MULTIPLE CARBOXYLASE DEFICIENCY - INHERITED AND ACQUIRED DISORDERS OFBIOTIN METABOLISM

Acquired biotin deficiency and the two known congenital disorders of b iotin metabolism, biotinidase and holocarboxylase synthetase (HCS) def iciency, all lead to deficiency of the 4 biotin-dependent carboxylases , i. e. to multiple carboxylase deficiency(MCD). The underlying mechan ism in HCS-deficiency, discovered in 1981, is decreased affinity of HC S for biotin impairing the formation of holocarboxylases at physiologi cal biotin levels. In biotinidase deficiency, discovered in 1983, IMCD results from progressive development of biotin-deficiency due to inab ility to liberate and recycle biotin which is lost in urine as biocyti n. MCD leads to typical organic aciduria and severe life-threatening i llness. Main symptoms and signs are feeding difficulties, neurologic a bnormalities (hypotonia, impaired consciousness, seizures, ataxia) and cutaneous changes (rash, alopecia). However, the clinical presentatio n and age of onset are extremely variable, and organic aciduria may in itially be absent in biotinidase deficiency. Therefore, the definitive diagnosis requires enzyme studies. MCD can be detected in lymphocytes obtained before treatment and biotinidase deficiency is confirmed or excluded by a colorimetric enzyme assay in plasma. Newborn screening f or biotinidase deficiency has resulted in the detection of patients wi th partial deficiency (10-30% of mean normal activity) in addition to patients with profound deficiency (0-10%). Severe illness has been obs erved mainly in patients with 0-activity or a Km-mutation, detection o f which requires detailed investigation. HCS-deficiency has to be conf irmed by enzyme assay in cultured cells. Both congenital disorders res pond clinically and biochemically to oral biotin therapy. Whereas 10 m g/day or less is sufficient to treat profound biotinidase deficiency, the optimal biotin dose for patients with HCS-deficiency must be asses sed individually. The prognosis of both disorders is good if biotin th erapy is introduced early and continued throughout life. However, dela yed commencement of therapy in biotinidase deficiency can result in ir reversible neurological damage, and in HCS-deficiency a few patients h ave responded only partially even to massive biotin doses of up to 100 mg/day.