Biotinidase deficiency

Barry Wolf MD PhD (Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.)
Originally released February 7, 1994; last updated January 20, 2020; expires January 20, 2023


The author explains that although all states in the United States and many countries perform newborn screening for biotinidase deficiency, there are still some countries where individuals with the disorder are not identified until they develop major clinical symptoms, some of which are irreversible.

Key points


• Biotinidase deficiency, an inherited neurocutaneous disorder, usually presents during childhood with neurologic symptoms, metabolic acidosis, mild hyperammonemia, and organic aciduria.


• Biotinidase deficiency is readily treated with pharmacological doses of the vitamin biotin.


• Biotinidase deficiency is screened for in most newborn screening programs in the United States and in many other countries.


• Individuals with biotinidase deficiency who are treated since birth do not appear to develop physical or cognitive problems.


• The major difficulty in individuals with biotinidase deficiency is compliance with biotin therapy, especially during adolescence, because most of them have never experienced symptoms.

Historical note and terminology

During the late 1970s, inherited isolated deficiencies of the 3 mitochondrial biotin-dependent carboxylases were described (Wolf and Feldman 1982). These include (1) pyruvate carboxylase, which converts pyruvate to oxaloacetate, the initial step of gluconeogenesis; (2) propionyl-CoA carboxylase, which catabolizes several branched-chain amino acids and odd-chain fatty acids; and (3) beta-methylcrotonyl-CoA carboxylase, which is involved in the catabolism of leucine. Each deficiency is due to a structural abnormality in one of the mitochondrial enzymes, whereas the activities of the other carboxylases are normal. Children with these disorders usually develop neurologic symptoms and metabolic compromise. Each disorder is treated by dietary restrictions but fails to respond to pharmacologic doses of biotin.

There were children who exhibited symptoms similar to those seen in isolated carboxylase deficiencies, had deficient activities of all 3 of the mitochondrial carboxylases, and responded to biotin therapy. In 1971, the first patient with such a disorder was reported as having biotin-responsive beta-methylcrotonylglycinuria (Gompertz et al 1971). This individual had metabolic ketoacidosis and elevated concentrations of urinary beta-methylcrotonic acid and beta-methylcrotonylglycine. Several days after starting oral biotin, his symptoms resolved, and the urinary metabolites cleared. The patient had deficient activity of all 3 mitochondrial carboxylases in his peripheral blood leukocytes and skin fibroblasts (Bartlett and Gompertz 1976; Weyler et al 1977), as well as deficient activity of acetyl-CoA carboxylase in his fibroblasts (Feldman and Wolf 1981). These findings prompted the diagnosis of multiple carboxylase deficiency.

Additional children with multiple or combined carboxylase deficiency were reported. Initially, these patients were classified as having either the early-onset (also referred to as neonatal) or the late-onset (also referred to as infantile or juvenile) form of multiple carboxylase deficiency, depending on the age of onset of symptoms (Sweetman 1981). Most of the patients with the early-onset form had deficient holocarboxylase synthetase activity. Two children with the late-onset form were reported as having transport defects because they exhibited abnormal responses to oral biotin-loading studies (Munnich et al 1981; Thoene et al 1981; Thoene et al 1983). This was supported by reports of 2 patients with low plasma biotin concentrations whose biotin concentrations failed to increase after the patients were administered an oral dose of the vitamin. In 1983, it was shown that the primary biochemical defect in most patients with late-onset multiple carboxylase deficiency was due to deficient activity of serum biotinidase (Wolf et al 1983a). Two patients with presumed intestinal transport defects were subsequently shown to have biotinidase deficiency (Thoene and Wolf 1983). When the tissue concentrations in these children were replete in biotin, their plasma biotin concentrations increased normally in response to a dose of biotin. Since then, more than 100 symptomatic individuals have been reported with biotinidase deficiency. Heterozygote detection, neonatal screening, and prenatal diagnosis of the disorder are possible. Human serum biotinidase has been purified and characterized, and the cDNA that encodes for the enzyme has been sequenced (Cole et al 1994a). A common mutation has been identified in many symptomatic individuals (Pomponio et al 1995).

The content you are trying to view is available only to logged in, current MedLink Neurology subscribers.

If you are a subscriber, please log in.

If you are a former subscriber or have registered before, please log in first and then click select a Service Plan or contact Subscriber Services. Site license users, click the Site License Acces link on the Homepage at an authorized computer.

If you have never registered before, click Learn More about MedLink Neurology  or view available Service Plans.

Find out how you can join MedLink Neurology