotonylglycine is prominent. In addition to biotinidase deficiency, an inherited deficiency of holocarboxylase synthetase gives rise to severe disease and to similar patterns of organic aciduria. Both conditions respond well to treatment with large doses of biotin (10 to 40 mg/day). Confirmatory testing is accomplished with quantitative measurement of biotinidase activity.
Fatty acids are derived from hydrolysis of triglycerides and catabolism of fat. The catabolism of fatty acids (Fig. 55-1) proceeds through the serial, oxidative removal of two carbons at a time as acetyl groups (each as acetyl-CoA). The reactions are catalyzed by a group of enzymes that exhibit specificities related to the chain length and other properties of the fatty acids: very long chain acyl-CoA dehydrogenase (VLCAD), long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) or trifunctional protein, medium-chain acyl-CoA dehydrogenase (MCAD), and short-chain acyl-CoA dehydrogenase (SCAD).