Development and characterization of a mouse with profound biotinidase deficiency: a biotin-responsive neurocutaneous disorder

Mol Genet Metab. 2011 Feb;102(2):161-9. doi: 10.1016/j.ymgme.2010.10.005. Epub 2010 Oct 13.


Biotinidase deficiency is the primary enzymatic defect in biotin-responsive, late-onset multiple carboxylase deficiency. Untreated children with profound biotinidase deficiency usually exhibit neurological symptoms including lethargy, hypotonia, seizures, developmental delay, sensorineural hearing loss and optic atrophy; and cutaneous symptoms including skin rash, conjunctivitis and alopecia. Although the clinical features of the disorder markedly improve or are prevented with biotin supplementation, some symptoms, once they occur, such as developmental delay, hearing loss and optic atrophy, are usually irreversible. To prevent development of symptoms, the disorder is screened for in the newborn period in essentially all states and in many countries. In order to better understand many aspects of the pathophysiology of the disorder, we have developed a transgenic biotinidase-deficient mouse. The mouse has a null mutation that results in no detectable serum biotinidase activity or cross-reacting material to antibody prepared against biotinidase. When fed a biotin-deficient diet these mice develop neurological and cutaneous symptoms, carboxylase deficiency, mild hyperammonemia, and exhibit increased urinary excretion of 3-hydroxyisovaleric acid and biotin and biotin metabolites. The clinical features are reversed with biotin supplementation. This biotinidase-deficient animal can be used to study systematically many aspects of the disorder and the role of biotinidase, biotin and biocytin in normal and in enzyme-deficient states.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Biotin / metabolism
  • Biotin / pharmacology*
  • Biotin / therapeutic use
  • Biotin / urine
  • Biotinidase / blood
  • Biotinidase / metabolism
  • Biotinidase Deficiency / drug therapy
  • Biotinidase Deficiency / genetics*
  • Biotinidase Deficiency / metabolism*
  • Body Weight / drug effects
  • Body Weight / genetics
  • Diet
  • Disease Models, Animal*
  • Female
  • Gene Expression Regulation, Enzymologic / genetics
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurocutaneous Syndromes / drug therapy
  • Neurocutaneous Syndromes / enzymology*
  • Neurocutaneous Syndromes / genetics
  • Vitamin B Complex / metabolism
  • Vitamin B Complex / pharmacology*
  • Vitamin B Complex / therapeutic use
  • Vitamin B Complex / urine


  • Vitamin B Complex
  • Biotin
  • Biotinidase