Biotinidase deficiency
Biotinidase deficiency Biotin is a cofactor for four mammalian carboxylases. Common to these are the incorporation and recycling of their biotin component by two other enzymes, holocarboxylase synthetase and biotinidase. Deficiency of one of these two enzymes leads to functional deficiency of all the carboxylases. Holocarboxylase synthetase deficiency usually presents before 3 months of age, and that of biotinidase at a later age, both with profound metabolic effects (Barth 1996).
Seizures occur in a small proportion of the early-onset synthetase-deficient patients, but in most of the bio- tinidase-deficient late-onset patients seizures are the presenting feature and the main neurological problem. These fits, although initially resistant to treatment, may later improve spontaneously (Wolf et al 1983). Later the children may develop other neurological features, with hypotonia, ataxia and progressive regression, together with alopecia and a characteristic skin rash. Unfortunately these latter helpful clinical signs only develop in a minority of patients (Collins et al 1994), so that their absence should not allay suspicion of the diagnosis.
Biotinidase deficiency is a treatable cause of severe neurological problems, since treatment with biotin is effective, although late complications may develop, including deafness and optic atrophy. In the large series of Salbert et al (1993) biotin therapy stopped the seizures within 24 hours in 12 of 16 children in whom anticonvulsant treatment had failed. Interestingly, multivitamin preparations given without a specific diagnosis, may contain enough biotin to suppress symptoms (Diamantopoulos et al 1986), a potential cause of diagnostic delay.
Biotinidase deficiency should also be considered in older children with progressive neurological deterioration. A variant has been described presenting with acute loss of vision at the age of 10 years. Progressive bilateral optic neuropathy, spastic paraparesis and a mainly motor neuropathy developed over the next 5 years (Ramaekers et al 1992). After 6 months' treatment with oral biotin (10 mg/d), the scotomata regressed, the pyramidal signs in the legs disappeared, and further progression of the neuropathy ceased. The authors conclude that the differential diagnosis of unexplained juvenile onset bilateral optic neuropathy, especially when associated with upper and lower motor neuron disease, should include biotinidase deficiency.
Biotinidase can be measured in plasma, avoiding the need for potentially dangerous loading or fasting studies.
The pathology of biotinidase deficiency is similar to that of Leigh's syndrome, and may be as destructive (Honavar et al 1992).
