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Biotin deficiency associated with total parenteral nutrition is an emerging clinical problem; criteria for diagnosis and dosage for treatment are unclear. We have diagnosed and successfully treated biotin deficiency in three patients. Each patient had alopecia totalis, hypotonia, and developmental delay. Two developed the characteristic scaly periorificial dermatitis; one had only an intermittent scaly rash on the cheeks and occipital scalp. Zinc and essential fatty acid supplements were adequate; serum zinc levels and triene/tetraene ratios confirmed sufficiency of these nutrients. None of the patients received biotin prior to diagnosis, and each had decreased excretion of urinary biotin and increased urinary excretion of organic acids diagnostic of deficiency of two biotin-dependent enzymes (methylcrotonyl-coenzyme A carboxylase and priopionyl-coenzyme A carboxylase). Only one patient had a plasma biotin concentration below the normal range (Ochromonicas danica assay). The rash, alopecia, and neurologic findings responded dramatically to biotin therapy (100 micrograms/day in all patients; an initial larger dose of 1 mg/day for 1 week plus 10 mg/day for 7 weeks in one patient), and did not recur. However, abnormal organic acid excretion persisted in one patient who did not receive the larger dose. We conclude that plasma biotin concentration does not reflect biotin status in all cases and speculate that the biotin supplement currently recommended for pediatric patients (20 micrograms/day) may not be adequate therapy for biotin deficiency and might not even be adequate to maintain normal biotin status during TPN.

A patient is described in whom lactic acidosis of very severe degree was found to coincide with the presence of beta-methylcrotonic acid and rho-hydroxyphenyllactic acid in urine in large amounts, while beta-hydroxyisovaleric acid was found to be a relatively minor excretion product. Beta-methylcrotonic acid is demonstrated, for the first time, to be present in blood and CSF. These findings are discussed in relation to the patients previously reported to have beta-methylcrotonylglycinuria and raise the possibility that our patient's organic aciduria may be secondary to acquired disease rather than to an inborn error of metabolism.

Two brothers, aged 7 and 5 years, who excreted large amounts of the leucine metabolites 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid, are described. The excretion of these metabolites could be enhanced by increasing the leucine intake. Restriction of the protein intake resulted in a marked reduction of the metabolite excretion. However, the excretion of the ultimate leucine metabolite, 3-hydroxy-3-methylglutaric acid, remained unchanged at a low level. The only clinical abnormality was speech retardation. A (partial) deficiency of 3-methylglutaconyl coenzyme A hydratase is proposed to be the most likely underlying defect.