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T Suormala

Publications and source records attributed to T Suormala.

At least 37 records · Page 2Linked to original sources
PubMed1996

Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency: long-term outcome in a case with neonatal onset.

UNLABELLED: A patient with early-onset 3-methylcrotonyl coenzyme A carboxylase (MCC) deficiency showing a severe clinical course is described. Abnormal eye and head movements suggestive of seizures were noticed soon after birth. Tonic convulsions at the age of 10 weeks led to admission. Urinary organic acid analysis using gas chromatography-mass spectrometry at 3 months of age revealed elevated concentrations of 3-hydroxyisovaleric acid (3HIVA) and 3-methylcrotonylglycine but normal levels of lactate, 3-hydroxypropionate and methylcitrate suggesting isolated MCC deficiency. This was confirmed by enzyme assays in lymphocytes and cultured skin fibroblasts: MCC activity was virtually undetectable whereas activities of propionyl-CoA and pyruvate carboxylases were within the normal range. A low protein (0.8-1.5 g/kg/day) diet supplemented with a leucine-free amino acid mixture resulted in a marked decrease of 3HIVA excretion. L-Carnitine and biotin administration had no effect on the clinical condition or metabolite excretion. Supplementation with glycine resulted in only a temporary fall of 3HIVA excretion and was therefore discontinued. L-Carnitine therapy was reintroduced later because of secondary carnitine deficiency. Compliance with treatment was poor until the age of 27 months resulting in a severe episode with seizures and coma. The general clinical condition of the patient was always good but his psychomotor development was delayed and seizures were not continuously under good control due to poor therapy compliance. The boy is now 10.5 years old and attending a school for children with learning handicaps. CONCLUSION: Isolated MCC deficiency of early-onset is a rare condition exhibiting a more severe clinical course than the later-onset form described in most other cases. The prognostic value of 3 HIVA measurements in CSF and serum should be evaluated in future cases.

Age of Onset↗
PubMed1996

Proliferation and differentiation of cultured human follicular keratinocytes are not influenced by biotin.

In humans and in animals, biotin deficiency causes pathological changes in the skin and its appendages. High doses of biotin may also have beneficial effects on skin, hair and fingernails in humans and animals with normal biotin status. Therefore, we investigated the effects of low and high concentrations of biotin on proliferation and differentiation of cultured outer root sheath cells from human hair follicles as an in vitro model for skin. The activities of biotin-dependent carboxylases were measured to evaluate the biotin status of the cells. In monolayer cultures of outer root sheath cells, proliferation and expression of the differentiation-specific keratins K1 and K10 were not influenced by extremely low concentrations of biotin (<2 x 10(-10) mol/l) or by pharmacological doses of biotin (10(-5) mol/l). Biotin deficiency of the cells was confirmed under the former condition by demonstrating decreased activities of the mitochondrial carboxylases. In organotypic cocultures of outer root sheath cells and dermal fibroblasts, in which stratified epithelia resembling epidermis were developed, the biotin concentration had no effect on the expression of all tested epidermal differentiation markers, including the suprabasal keratins K1 and K10, the hyperproliferation-associated keratin K16, involucrin and filaggrin.

Adult↗
PubMed1995

Biotinidase Km-variants: detection and detailed biochemical investigations.

We describe a simple method for the detection of biotinidase Km-variants and detailed biochemical investigations in 5 such patient. They were detected among 103 patients with plasma biotinidase activity which ranged from undetectable to 30% of the mean normal value. Two different types of biotinidase Km-variants were found. (1) In 3 infants biotinidase had a single 105-430-fold elevated Km for biocytin. Biotinidase showed very low activities (0.2-4% of the mean normal value) in the routine colorimetric assay and was not functional in vivo. Accordingly, these patients presented with classical clinical illness. (2) In two patients biotinidase showed biphasic kinetics indicating the presence of one component with a normal Km and reduced Vmax (1.7% and 12%), and another with 330- and 59-fold elevated Km, respectively. In these two patients, biotinidase proved to be at least partially functional in vivo. However, the first patient developed severe symptoms and biotin deficiency late, at the age of 10-15 years, and the second had marginal biotin deficiency at the age of 2 years but no clinical symptoms. Comparative studies revealed that both patients had more severe biotin deficiency than age-matched patients with similar levels of residual biotinidase activity and a single normal Km. Therefore, all patients with residual biotinidase activity should be evaluated for the presence of a Km-mutation, since such patients should be treated with biotin. These can easily be detected by including a second substrate concentration (1.5 mmol/L) in the routine colorimetric biotinidase assay which is performed with 0.15 mmol/L biotin. Increased activity with the higher substrate concentration indicates the presence of a Km-mutation. Detailed kinetic studies are needed to evaluate the distinct forms of Km-variants.

Amidohydrolases↗
PubMed1994

Propionic acidaemia: clinical, biochemical and therapeutic aspects. Experience in 30 patients.

