Multiple Carboxylase Deficiency Research Articles

Biotin Transport in the Rat Central Nervous System.

Previous studies in the biotin-deficient rat have shown that brain biotin concentrations and the activity of biotin-dependent carboxylases are relatively preserved in the face of biotin starvation and systemic biotin deficiency. These data suggested the existence of a concentration mechanism for biotin in brain, and the present studies were undertaken to further characterize brain biotin transport. We presently show that rat cerebrospinal fluid biotin concentrations are 2.5 times higher than serum concentrations, consistent with the existence of a concentrative mechanism for biotin. Further, we demonstrate uptake of 3H-biotin into rat brain from blood at physiologic biotin concentrations, using single pass clearance measurements of a brain uptake index. The calculated brain uptake indices for biotin, and the inhibition kinetics, are consistent with the possible existence of a low affinity mediated uptake mechanism. The results have implications for the pathophysiology of human biotin-responsive multiple carboxylase deficiency.

Neonatal screening for biotinidase deficiency in East‐Hungary

There are two types of multiple carboxylase deficiency, the neonatal form with holocarboxylase synthetase defect and the late-onset form with biotinidase deficiency. We report our preliminary experiences in screening for biotinidase deficiency. In total 43,493 infants were screened for the deficiency of the enzyme biotinidase; 0.14% false positive results that necessitated requests for second blood samples and two newborns with a biotinidase defect were identified during our pilot study. The definitive diagnosis required the demonstration of enzyme deficiency in serum. Both of the patients have residual biotinidase activity: 3.59% and 7.55%. These two newborns with biotinidase deficiency are treated with daily supplementation of free biotin. According to our preliminary results biotinidase deficiency satisfies all the criteria for incorporation into the national newborn mass screening.

Fatty acid transport in multiple carboxylase deficiency fibroblasts

Holocarboxylase synthetase (HS) and biotinidase deficiencies have been identified as causes of biotin-responsive multiple carboxylase deficiency. Acetyl-CoA carboxylase (ACC) deficiency has been shown to occur in multiple carboxylase deficiency, and HS(-) fibroblasts are being employed to investigate compensatory regulatory responses in cells deficient in ACC. In previous studies, biotin starved HS(-) fibroblasts showed a reduced fatty acid content, an abnormal percentage composition of fatty acids, and a preservation of longer-chain fatty acid contents of cells. We herein ask whether the mutant cells show compensatory increases in the transport of longer-chain fatty acids from the medium into fibroblasts. In the present experiments there was no change in the uptake of arachidonate, palmitate or oleate following growth of mutant and control fibroblasts in (+) or (-) biotin conditions. Differential fatty acid uptake from the medium is therefore not a compensatory mechanism in HS(-) cells, and cannot account for the specific changes in fatty acid composition produced by biotin restriction.

Nutritional therapy for selected inborn errors of metabolism.

Nutritional approaches are available for the management of several different classes of inborn metabolism errors. In phenylketonuria (PKU), phenylalanine is not properly metabolized; and its accumulation leads to neurologic dysfunction and metal retardation. Altering the diet to limit phenylalanine intake led to remarkable improvement in children with PKU. It was later found that instituting dietary therapy immediately after identification of the disorder in newborns prevented mental retardation. Throughout the 1960s nutritional therapies were found for other inborn disorders, including galactosemia, maple syrup urine disease, and homocystinuria. For the group of disorders associated with defects in the urea cycle, leading to profound hyperammonemia, therapy based on the concept of waste nitrogen excretion (i.e., by increasing excretion of urea cycle intermediates in the urine, nitrogen that would otherwise recycle as ammonia can be eliminated) dramatically produced better control of hyperammonemia and its consequences. Some inborn errors of metabolism respond to vitamin therapy. Biotin-related multiple carboxylase synthetase deficiency can be produced by either of two enzyme defects--holocarboxylase synthetase deficiency or biotinidase deficiency. Both are treatable with biotin supplementation. The symptoms of multiple carboxylase deficiency can also occur after intestinal resection or ingestion of raw eggs. Multiple carboxylase deficiency has been treated successfully in utero by giving the mother biotin supplements. Peroxisomal disorders may respond to dietary management. Liver disease in hereditary tyrosinemia may be accentuated by hypermethioninemia and treated by controlling the blood methionine level. Glycogen storage disease Type I, which causes hypoglycemia, can be controlled by oral administration of cornstarch.

