Multiple carboxylase

Diabetes - insulin dependent Methyl malonic, propionic or isovaleric acidaemias Pyruvate carboxylase and multiple carboxylase deficiency Gluconeogenesis enzyme deficiency glucose-6-phosphatase, fructose-1,6-diphosphatase or abnormality of glycogen synthesis (glycogen synthase) Ketolysis defects Succinyl coenzyme A 3-keto acid transferase ACAC coenzyme A thiolase... 

Methyl crotonylglycine C5 l LEU 3-Methylcrotonyl-CoA carboxylase deficiency Multiple carboxylase deficiency... 

It is important to note that normal plasma biotinidase activity does not exclude that the patient has another cause of multiple carboxylase deficiency (i.e. HCS deficiency or acquired biotin deficiency) [2, 30]. 

Diagnosis of HCS deficiency can be made by showing multiple carboxylase deficiency in skin fibroblasts cultured in low biotin medium but normal or clearly higher activities in high biotin medium [2, 30]. 

Baumgartner ER, Suormala T (1997) Multiple carboxylase deficiency inherited and acquired disorders of biotin metabolism. Int J Vitam Nutr Res 67 377-384... 

Wolf B, Grier RE, Allen RJ, Goodman SI, Kien CL (1983) Biotinidase deficiency the enzymatic defect in late-onset multiple carboxylase deficiency. Clin Chim Acta 131 273-281... 

A closely related disease is caused by a deficiency of propionyl-CoA carboxylase.3 This may be a result of a defective structural gene for one of the two subunits of the enzyme, of a defect in the enzyme that attaches biotin to carboxylases, or of biotinitase, the enzyme that hydrolytically releases biotin from linkage with lysine (Chapter 14). The latter two defects lead to a multiple carboxylase deficiency and to methylmalonyl aciduria as well as ketoacidosis and propionic acidemia. ... 

To determine the type of multiple carboxylase deficiency, blood was obtained to determine the biotin holocarboxylase synthetase activity in leukocytes, and serum was sent to determine the biotinidase activity. The results of the serum biotinidase activity returned first and indicated less than 1% of mean normal serum activity, confirming that the child had profound biotinidase deficiency (less than 10% of mean normal serum biotinidase activity). Subsequently, biotin holocarboxylase synthetase activity was found to be normal. Although many states screen for biotinidase deficiency in the newborn period, this child was bom in a state where newborn screening for biotinidase deficiency is not performed. 

Figure 12-2. Metabolic pathways involving the four biotin-dependent carboxylases. The solid rectangular blocks indicate the locations of the enzymes ACC, acetyl-CoA carboxylase PMCC, P-methylcrotonyl-CoA carboxylase PC, pyruvate carboxylase PCC, propionyl-CoA carboxylase. Isolated deficiencies of the first three carboxylases (mitochondrial) have been established (isolated ACC deficiency has not been confirmed). At least the activities of the three mitochondrial carboxylases can be secondarily deficient in the untreated multiple carboxylase deficiencies, biotin holocarboxylase synthetase deficiency and biotinidase deficiency. Lowercase characters indicate metabolites that are frequently found at elevated concentrations in urine of children with both multiple carboxylase deficiencies. The isolated deficiencies have elevations of those metabolites directly related to their respective enzyme deficiency.

Urinary organic acid analysis is useful for differentiating isolated carboxylase deficiencies from the biotin-responsive multiple carboxylase deficiencies. P-Hydroxyisovalerate is the most common urinary metabolite observed in isolated P-methylcrotonyl-CoA carboxylase deficiency, biotinidase deficiency, biotin holo-carboxylase synthetase deficiency, and acquired biotin deficiency. In addition to P-hydroxy-isovalerate, elevated concentrations of urinary lactate, methylcitrate, and P-hydroxypropionate are indicative of multiple carboxylase deficiency. 

Children with any of the isolated carboxylase deficiencies do not improve with biotin supplementation, whereas those with multiple carboxylase deficiency do. A trial of biotin is often expedient and useful in discriminating between the isolated carboxylase deficiencies and the multiple carboxylase deficiencies. Isolated carboxylase deficiencies can be definitively confirmed by demonstrating deficient enzyme activity of one of three mitochondrial carboxylases in extracts of peripheral blood leukocytes (prior to biotin therapy) or cultured fibroblasts, whereas the activities of the other two carboxylases are normal. 