Comprehensive data on 30 patients with propionic acidaemia, diagnosed by selective screening for inborn errors of metabolism, are presented. The most valuable diagnostic metabolites found were methylcitric-, 3-hydroxypropionic-, and 2-methyl-3-oxovaleric acids. Hyperlysinaemia and hyperlysinuria are also characteristic findings in this disease. The metabolic pattern found in propionic acidaemia is discussed extensively as are enzymatic findings. Residual activity of propionyl-CoA carboxylase is neither a predictive marker for severity nor for outcome of the disease. Propionate fixation assays were less reliable for confirmation of propionic acidaemia and of no prognostic value. Clinical presentation of the disease is discussed in detail. Besides the well-known unspecific findings (poor appetite, feeding difficulties, vomiting, dehydration, weight loss, muscular hypotonia, dyspnoea, somnolence, apathy, convulsion, coma, severe metabolic acidosis, hyperammonaemia) various skin abnormalities have been detected in about 50% of all patients. In 27% "dermatitis acidemica" was found.

Amino Acid Metabolism, Inborn Errors↗
PubMed1993

Holocarboxylase synthetase deficiency: early diagnosis and management of a new case.

We present a new case of holocarboxylase synthetase (HCS) deficiency, a rare autosomal recessive metabolic disorder, causing the "early-onset" form of multiple carboxylase deficiency. The patient was born at term of healthy consanguineous parents after an uncomplicated pregnancy. On the 2nd day of life she refused oral feeding, became tachydyspnoeic and showed excessive weight loss. Laboratory studies showed metabolic acidosis, marked lactic acidaemia, hyperammonaemia and increased urinary excretion of 3-hydroxyisovaleric acid, 3-methylcrotonylglycine, 3-hydroxpropionic acid and methylcitric acid. Peritoneal dialysis combined with oral supplementation of biotin (10 mg/day) started on the 3rd day of life resulted in rapid clinical recovery and normalisation of biochemical parameters. HCS deficiency was established in lymphocytes and skin fibroblasts. The activities of all biotin-dependent carboxylases were severely decreased in fibroblasts grown in medium with moderate biotin concentration (10(-8) mol/l) but normal in a high biotin medium (10(-5) mol/l). Mitochondrial carboxylase activities in lymphocytes were 23%-29% of mean normal during therapy with 20 mg of biotin/day, with the higher dose of 40 mg/day they were within (3-methylcrotoryl-CoA carboxylase, pyruvate carboxylase) or slightly below (propionyl-CoA carboxylase) the normal range. At the age of 3 years the patient's physical and psychomotor development are normal. Early biotin supplementation should be considered in newborns with lactic acidosis and organoaciduria until a final diagnosis has been established. Furthermore, the required individual dose of biotin has to be carefully evaluated biochemically for the individual patient.

Biotin↗
PubMed1992

Isolated biotin-resistant deficiency of 3-methylcrotonyl-CoA carboxylase presenting as a clinically severe form in a newborn with fatal outcome.

The son of Kurdish, consanguineous parents (cousin marriage) presented from the first day of life with initially focal and later generalized attacks of epileptic seizures and a severe generalized muscular hypotonia. Urinary excretion of 3-hydroxyisovalerate and of 3-methylcrotonylglycine was persistently increased. Diagnosis of isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency was confirmed in cultured fibroblasts. Psychomotor retardation was progressive, seizures and marked EEG abnormalities persisted. Treatment with leucine and protein-resistricted diet under hospital control did not significantly improve these conditions. The patient died from a cardiac and circulatory failure after a prolonged epileptic attack, with bronchial aspiration. The non-responsiveness of our patient to therapy and the fatal outcome indicate the existence of a severe neonatal variant of this otherwise rather benign genetic enzyme deficiency.

Amnion↗
PubMed1991

[Biotinidase deficiency. Results of neonatal screening 1985-1989 in Lower Saxony].

During a five-year-period (1985-1989) 420,000 newborns in Lower Saxony, FRG, were screened for biotinidase deficiency using biotinyl-para-amino-benzoic-acid as substrate. Three newborns with profound biotinidase deficiency (activity 1.1%, 2.1%, 2.3% of mean normal activity level) were detected. Nine newborns had partial biotinidase deficiency (activity 17-26% of mean normal activity level), thus giving an incidence of 1:140,000 with profound, and 1:46,667 with partial biotinidase deficiency, respectively. The infants with profound biotinidase deficiency are treated with biotin (2 x 5 mg/day) from the 3rd, 6th and 8th week of life and have developed normally so far. The children with partial biotinidase deficiency are not treated but followed up closely. The necessity of newborn screening for biotinidase deficiency is stressed.

Amidohydrolases↗
PubMed1990

The gene coding for the alpha-chain of human propionyl-CoA carboxylase maps to chromosome band 13q32.

