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Results for “Multiple Carboxylase Deficiency”

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PubMed1996

[Cloning of the holocarboxylase synthetase cDNA and identification of mutations prevalent in Japanese HCS-deficient patients].

Holocarboxylase synthetase (HCS) plays an essential role in biotin utilization in cells and its deficiency causes biotin-responsive multiple carboxylase deficiency in humans. We have cloned the human HCS cDNA, which maps to chromosome 21q22.1. Two mutations in the HCS genes of Japanese patients with HCS deficiency have been identified: a transition from T to C which causes an amino acid substitution of proline for leucine at position 237 (L237P) and A single guanine base deletion (delta G1067) followed by premature termination. Transient expression in cultured fibroblasts from a patient after site-directed mutagenesis showed that the L237P mutation was responsible for decreased HCS activity. Hybridization analysis using allele-specific oligonucleotide probes demonstrated that the prevalence of the mutations--L237P and delta G1067--was 50% and 30%, respectively, among Japanese patients with HCS deficiency.

Amino Acid Sequence↗

PubMed1986

[Results of a pilot study of neonatal screening for congenital biotinidase deficiency].

Biotinidase activity was determined in a pilot study of 78,000 dried blood samples on filter paper. In the assay the liberation of p-aminobenzoic-acid from biotinyl-p-aminobenzoic-acid by biotinidase is tested. One boy was identified to be with biotinidase deficiency. Transient reduction of biotinidase activity to virtually negative test results was observed in 8 preterm babies (recall: 0,01%). Specificity and sensitivity of the test were nearly 100%. We suggest that screening for biotinidase deficiency should be incorporated into existing neonatal screening programs for inborn errors of metabolism. This suggestion is based on the ease of testing, the necessity for presymptomatic laboratory diagnosis, and on the effectiveness of early treatment of the multiple carboxylase deficiency caused by defective biotinidase.

Amidohydrolases↗

PubMed1985

Pyruvate carboxylase deficiencies: complementation studies between "French" and "American" phenotypes in cultured fibroblasts.

Pyruvate carboxylase (PC) deficiencies (McKusick 26615) are heterogeneous clinically and biochemically. We performed a complementation study with fibroblast strains from seven patients, (four patients with "French" phenotype, two patients with "American" phenotype, one patient with biotin responsive multiple carboxylase deficiency, MCD). The six isolated pyruvate carboxylase mutants (two cross-reacting material CRM -ve and four CRM +ve) failed to complement each other, but did complement a form of biotin responsive MCD.

Amino Acid Metabolism, Inborn Errors↗

PubMed1980

Evidence for two genetic complementation groups in pyruvate carboxylase-deficient human fibroblast cell lines.

We have examined genetic complementation in pyruvate carboxylase deficiency by comparing the enzyme activity in polyethylene glycol-induced heterokaryons with that in unfused mixtures of fibroblasts from three affected children. Complementation, manifested as a three- to sevenfold increase in pyruvate carboxylase activity, was observed in fusions between a biotin-responsive multiple carboxylase (pyruvate carboxylase, propionyl CoA carboxylase, and beta-methylcrotonyl CoA carboxylase) deficient fibroblast line and two other lines deficient only in pyruvate carboxylase activity. Kinetic analysis of complementing pyruvate carboxylase deficient lines, measured by the rate of restoration of enzyme activity as a function of time, revealed that maximum restoration was achieved within 10-24 hr after fusion. This profile is similar to those oberved for fusions between the multiple carboxylase deficient line and two lines deficient in propionyl CoA carboxylase activity that are known to represent different gene mutations. Although the patients with pyruvate carboxylase deficiency had similar clinica findings, our studies indicate that pyruvate carboxylase deficiency is genetically heterogeneous, with at least two distinct, probably intergenic, complementation groups.

Biotin↗

PubMed1993

[Biotinidase deficiency. Progressive encephalopathy curable with biotin].

