Deficiency biotinidase

1 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. 

The problem is a functional deficiency of biotin, due both to inability to release free biotin from dietary biocytin and also to failure of the normal recovery of free biotin by biotinidase action on the biocytin released by proteolysis of biotin-containing enzymes. Normal intakes of biotin are inadequate to meet the requirements of these patients the provision of pharmacological doses of free biotin provides an adequate amount to meet requirements without the need for reutUization. The delayed development of clinical and biocheimcal abnormalities is a result of the accumulation of biotin by the fetus, so that at birth the infant has adequate stores of the vitamin. 

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C5-OH 3-Hydroxy isovaleryl- Biotinidase deficiency, HMG deficiency, MCC deficiency, MCD deficiency, MGA deficiency... 

Patients with complete biotinidase deficiency usually present between 3 and 6 months of age, but severe illness has already been noted at the 2nd and 3rd week of life [9]. On the contrary, patients defined as having profound biotinidase deficiency, who have levels of residual activity as low as 1-3%, may never develop obvious clinical symptoms [17, 33], but may suffer from moderate biotin deficiency when carefully evaluated [25]. Biotin deficiency can be effectively avoided by oral... 

The natural substrate of biotinidase is biocytin, but it also readily cleaves an amine bond between biotin and a variety of different compounds, allowing the use of artificial substrates for the quantitation of biotinidase activity. The most common method is the colorimetric assay described by Knappe and coworkers in 1963 [14, 32], which uses biotinyl-p-aminobenzoic acid (B-PABA) as substrate. The assay of plasma biotinidase activity by this method allows rapid detection of individuals with biotinidase deficiency. 

Since the colorimetric assay is inexpensive, reproducible and easy to perform, and can be adapted to detect biotinidase Km variants [26], we recommend the use of this assay for routine determination of biotinidase activity in plasma and describe here its use for diagnosis of patients with different forms of biotinidase deficiency. 

In addition to its hydrolase activity with maximal velocity at acidic pH, biotinidase also possesses biotinyl-transferase activity at physiological pH, resulting in the biotinylation of nucleophilic compounds such as histones [13]. This activity may play an important role in the regulation of gene expression [30]. Both hydrolase and transferase activities are affected in patients with biotinidase deficiency [13]. 

Table 3.7.2 Biotinidase activity in plasma from normal subjects, patients with different forms of biotinidase deficiency and in obligate heterozygotes (parents) measured at 30°C by colorimetric assay using two different substrate concentrations. Km Michaelis-Menten constant, n number of individuals ... 

Activities obtained in plasma of (1) patients with profound biotinidase deficiency (less than 10% residual activity), (2) subjects with partial biotinidase deficiency (10-30% residual activity), (3) some of their parents (obligate heterozygotes) and (4) individual patients with a biotinidase Km defect are also shown in Table 3.7.2. Patients with complete biotinidase deficiency defined by assay with a sensitive HPLC method... 

Patients with HCS deficiency (MIM 253270) can show severe illness very early, within the first hours or days of life, but they can also present later with clinical findings similar to those seen in biotinidase deficiency. The majority of HCS-defi-cient patients show reduced affinity of HCS for biotin and respond well to oral biotin therapy, but usually require higher doses (20-100 mg/day) than are required for biotinidase deficiency. A few patients respond only partially to high-dose biotin therapy... 

Blood samples collected shortly after blood transfusions can contain significant levels of biotinidase activity in patients with biotinidase deficiency. 

Family studies often reveal older siblings or parents with partial or profound biotinidase deficiency [17, 25, 33]. These individuals are usually asymptomatic but may suffer from moderate biotin deficiency [23] and might benefit from biotin therapy. Therefore, all family members should be investigated. 

Haagerup A, Andersen JB, Blichfeldt S, Christensen ME (1997) Biotinidase deficiency two cases of very early presentation. Dev Med Child Neurol 39 832-835... 

Heard GS, Secor McVoy JR, Wolf (1984) A screening method for biotinidase deficiency in newborns. Clin Chem 30 125-127... 

Heard GS, Wolf B, Jefferson LG, Weissbecker KA, Nance WE, Secor McVoy JR, Napolitano A, Mitchell PL, Lambert FW, Linyear AS (1986) Neonatal screening for biotinidase deficiency results of a 1-year pilot study. J Pediatr 108 40-46... 

Hymes J, Fleischhauer K, Wolf (1995) Biotinylation of histones by human serum biotinidase assessment of biotinyl-transferase activity in sera from normal individuals and children with biotinidase deficiency. Biochem Mol Med 56 76-83... 

Moslinger D, Stockler-Ipsiroglu S, Scheibenreiter S, Tiefenthaler M, Miihl A, Seidl R, Strobl W, Plecko B, Suormala T, Baumgather ER (2001) Clinical and neuropsychological outcome in 33 patients with biotinidase deficiency ascertained by nationwide newborn screening and family studies in Austria. Eur J Pediatr 160 277-282... 

Santer R, Gokcay G, Demirkol M, Gal A, Lukacs Z (2005) Hyperchylomicronaemia due to lipoprotein lipase deficiency as a cause of false-positive newborn screening for biotinidase deficiency. J Inherit Metab Dis 28 137-140... 

Suormala TM, Baumgartner ER, Bausch J, Holick W, Wick H (1988) Quantitative determination of biocytin in urine of patients with biotinidase deficiency using high-performance liquid chromatography (HPLC). Clin Chim Acta 177 253-270... 

Suormala TM, Baumgartner ER, Wick H, Scheibenreiter S, Schweitzer S (1990) Comparison of patients with complete and partial biotinidase deficiency biochemical studies. J Inherit Metab Dis 13 76-92... 

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... 

Wolf B, Norrgard KJ, Pomponio RJ, Mock DM, McVoy JRS, Fleischhauer K, Shapiro S, Blitzer MG, Hymes J (1997) Profound biotinidase deficiency in two asymptomatic adults. Am J Med... 

Wolf B, Secor McVoy J (1983) A sensitive radioassay for biotinidase activity deficient activity in tissues of serum biotinidase-deficient individuals. Clin Chim Acta 135 275-281... 

Biotin is a cofactor of various carboxylases, but its effectiveness in pyruvate carboxylase deficiency is unproven. However, it has been used effectively in cases of biotinidase deficiency, a vary rare cause of congenital lactic acidosis. 

Figure 12-1. A child with biotinidase deficiency (A) prior to diagnosis and therapy and (B) after several months of biotin treatment.

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. 

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. 

Biotinidase deficiency and biotin holocarboxylase synthetase deficiency can be definitively diagnosed by direct enzymatic assay. Biotinidase activity in plasma or serum is usually determined by using the artificial substrate, biotinyLp-aminobenz< >ate. If biotinidase activity is present, then biotin is cleaved, releasing jD-aminobenzoatc. The / -aminobenzoate then is reacted with reagents that result in the development of purple color that can be quantitated colorimetrically. In the absence of biotinidase activity,/ -aminobenzoate is not liberated. Biotinidase activity in patients with an isolated carboxylase deficiency or biotin holocarboxylase synthetase deficiency is normal. 

Plasma biotin concentrations may be deficient in patients with biotinidase deficiency, but also can be normal prior to therapy. Again, it is important to be certain that the method used to determine the biotin concentration measures free biotin and does not also measure biotin derivatives, such as biocytin. 

The age of onset of symptoms of children with profound biotinidase deficiency varies from several months to 10 years old, with a mean age of presentation between 3 and 6 months old. The most common neurological features of this disorder are seizures, hypotonia, and ataxia. Myoclonic seizures are the most... 

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