The human gene encoding the alpha-polypeptide of propionyl-CoA carboxylase (PCC) has hitherto been localized to the distal half of the long arm of chromosome 13, segment 13q22----q34. We studied the enzyme activities of mitochondrial carboxylases in cell cultures obtained from patients with different deletions of chromosome 13. By setting the PCC activity in normal diploid cell cultures (control group) at 100%, cell cultures with trisomy 13 showed 150% activity. In contrast, one of four patients with partial monosomy 13 had an enzyme activity of only 50%. Thus, by comparative deletion mapping, combined with studies of the gene-dosage effect, we have been able to assign the PCCA gene locus to chromosome band 13q32.

Carbon-Carbon Ligases↗
PubMed1990

Methylmalonic aciduria with homocystinuria: biochemical studies, treatment, and clinical course of a Cbl-C patient.

A patient with infantile onset methylmalonic aciduria and homocystinuria (Cbl-C mutant) is described. Therapy with hydroxycobalamin, folate and vitamin B6 improved his condition. As hypomethioninaemia and homocystinaemia persisted, he was treated with intramuscular methylcobalamin, but without success. Treatment with betaine started at 25 months of age, normalized plasma methionine and elicited disappearance of homocystinaemia. Results of biochemical studies in cultured fibroblasts paralleled those described for other Cbl-C patients except that methylmalonyl-coenzyme A mutase activity in disrupted fibroblasts was in the normal range.

Betaine↗
PubMed1988

Low biotinidase activity in plasma of some preterm infants: possible source of false-positive screening results.

Screening for biotinidase deficiency has been added recently to some national screening programmes. To clarify the problem of false-positive screening tests in premature infants, we have studied biotinidase activities in the plasma of this population in more detail. In 64 newborns (premature and term babies) biotinidase activities correlated positively with gestational age from the 2nd to the 30th day of life. During the 1st-3rd day the activities were below the normal adult range in all 64 infants. In 56 infants the activities subsequently increased gradually and reached the normal adult range during the 4th-40th day of life. In contrast, the biotinidase activities in eight preterm infants dropped during the 3rd-7th day of life. Impaired liver function as a possible cause for this finding could be ruled out in these infants. The lowest activities in these infants were measured during the 4th-6th day of life, i.e. unfortunately at a time when samples for the screening are normally taken. According to our data, 4-8 out of 48 preterm or small-for-date infants with biotinidase activities ranging from 4.7%-26% of the mean adult value would have given false-positive screening tests. A positive screening test was also obtained in a newborn and in an older unrelated child with a partial biotinidase deficiency. In these children the biotinidase activity did not rise but remained slightly below or at the lower range for heterozygotes (at 31% and 38% of the mean adult value). Currently we do not know whether such individuals are heterozygotes, or whether they have a variant of biotinidase deficiency. However, these children have developed normally without biotin therapy.

Age Factors↗
PubMed1985

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/l 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.

Acyl Coenzyme A↗
PubMed1985

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.

Amidohydrolases↗
PubMed1985

Biotinidase deficiency: factors responsible for the increased biotin requirement.

Inability to recycle biotin from endogenous biocytin in congenital biotinidase deficiency is associated with increased requirement of exogenous free biotin. We have observed that severe biotin depletion with clinical and biochemical consequences occurs within 12 days after birth in a newborn patient and within 15-20 days after withdrawal of biotin supplementation in four other patients. Our studies have shown that: Urinary loss of biotin and biocytin are major causes for this rapid biotin depletion. Intestinal absorption of biotin seems to be normal at least at the loading dose of 1.5 micrograms/kg. At normal or subnormal plasma biotin concentrations biocytin is found in low concentrations (below 1 nmol l-1) in plasma of patients but at much higher concentrations in urine (100-600 nmol l-1). An oral load of biocytin results in patients in unchanged biotin levels but in a marked rise of biocytin in plasma followed by rapid renal excretion of biocytin whereas in controls biotin levels in plasma increase rapidly and biocytin remains below detection levels.

Amidohydrolases↗
PubMed1985

Biotinidase deficiency associated with renal loss of biocytin and biotin.

Clinical and biochemical investigations in six patients with congenital biotinidase deficiency are presented. The time course of biotin depletion in relation to carboxylase activities and clinical onset of symptoms was studied after withdrawal of biotin supplementation. Renal biotin clearance studies were performed in patients and controls. Renal loss of biocytin and biotin itself are shown to be a major cause for the increased biotin requirement in patients with congenital biotinidase deficiency.

Amidohydrolases↗
PubMed1984

Detection of biocytin in urine of children with congenital biotinidase deficiency.

The possible excretion of biocytin or biotinyl-peptides was investigated in urines of children with congenital biotinidase deficiency. Treatment of urine samples of affected children with normal plasma (as source of biotinidase) liberated additional free biotin (L. plantarum assay), indicating the presence of biotinyl-compounds. Using thin-layer chromatography the occurrence of biocytin was demonstrated in all urine samples of the affected children. In contrast, no biocytin could be detected in urines of healthy subjects.

Adult↗