BACKGROUND: Multiple carboxylase deficiency is a rare cause of progressive encephalopathy. There are 2 forms: the neonatal-onset form of holocarboxylase synthetase deficiency and the late-onset form of biotinidase deficiency. This report describes a case of biotinidase deficiency. CASE REPORT: A boy began to have repeated convulsions at the age of 3 months. The brain CT-scan and MRI were normal and the patient was given valproic acid and carbamazepine. Progressive neurological degradation was noted from the 4th month of life and myoclonic seizures began 2 months later. At admission, the patient had seizures, myoclonic fits and hypotonia. He had a skin rash but no alopecia. Biochemical investigation showed lactic acidosis, mainly in the CSF, moderate hyperammonemia and hyperalaninemia. Chromatography of organic acids showed several abnormal peaks suggesting biotinidase deficiency. The patient was given biotin (20 mg/day) orally. This treatment produced a pronounced, rapid, clinical and biochemical improvement and antiepileptic drugs were discontinued. There was no developmental delay at the age of 18 months. CONCLUSION: The clinical findings of neurologic abnormalities and dermatological signs led to the diagnosis of a metabolic disease that, fortunately, can be treated. This disease could benefit from a mass neonatal screening program.

Amidohydrolases↗

PubMed1997

Characterization of mutant holocarboxylase synthetase (HCS): a Km for biotin was not elevated in a patient with HCS deficiency.

Holocarboxylase synthetase (HCS) is an essential enzyme for the biotinylation of several mammalian carboxylases. A deficiency of HCS is accountable for early onset biotin-responsive multiple carboxylase deficiency. To address the mechanism of biotin responsiveness, we analyzed the kinetic properties of the previously identified mutant, L237P, and another mutant, V550M, described in this report. The V550M mutant contains a G to A transition at position 1935, which is within the putative biotin binding site, whereas the mutation in L237P occurs outside the biotin binding site. Km and Vmax values for the mutant proteins were determined by overexpressing cDNAs encoding the mutants in transformed fibroblasts from an HCS-deficient patient. Enzyme activity assays were performed using apo-carboxyl carrier protein as a substrate. A Km for biotin that was larger than the value found for the wild-type cDNA was observed in fibroblasts transfected with the V550M cDNA, but not the L237P cDNA. The Vmax for the expressed L237P cDNA was 4.3% of that observed for the wild-type cDNA. Biotin-responsiveness in the patient with the L237P mutation was neither due to an increased affinity for biotin nor a restoration of stability of the mutant by biotin treatment. A new mechanism of biotin responsiveness in HCS deficiency is presented.

Biotin↗

PubMed1986

Neurological deterioration and lactic acidemia in biotinidase deficiency. A treatable condition mimicking Leigh's disease.

A six-month-old girl with chronic lactic acidosis and neurological deterioration is described, who underwent a sudden severe decompensation during her initial neurological investigations. She responded dramatically to biotin therapy. The diagnosis of late onset multiple carboxylase deficiency due to biotinidase deficiency was confirmed. This entity should be considered in the differential diagnosis of hyperlactacidemic encephalopathies.

Acidosis, Lactic↗

PubMed1999

Prenatal diagnosis of holocarboxylase synthetase deficiency by assay of the enzyme in chorionic villus material followed by prenatal treatment.

Deficiency of holocarboxylase synthetase leads to multiple carboxylase deficiency, which is fatal in the absence of prompt diagnosis and treatment with biotin. In a pregnancy at risk for deficiency of holocarboxylase synthetase, prenatal diagnosis was performed by assay of the enzyme in chorionic villus material. The Km for biotin was 220.8 nmol/l, which was 33 times the control value of 6.6 nmol/l. Biotinyl AMP synthesis was undetectable in cultured chorionic villus material. Prenatal treatment of the mother was begun with 10 mg a day of biotin and continued through pregnancy. There was no accumulation of the characteristic metabolites in the urine at birth and prior to oral treatment of the newborn. Holocarboxylase synthetase activity was undetectable in lymphocytes and in fibroblasts of the newborn. Furthermore, the activities of all three carboxylases in fibroblasts of the infant were deficient. The newborn was clinically well and maintained on biotin treatment after birth at 20 mg per day. Carboxylase activities in lymphocytes were normal or slightly lower than the normal range.

