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Biomedical subjects

E Mayatepek

Publications and source records attributed to E Mayatepek.

At least 91 records · Page 5Linked to original sources
PubMed1999

Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria.

Large neutral amino acids (LNAAs), including phenylalanine (Phe), compete for transport across the blood-brain barrier (BBB) via the L-type amino acid carrier. Accordingly, elevated plasma Phe impairs brain uptake of other LNAAs in patients with phenylketonuria (PKU). Direct effects of elevated brain Phe and depleted LNAAs are probably major causes for disturbed brain development and function in PKU. Competition for the carrier might conversely be put to use to lower Phe influx when the plasma concentrations of all other LNAAs are increased. This hypothesis was tested by measuring brain Phe in patients with PKU by quantitative 1H magnetic resonance spectroscopy during an oral Phe challenge with and without additional supplementation with all other LNAAs. Baseline plasma Phe was approximately 1,000 micromol/l and brain Phe was approximately 250 micromol/l in both series. Without LNAA supplementation, brain Phe increased to approximately 400 micromol/l after the oral Phe load. Electroencephalogram (EEG) spectral analysis revealed acutely disturbed brain activity. With concurrent LNAA supplementation, Phe influx was completely blocked and there was no slowing of EEG activity. These results are relevant for further characterization of the LNAA carrier and of the pathophysiology underlying brain dysfunction in PKU and for treatment of patients with PKU, as brain function might be improved by continued LNAA supplementation.

Adult↗
PubMed1999

Diagnosis of mitochondrial trifunctional protein deficiency in a blood spot from the newborn screening card by tandem mass spectrometry and DNA analysis.

Trifunctional protein (TFP) plays a significant role in the mitochondrial beta-oxidation of long-chain fatty acids. Its deficiency impairs the energy generating function of this pathway and causes hypoketotic hypoglycemia once hepatic glycogen stores are depleted. A Reye-like syndrome, cardiomyopathy, and sudden death may follow. The diagnosis is based on demonstration of significantly decreased enzyme activity of at least two of the three involved enzymes in fibroblasts. The possibility of prospective diagnosis of TFP deficiency by newborn screening using tandem mass spectrometry (MS/MS) has not been evaluated. We report the postmortem diagnosis of a male newborn, who suffered sudden death at 2 wk of age, and his younger sister, who died of cardiomyopathy complicated by acute heart failure at the age of 6 mo, after she had acquired a common viral infection. Blood spots from the original newborn screening cards were the only remaining material from the patients. Analysis by MS/MS revealed acylcarnitine profiles consistent with either TFP or long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) deficiency. To prove the diagnosis, the alpha- and beta-subunit genes coding for TFP were examined. The patients were compound heterozygous for a 4-bp-deletion and an a-->g missense mutation, both in the same exon 3 donor consensus splice site. This is the first report of the diagnosis of TFP deficiency using blood spots obtained for newborn screening and suggests that TFP deficiency may be detectable by prospective newborn screening using MS/MS.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1998

Leukotriene C4-synthesis deficiency: a new inborn error of metabolism linked to a fatal developmental syndrome.

BACKGROUND: Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent lipid mediators derived from arachidonic acid in the 5-lipoxygenase pathway that exert profound biological effects. We investigated synthesis and metabolism of leukotrienes in an infant who presented with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly. The course of the disease was rapidly progressive and the infant died aged 6 months. METHODS: Cysteinyl leukotrienes and LTB4 were analysed in cerebrospinal fluid, plasma, urine, and stimulated monocytes by EIA. We measured [3H]-LTC4 formation from [3H]-LTA4 in monocytes and platelets by radio-high-pressure liquid chromatography. FINDINGS: Concentrations of LTC4 and its metabolites were below the detection limit in the cerebrospinal fluid, plasma and urine. LTC4 could not be generated in stimulated monocytes, whereas LTB4 synthesis was increased. [3H]-LTC4 could not be made from [3H]-LTA4 in the patient's monocytes or platelets. INTERPRETATION: In this patient, inability to synthesise LTC4 suggests a deficiency of LTC4 synthase. This defect is a new inborn error of human eicosanoid metabolism and may be associated with the clinical disorder. Leukotriene analysis should be done in all patients with neurological symptoms who are candidates for metabolic diseases.

