An unusual clinical course of a patient with biotinidase deficiency, causing Leigh syndrome, is reported. Laryngeal stridor was the major presenting symptom followed by progressive neurologic deterioration and death at the age of 21.5 mo. Absence of skin and hair abnormalities as well as of organic aciduria delayed the correct diagnosis. Necropsy revealed subacute necrotizing encephalopathy (Leigh syndrome). Carboxylase activities (propionyl CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, pyruvate carboxylase) measured in lymphocytes 1 day before death were decreased to 10% of normal values. Propionyl-CoA carboxylase was shown to be the only stable carboxylase in human postmortem tissue; in our patient it was moderately decreased in postmortem liver (29% of control) and kidney (42%), but severely decreased in brain (3%). These findings might explain the severity of neurological symptoms in the absence of marked organic aciduria. They indicate that in biotinidase deficiency the CNS may become biotin depleted earlier and more severely than other organs. Biotinidase deficiency should be included in the differential diagnosis of Leigh syndrome and of unexplained respiratory problems.