Comparison of patients with complete and partial biotinidase deficiency: Biochemical studies

Seventeen partially biotinidase-deficient patients detected by neonatal screening or family studies were compared with four patients with classical biotinidase deficiency. Using a sensitive HPLC method for biotinidase in plasma (substrate: biocytin) the patients could be divided into two groups: one with residual biotinidase activity, and the second with undetectable biotinidase activity (0-activity). Biocytin excretion, characteristically elevated in 0-activity patients, decreased rapidly with increasing residual biotinidase activity and was almost normal when residual activity exceeded 2-3% of mean normal. In one patient with classical disease (0-activity) biotin deficiency, typical organic aciduria and multiple carboxylase deficiency were found as early as at the second week of life. In contrast, 13 infants with residual activities from 1.2% to 23% had no remarkable clinical or biochemical abnormalities. However, in three 5-, 14- and 15-year-old healthy siblings with residual biotinidase activities between 2.3% and 4.2%, biotin deficiency was proven by decreased activities of the mitochondrial carboxylases in lymphocytes (30-57% of mean normal) and, in the older siblings, also by subnormal plasma biotin concentrations. In biotinidase deficiency, biotin depletion presumably occurs earlier in the brain than in other tissues and may thus first affect the central nervous system. For this reason and because of discrete biochemical abnormalities found in a patient with residual biotinidase activity of 8%, we suggest that at least all patients with residual activities below 10% should be treated with biotin.

Biotin-responsive multiple carboxylase deficiency and immunodeficiency.

Biotin-responsive multiple carboxylase deficiency and immunodeficiency.

Abnormal fatty acid composition of biotin‐responsive multiple carboxylase deficiency fibroblasts

Clinical and biochemical correlations in the biotin-responsive multiple carboxylase deficiencies have suggested that disordered lipogenesis plays a role in the pathogenesis of the disease. In particular, the activity of biotin-dependent acetyl CoA carboxylase and the de novo synthesis of fatty acids are reduced in mutant fibroblasts. In the present work, we examine the biochemical consequences of these deficiencies, and document and characterize an abnormal fatty acid composition in holocarboxylase synthetase deficiency fibroblasts. Following growth in biotin-restricted medium, the total fatty acid content of mutant cells is reduced. There were significant reductions in the percentage as 16:0, 18:0 and 20:3N9 fatty acids, with the proportion of longer-chain fatty acids either increased or maintained at control levels. The cellular content of 16:0, 16:1, 18:0, 18:1 and 20:3N9 fatty acids was reduced, while that of the longer-chain fatty acids was preserved at control levels in mutant cells deprived of biotin. We speculate that the components of the altered fatty acid pools may be disproportionately incorporated into complex lipids in mutant cells, with pathologic effects on the multiple carboxylase deficiency phenotype.

Results of neonatal and selective screening for biotinidase deficiency

Biotinidase deficiency (Wolf et al., 1983a) is the primary enzyme defect in 'late onset' multiple carboxylase deficiency (McKusick 25327). Biotinidase (EC 3.5.1.12) catalyses the cleavage of biotin from biocytin (e-N-biotinyl-L-lysine) or biotinyl peptides, the products of carboxylase degradation. This inherited autosomal recessive disorder usually appears during childhood with cutaneous and neurological manifestations. If diagnosed early, the disorder can be treated effectively with physiological doses of biotin. Here we present the results of the neonatal and selective screening for biotinidase deficiency that we have conducted in our centre from September 1985 to June 1986.

Pyruvate carboxylase responsive to ketosis in a multiple carboxylase deficiency patient

Pyruvate carboxylase responsive to ketosis in a multiple carboxylase deficiency patient

Effect of biotin deficiency and supplementation on lipid metabolism in rats: cholesterol and lipoproteins

The effect of biotin deficiency and supplementation upon tissue cholesterol and serum lipoprotein profile in rats was investigated. Biotin-dependent carboxylases in liver of deficient animals were decreased to 12–27% of control activity. The brain carboxylase activities of deficient rats were reduced less than in liver. The total, free, and esterified cholesterol were decreased in the serum of deficient rats compared to those in control or supplemented rats. Deficient rats had increased serum low-density lipoprotein fractions and decreased very low-density lipoprotein fractions, but no change in the high-density lipoprotein fractions. No differences were found between groups in the cholesterol content of liver, cerebrum, or cerebellum. Pharmacologic doses of biotin had no effect on tissue cholesterol content or serum lipoprotein profile. These results suggest that the neurologic symptoms in biotin deficiency and in the inherited multiple carboxylase deficiencies are not due to alterations in the content of cholesterol or lipoproteins.

Multiple carboxylase deficiency due to deficiency of biotinidase

A patient with biotinidase deficiency was studied in whom the first admission to hospital for acidosis occurred at 5 years of age. Sensorineural abnormalities of the optic and auditory nerves antedated diagnosis and treatment with biotin, and these sensory losses did not resolve with treatment. The other clinical manifestations of the disease were highly responsive to biotin. Biotinidase was assayed using 14C-labeled natural substrate. The activity in the patient approximated 1% of the control level.