The organic acid analysis in the urine of this child was consistent with biotin deficiency or multiple carboxylase deficiency. Biotin deficiency usually can be excluded unless there is a history of dietary indiscretion, such as consuming a diet containing raw eggs or few biotin-containing foods, or there is a history of prolonged parenteral hyperalimentation without biotin supplementation. Low serum biotin concentrations can be useful in differentiating... 

The age of onset of symptoms may be useful in discriminating between these two multiple carboxylase deficiencies. Although children... 

Both multiple carboxylase deficiencies are characterized by deficient activities of the three mitochondrial carboxylases in peripheral blood leukocytes prior to biotin treatment. The carboxylase activities increase to near normal or normal after treatment with pharmacological doses of biotin. Patients with biotin holocarboxylase synthetase deficiency have deficient activities of the three mitochondrial carboxylases in fibroblasts incubated in medium with low biotin concentrations (containing only the biotin contributed by fetal calf serum added to the medium for cell growth), whereas patients with biotinidase deficiency have normal carboxylase activities under these conditions. The activities of the carboxylases in biotin holocarboxylase synthetase deficiency become near normal to normal when cultured in medium supplemented with high concentrations of biotin. 

In 1971, a child with biotin-responsive (J-methylcrotonylglycinuria was reported.This individual had metabolic ketoacidosis and elevated concentrations of urinary P-methylcrotonic acid and 5-methylcrotonylglycine. Several days after being given oral biotin, his symptoms resolved, and the urinary metabolites cleared. He subsequently was shown to have deficient activities of all three mitochondrial carboxylases in his peripheral blood leukocytes and skin fibroblasts. This was the first child to be diagnosed with what was called multiple carboxylase deficiency. 

Additional children with multiple carboxylase deficiency were reported. Initially, these children were classified as having either the early-onset form (referred to as the neonatal or infantile form) or the late-onset form (referred to as the juvenile form) of multiple carboxylase deficiency, depending on the age of onset of... 

Two children with the late-onset form initially were reported as having a defect in intestinal transport of biotin. This conclusion was supported by finding low plasma biotin concentrations when these children were administered oral biotin compared to the concentrations of plasma biotin of unaffected control subject. In 1983, it was demonstrated that the primary biochemical defect in most patients with late-onset multiple carboxylase deficiency was a deficiency of serum biotinidase activity. The two children with a putative defect in intestinal biotin transport both were confirmed to have biotinidase deficiency. This disparity was reconciled by demonstrating that, in both cases, the children were biotin depleted at the time the biotin-loading studies were performed. Therefore, when the children initially were given biotin, although the vitamin was transported into the blood normally, it was rapidly taken up... 

Individuals with untreated biotinidase deficiency develop biotin deficiency because they cannot recycle endogenous biotin. The biotin deficiency subsequently results in the lack of substrate for biotin holocarboxylase synthetase. Without the availability of biotin to be added to the apocarboxylases, multiple carboxylase deficiency occurs, and the abnormal metabolites accumulate. 

Holocarboxylase Synthetase Deficiency Genetic deficiency of holocarboxylase synthetase leads to the neonatal form of multiple carboxylase... 

Table 11.1 Abnormal Urinary Organic Acids in Biotin Deficiency and Multiple Carboxylase Deficiency from Lack of Holocarboxylase Synthetase or Biotinidase...

Biotinidase Deficiency Genetic lack of biotinidase results in the late-onset variant of multiple carboxylase deficiency. Patients generally present later in life than those with holocarboxylase synthetase deficiency (Section 11.2.2.1) and have a lower than normal blood concentration of biotin. Culture of fibroblasts in media containing low concentrations of biotin results in normal activities of carboxylases, and holocarboxylase synthetase activity is normal. 

Most dietary biotin is bound to protein, the amide linkage being broken prior to absorption. At least eight children have been described who have multiple carboxylase deficiency with low activities of several of the biotin-requiring carboxylases, i.e., multiple carboxylase deficiency (Table 38-1). Pharmacological doses of biotin restored the activities of the carboxylases in these patients, indicating that the defect was not in the apocarboxylases. Thus, the defect is presumably in the intestinal transport system, in holocarboxylase synthetase, or in some step in cellular uptake or intracellular transport of biotin. 

Multiple carboxylase deficiency Non-ketotic hyperglycinaemia S-Oxoprolinuria Phenylketonuria Propionic acidaemia... 

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