Profound biotinidase 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... 

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... 

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. 

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... 

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. 

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... 

Electroencephalographic findings in individuals with untreated profound biotinidase deficiency have ranged from normal to markedly abnormal and are usually nonspecific. Demyelin-ation and other cerebral abnormalities have been seen in some children with biotinidase deficiency. These findings sometimes improve following biotin treatment. 

If the child with profound biotinidase deficiency is symptomatic, then the biochemical abnormalities and seizures resolve rapidly after biotin treatment. This is usually followed by improvement of the cutaneous abnormalities. Hair growth returns over a period of weeks to months in the children with alopecia. Optic atrophy and hearing loss are usually resistant to therapy, especially if several months have elapsed between the time of diagnosis and the initiation of treatment. Some treated children have rapidly regained lost developmental milestones, whereas others have continued to show deficits. 

Some children with profound biotinidase deficiency exhibit symptoms, such as seizures, but do not have metabolic acidemia or elevations of the characteristic organic acids in their plasma or blood. What is a possible explanation for this observation ... 

I omponio, R. J., Reynolds, T. R Mandel, H., Admoni, O., MeJone, F, Buck, G. A., and Wolf, B, (1997). Profound biotinidase deficiency caused by point mutation that creates a downstream ciyptLc 3 splice acceptor site within an exon of the human biotinidase gene. Huftmts Mol. Genet. 6,739-745. 

Pindolia, K., Jordan, M., Guo, C., Matthews, N., Mock, D.M., Strovel, E., Blitzer, M., and Wolf, B., 2011. Development and characterization of a mouse with profound biotinidase deficiency a biotin-responsive neurocuta-neous disorder. Molecular Genetics and Metabolism. 102 161-169. 

Children with profound biotinidase activity have less than 10% of mean normal serum enzyme activity. Deficient biotinidase activity has also been demonstrated in extracts of leukocytes and fibroblasts. At least one patient was shown to have deficient biotinidase activity in his liver. More than 300 symptomatic individuals have been reported with biotinidase deficiency. The parents of these children usually have serum enzyme activities intermediate between those of the patients and those of normal individuals. 

Heterozygous individuals usually have intermediate enzyme activity, especially in families with a profound deficiency, with some overlap with the normal range. Thus, biotinidase activity with 0.15 mM substrate was within the normal range in 6 (5%) out of 117 parents from families with a profound deficiency, and in 15 (20%) out of 75 parents from families with a partial deficiency. 

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