Biotin↗

PubMed1989

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.

Glycogen Storage Disease Type I↗

PubMed2005

From an inborn error patient to a search for regulatory meaning: a biotin conducted voyage.

This article summarizes some findings of a research that I have pursued for the past 25 years, whose roots are immersed in the field of inherited metabolic disorders, and deal with different aspects of the vitamin biotin, starting with a patient with multiple carboxylase deficiency (MCD). Several of MCD clinical manifestations resemble those of infant malnutrition; we demonstrated that about one-third of infants with this common nutritional disorder were indeed biotin-deficient, and that this deficiency is metabolically significant, by studying urine instead of blood, studying urinary organic acids by gas chromatography-mass spectrometry. Remarkably, the metabolic abnormalities became apparent only after protein feeding was started, suggesting that this phenomenon may contribute to the worsening of malnourished individuals when they are abruptly fed. Afterwards, we studied biotin deficiency at the tissue level. Carboxylase activities and masses were significantly reduced in liver, kidney, muscle, adipose tissue, intestine, and spleen, but brain and heart were spared; their mRNAs remained unchanged. On the other hand, holocarboxylase synthetase (HCS) mRNA levels were markedly low in the deficient animals, and increased upon biotin injection. Over 2000 human genes have been identified that depend on biotin for expression. To probe into the "logic" of this enigma, we have started comparative studies among evolutionarily distant organisms, such as mouse and Saccharomyces cerevisiae, and we are now looking for biotin effects on specific genes and proteins, such as HCS and hexokinases, and on their proteomes.

Animals↗

PubMed1991

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.

Amidohydrolases↗

PubMed2003

Biotinidase Deficiency: New Directions and Practical Concerns.

Biotinidase deficiency is a readily treatable inherited disorder. Discovery of the enzyme deficiency as the cause for late-onset multiple carboxylase deficiency initially seemed to answer almost all of the questions about the disorder. However, as is the case for most inborn errors of metabolism, finding the enzyme that causes the disorder, cloning the gene, and determining the spectrum of clinical features of the disease only opens a Pandora's box. As researchers have found, there are still many important and interesting questions about this disorder that must be addressed and answered. However, when compared with other inherited metabolic diseases, biotinidase deficiency is still one of the most readily treatable. If a child must have an inborn error of metabolism, let it be biotinidase deficiency and let it be identified by newborn screening.

Journal Article↗

PubMedDate not supplied

A qualitative assessment of biotinidase deficiency.

Screening programs for late-onset, biotin-responsive, multiple carboxylase deficiency (LMCD) detect colormetrically the presence of biotinidase activity in dried samples of whole-blood spotted on filter-papers as used in the neonatal screening of phenylketonuria. A sensitive and stable qualitative technique is described using 10 microliter of serum that avoids problems associated with poor sample collection, improper drying of blood-spots and transient color development. The modified assay is timely and suitable for the clinical laboratory not involved in mass screening programs.

4-Aminobenzoic Acid↗

PubMed1994

Acylcarnitine profile in tissues and body fluids of biotin-deficient rats with and without L-carnitine supplementation.

