Homozygous hypobetalipoproteinaemia and phenylketonuria.

Two patients, aged 0.1 and 2 years, with homozygous hypobetalipoproteinaemia, one with PKU in addition are described. The clinical evaluation showed no neurologic abnormalities. Treatment with a fat-reduced, protein and carbohydrate-enriched diet was combined with vitamin A and E supplementation, according to the suggestions for classical abetalipoproteinaemia. In the patient with PKU the protein intake was increased by using a phenylalanine-free, amino acid mixture. Only by this, were normal growth and weight gain achieved.

Intestinal absorption and renal excretion of biotin in patients with biotinidase deficiency.

We have investigated four patients from three unrelated families with typical clinical and biochemical features of "late-onset" multiple carboxylase deficiency. All patients suffered from biotinidase deficiency (plasma biotinidase activities 1.4%-3% of normal). Intestinal absorption of biotin, measured in three of the patients using a single load of 1.5 micrograms/kg, was found to be normal. Deficient activities of the mitochondrial biotin-dependent carboxylases in lymphocytes of one of these patients increased from 25% of mean basal control values to 33%-36% within 45 min and to 46%-47% within 2 h of the 1.5 micrograms/kg biotin load. After a high biotin load of 100 micrograms/kg, the values normalised within 45 min in all three patients studied. These results indicate normal cellular transport of biotin and normal holocarboxylase synthesis. After cessation of biotin supplementation, the plasma and urinary biotin in patients decreased to subnormal levels. In one patient, available for more detailed studies, both plasma and urinary biotin declined about twice as fast as in controls (apparent half-life 12-14 h in the patient and 26 h in controls). These results point to increased excretion of free biotin in our patient. Renal loss of biotin is one of the factors contributing to the high biotin requirement observed in patients with biotinidase deficiency.

Biotinidase deficiency associated with renal loss of biocytin and biotin.

Clinical and biochemical investigations in six patients with congenital biotinidase deficiency are presented. The time course of biotin depletion in relation to carboxylase activities and clinical onset of symptoms was studied after withdrawal of biotin supplementation. Renal biotin clearance studies were performed in patients and controls. Renal loss of biocytin and biotin itself are shown to be a major cause for the increased biotin requirement in patients with congenital biotinidase deficiency.

Biotinidase deficiency: factors responsible for the increased biotin requirement.

Inability to recycle biotin from endogenous biocytin in congenital biotinidase deficiency is associated with increased requirement of exogenous free biotin. We have observed that severe biotin depletion with clinical and biochemical consequences occurs within 12 days after birth in a newborn patient and within 15-20 days after withdrawal of biotin supplementation in four other patients. Our studies have shown that: Urinary loss of biotin and biocytin are major causes for this rapid biotin depletion. Intestinal absorption of biotin seems to be normal at least at the loading dose of 1.5 micrograms/kg. At normal or subnormal plasma biotin concentrations biocytin is found in low concentrations (below 1 nmol l-1) in plasma of patients but at much higher concentrations in urine (100-600 nmol l-1). An oral load of biocytin results in patients in unchanged biotin levels but in a marked rise of biocytin in plasma followed by rapid renal excretion of biocytin whereas in controls biotin levels in plasma increase rapidly and biocytin remains below detection levels.

Effect of graded biotin levels in the diet on liver pyruvate carboxylase of chicks fed ad libitum and after starvation.

Decreasing levels of biotin in the diet from 200 mug/kg to 0 mug/kg reduced the pyruvate carboxylase activity per g liver and in the whole liver of chicks to 17% of the normal activity. Oral supplementation with 3 mg biotin per chick increased the enzyme activity within 24 hours back to normal. In animals well supplemented with biotin (200 mug/kg diet) 24 hours of starvation increased the per g liver pyruvate carboxylase activity. When the pyruvate carboxylase activities were related to the whole liver, no effect of starvation was found.