Biotinidase deficiency: initial clinical features and rapid diagnosis.

Biotinidase deficiency is the primary defect in most individuals with late-onset multiple carboxylase deficiency. We have reviewed the presenting clinical features of 31 children with the disorder. Seizures, either alone or with other neurological or cutaneous findings, are the most frequent initial symptom observed. Other neurological symptoms, such as hypotonia, ataxia, hearing loss, optic atrophy, and developmental delay, are seen, in addition to skin rash and alopecia. The disorder is also characterized by ketolactic acidosis and organic aciduria. Biotinidase activity may be diagnosed using a simple, rapid, semiquantitative colorimetric procedure. Samples of whole blood spotted on the same filter paper used by most states to screen for phenylketonuria and other inborn errors of metabolism may be sent to an appropriate reference laboratory. None of the common anticonvulsants or sedatives used to treat newborns and children interfere with the test. Because biotinidase deficiency can be treated readily with biotin, this disorder should be considered in children with infantile seizures, especially in the presence of other characteristic neurological or cutaneous features.

Prenatal Treatment of Biotin‐responsive Multiple Carboxylase Deficiencya

The prenatal diagnosis and prenatal treatment of a fetus with the neonatal-onset variant of biotin-responsive multiple carboxylase deficiency are described. Pre-amniocentesis maternal urinary organic-acid profiles were normal. Amniotic-fluid methylcitrate (17 weeks' gestation) was ten standard deviations above the control mean. Amniotic-fluid-cell propionyl CoA carboxylase, pyruvate carboxylase, and 3-methylcrotonyl CoA carboxylase activities were indistinguishable from activities in controls after cell growth in biotin-supplemented media. In contrast, growth in biotin-restricted media resulted in carboxylase activities significantly below control values. The fetus was considered to be affected, and the mother was begun on oral biotin at 231/2 weeks' gestation. The full-term baby girl exhibited no clinical or chemical aberrations during the first 4 days of life, before the start of postnatal biotin supplementation. Cord-blood biotin was 34 times the upper normal neonatal concentration. The diagnosis was confirmed by carboxylase assays on cultured skin fibroblasts obtained after birth; by slightly raised urinary organic-acid levels later in infancy; and by demonstration of· fibroblast holocarboxylase synthetase with an elevated Km(biotin) and a depressed Vmax. Growth and development of the baby have been normal to age 11/4 years on oral biotin. The prenatal diagnosis of neonatal-onset biotin-responsive multiple carboxylase deficiency can be made by means of enzymatic studies of amniotic-fluid cells. Amniotic-fluid methylcitrate should be a useful adjunct to enzymatic studies. Prenatal treatment was effective in our patient, and there was no apparent toxicity to mother or baby from biotin supplementation during the last 16 weeks of pregnancy.

Prenatal treatment of multiple carboxylase deficiency.

Annals of the New York Academy of SciencesVolume 447, Issue 1 p. 263-271 Prenatal Treatment of Multiple Carboxylase Deficiency KARL S. ROTH, KARL S. ROTH Department of Pediatrics Medical College of Virginia Richmond, Virginia 23298Search for more papers by this author KARL S. ROTH, KARL S. ROTH Department of Pediatrics Medical College of Virginia Richmond, Virginia 23298Search for more papers by this author First published: June 1985 https://doi.org/10.1111/j.1749-6632.1985.tb18444.xCitations: 9AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume447, Issue1BiotinJune 1985Pages 263-271 RelatedInformation

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: a novel vitamin recycling defect.

The recent finding that biotinidase deficiency is the primary biochemical defect in late-onset multiple carboxylase deficiency was stimulated new interest in the inherited disorders of biotin-dependent carboxylases. The clinical and biochemical features of biotinidase deficiency are discussed. We also speculate about two exciting areas currently being investigated: the localization of action biotinidase, and the possible role of the enzyme as a binding or carrier protein for biotin.

Rapid differential diagnosis of carboxylase deficiencies and evaluation for biotin-responsiveness in a single blood sample

We have developed a method for rapid differential diagnosis of isolated or multiple deficiencies of the 3 mitochondrial biotin-dependent carboxylases: propionyl-CoA (PCC), 3-methylcrotonyl-CoA (MCC) and pyruvate carboxylase (PC), and for simultaneous evaluation of biotin-responsiveness using a single blood sample. Lymphocytes were isolated from heparinized blood and preincubated without and with 10 −5 mol/1 biotin in medium before determination of PCC, MCC and PC activities. Plasma was used for estimation of biotin concentration and biotinidase activity. A definitive diagnosis could be made in 7 of 9 patients studied up to now: 4 patients suffered from biotin-nonresponsive isolated PCC-deficiency, and 3 patients from biotin-responsive multiple carboxylase deficiency caused by deficient biotinidase activity. In two patients, a carboxylase deficiency was excluded. These results were confirmed in studies using fibroblasts. In addition, a simple method for detection of deficiency in holocarboxylase synthesis is described.