Since biotin-deficient (BD) rats are a good animal model for human multiple carboxylase deficiency and have low plasma free carnitine levels, short-chain acylcarnitine profiles in biotin-deficient rats with L-carnitine supplementation (BDC rats) and BD rats were investigated by fast-atom bombardment and tandem mass spectrometry and gas chromatography/mass spectrometry. By the latter method, 3-hydroxyisovalerylcarnitine was identified in BD rats, and showed the greatest accumulation among short-chain acylcarnitines in tissues of BD rats, while the tissue levels of propionic acid were more markedly elevated than those of 3-hydroxyisovaleric acid. The tissue levels of 3-hydroxyisovaleryl-carnitine were significantly lower and those of propionyl-carnitine were somewhat higher in BDC rats than in BD rats, while the tissue levels of propionic acid and 3-hydroxyisovaleric acid in BDC rats were lower than those in BD rats. These changes were more apparent in kidney than in other tissues. The amounts of urinary excretion of acylcarnitines were markedly larger, and those of 3-hydroxyisovaleric acid were somewhat smaller in BDC rats than in BD rats, while those of propionic acid were very low in BD and BDC rats as compared with those of 3-hydroxyisovaleric acid. It seems that the relationship between the concentrations of 3-hydroxyisovalerylcarnitine and those of propionylcarnitine reflects the unique metabolism of the related metabolites in tissues, especially in kidney, which may be influenced by their urinary excretion and the availability of free carnitine. These data in biotin deficiency suggest that carnitine supplementation is possibly beneficial for patients with holocarboxylase synthetase deficiency who respond incompletely to biotin therapy.

Acetylcarnitine↗

PubMed1985

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.

Adult↗

PubMed1993

Cutaneous findings of nutritional deficiencies in children.

Nutritional deficiencies may be associated with a variety of cutaneous findings in children. This review emphasizes new developments relating to cutaneous findings of nutritional deficiencies. Zinc deficiency, acrodermatitis enteropathica, and acrodermatitis enteropathica-like eruptions are seen with a variety of conditions including cystic fibrosis, anorexia nervosa, and breastfeeding. Similar cutaneous findings not related to zinc deficiency may also occur with such metabolic disorders as methylmalonic aciduria, multiple carboxylase deficiency, essential fatty acid deficiency and other amino acid deficiencies. Vitamin K deficiency is associated with hemorrhagic disease of the newborn and coagulopathy. Vitamin A deficiency presents with a variety of systemic findings and distinctive dermatologic findings. Acute vitamin A deficiency may be seen in children infected with measles and is associated with more severe disease. The systemic and cutaneous findings of vitamin C deficiency, scurvy, are discussed.

Ascorbic Acid Deficiency↗

PubMed1999

Relationship between kinetic properties of mutant enzyme and biochemical and clinical responsiveness to biotin in holocarboxylase synthetase deficiency.

Holocarboxylase synthetase (HCS) deficiency is a metabolic disorder that causes a biotin-responsive multiple carboxylase deficiency. We analyzed the kinetic properties of seven mutant HCS proteins. Two of these enzymes harbored mutations within the putative biotin-binding region of HCS and showed elevated Km values for biotin compared with that of the wild-type form (Km mutant; Gly581Ser: 45 times, delThr610: 3 times). The remaining five mutations (Arg183Pro, Leu216Arg, Leu237Pro, Val333Glu, and Val363Asp) were located outside the biotin-binding region. The enzymes containing these mutations showed normal or low Km values for biotin (non-Km mutant). Symptoms of patients who have the non-Km, mutants, as well as those of patients who have the Km, mutants, responded to biotin therapy. This is probably because the Km value for biotin of normal HCS is higher than the physiologic concentration of biotin in human cells. The Vmax values of all mutant HCS proteins were considerably decreased, but to a variable degree. The responsiveness to biotin supplementation of propionyl-CoA carboxylase activity in cultured cells bearing the mutations correlated well with the degree of reduction in the Vmax of HCS. Patients who have mutant HCS proteins with lower Vmax showed poorer clinical and biochemical responses to biotin therapy. These observations suggest that the reduction of Vmax is an essential factor for pathophysiology and prognosis of HCS deficiency under treatment with large amounts of biotin. The determination of HCS genotype can be valuable for characterizing the clinical phenotype in HCS deficient patients.

Biotin↗

PubMed1985

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.

Acidosis↗