Lipid metabolism in biotin‐responsive multiple carboxylase deficiency

Journal of Inherited Metabolic DiseaseVolume 8, Issue 4 p. 184-186 Article Lipid metabolism in biotin-responsive multiple carboxylase deficiency M. del C. Gonzalez-Rios, M. del C. Gonzalez-Rios Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, 94143 USA Division of Genetics, Department of Pediatrics, University of Puerto Rico, San Juan, PR, 00936 USASearch for more papers by this authorS. C. Whitney, S. C. Whitney Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, 94143 USASearch for more papers by this authorM. L. Williams, M. L. Williams Department of Dermatology, University of California, San Francisco, CA, 94143 USASearch for more papers by this authorP. M. Elias, P. M. Elias Department of Dermatology, University of California, San Francisco, CA, 94143 USASearch for more papers by this authorS. Packman, S. Packman Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, 94143 USASearch for more papers by this author M. del C. Gonzalez-Rios, M. del C. Gonzalez-Rios Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, 94143 USA Division of Genetics, Department of Pediatrics, University of Puerto Rico, San Juan, PR, 00936 USASearch for more papers by this authorS. C. Whitney, S. C. Whitney Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, 94143 USASearch for more papers by this authorM. L. Williams, M. L. Williams Department of Dermatology, University of California, San Francisco, CA, 94143 USASearch for more papers by this authorP. M. Elias, P. M. Elias Department of Dermatology, University of California, San Francisco, CA, 94143 USASearch for more papers by this authorS. Packman, S. Packman Department of Pediatrics, Division of Genetics, University of California, San Francisco, CA, 94143 USASearch for more papers by this author First published: 29 October 1984 https://doi.org/10.1007/BF01805432Citations: 5 Division of Genetics, Department of Pediatrics, University of California, San Francisco, CA 94143, USA AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume8, Issue4December 1985Pages 184-186 RelatedInformation

CELLULAR IMMUNODEFICIENCY IN BIOTIN DEFICIENT RATS

Biotin dependent multiple carboxylase deficiency, an inborn error of metabolism is associated with many clinical and laboratory abnormalities including combined immunodeficiency. We studied biotin dependent carboxylase activities and lymphocyte responses to a T cell mitogen (Con A) in biotin deficient (DEF) and biotin supplemented (CNT) pair fed Sprague-Dawley rats. Body and liver weights after 10 weeks on the deficient diet were 275 ± 25 gms. and 8.1 ± 1.4 gms. respectively for the DEF rats and 267 ± 21 and 7.4 ± 1.3 for the CNT rats. Lymphocyte Con A responses were normal in thymus (T) and spleen (S) but significantly lower (p <.01) in lymph nodes (LN) from DEF rats:Propionyl-CoA (PCC) and pyruvate (PC) carboxylase activities in DEF livers were 20% and 15% of CNT livers respectively. PCC in lymphocytes from T, S, and LN from DEF rats were 6%, 55% and 88% of CNT respectively. These results indicate: 1) T cell mitogen responses are most susceptible to biotin deficiency in the more differentiated LN; 2) PCC activity is most affected by biotin deficiency in the less differentiated T and is not the cause of depressed Con A responses by biotin deficient LN. It is possible that biotin metabolism and/or the role of biotin dependent carboxylases in lymphocytes changes with maturation and could explain the differential susceptibility of lymphocytes to the biotin deficient state.

Different organic acid patterns in urine and in cerebrospinal fluid in a patient with biotinidase deficiency.

Multiple carboxylase deficiency (MCD) is characterized by decreased activities of the biotin-dependent carboxy-lases and a specific urinary organic acid pattern. The early-onset form is due to a defect of holocarboxylase-synthetase (Sweetman, 1981) while deficient biotinidase activity leads to the late-onset form (Wolf et al., 1983). Both forms are responsive to administration of biotin in pharmacological dosage. We report preliminary results of original studies carried out on the cerebrospinal fluid (CSF) of a new case of biotinidase-deficient MCD.KeywordsPyruvate CarboxylaseDeficient BiotinidaseBiotinidase ActivityPyruvate Carboxylase ActivityCentral Nervous System LevelThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.