Abnormalities, Multiple↗
PubMed1998

Specific and rapid quantification of 8-iso-prostaglandin F2alpha in urine of healthy humans and patients with Zellweger syndrome by gas chromatography-tandem mass spectrometry.

8-iso-Prostaglandin F2alpha (8-iso-PGF2alpha) is currently discussed as a potential index parameter of oxidative stress in vivo. We describe in this article a fully validated gas chromatographic-tandem mass spectrometric method for the quantitative determination of 8-iso-PGF2alpha in human urine. The method is highly specific and requires a single thin-layer chromatographic step for sample purification. Inter- and intraday imprecision were below 8%. Mean inaccuracy was 5.3% for added levels of 8-iso-PGF2alpha up to 2000 pg/ml of urine. We measured highly elevated excretion of 8-iso-PGF2alpha in the urine of children with peroxisomal beta-oxidation deficiency, i.e. Zellweger syndrome, (63.3+/-16.6 ng/mg creatinine) compared to that of healthy children (0.51+/-0.16 ng/mg creatinine) (mean+/-S.D., both n=5). The method could be useful for diagnosing Zellweger syndrome and for investigating the utility of 8-iso-PGF2alpha as a novel marker for oxidative stress in vivo in man.

Adult↗
PubMed1998

Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene.

Newborn screening for biotinidase deficiency has identified children with profound biotinidase deficiency (<10% of mean normal serum activity) and those with partial biotinidase deficiency (10%-30% of mean normal serum activity). Children with partial biotinidase deficiency and who are not treated with biotin do not usually exhibit symptoms unless they are stressed (i.e., prolonged infection). We found that 18 of 19 randomly selected individuals with partial deficiency have the transversion missense mutation G1330>C, which substitutes a histidine for aspartic acid444 (D444H) in one allele of the biotinidase gene. We have previously estimated that the D444H mutation results in 48% of normal enzyme activity for that allele and occurs with an estimated frequency of 0.039 in the general population. The D444H mutation in biotinidase deficiency is similar to the Duarte variant in galactosemia. The D444H mutation in one allele in combination with a mutation for profound deficiency in the other allele is the common cause of partial biotinidase deficiency.

Alleles↗
PubMed1998

The clinical manifestation of the kwashiorkor syndrome is related to increased lipid peroxidation.

Along with the onset of severe kwashiorkor symptoms, a 20-month-old child showed biochemical signs of markedly increased lipid peroxidation, with a decrease of plasma antioxidants and decreased proportions of polyunsaturated fatty acids in plasma and red cell phospholipids. Additionally, plasma concentrations of the lipid peroxidation products malondialdehyde and hexanal, as well as the urinary excretion of leukotriene E4, were found to be increased. All biochemical alterations normalized along with subsequent clinical improvement. These findings suggest that the extent of lipid peroxidation is strongly related to the severity of the kwashiorkor syndrome.

Aldehydes↗
PubMed1998

Transient trimethylaminuria in childhood.

Trimethylaminuria, also called fish-odour syndrome, is an inherited disorder caused by deficient N-oxidation and increased excretion of trimethylamine. This study reports on two unrelated and otherwise healthy children with transient trimethylaminuria, a hitherto unknown abnormality, without N-oxidation deficiency. This demonstrates that a diagnosis of fish-odour syndrome should include the analysis of urinary excretion not only of trimethylamine but also of trimethylamine-N-oxide. Since transient trimethylaminuria may be a common condition and no cause for it can presently be recognized, such patients will require careful follow-up.

Child, Preschool↗
PubMed1998

Mutation and polymorphism analysis of the human homogentisate 1, 2-dioxygenase gene in alkaptonuria patients.

Alkaptonuria (AKU), a rare hereditary disorder of phenylalanine and tyrosine catabolism, was the first disease to be interpreted as an inborn error of metabolism. AKU patients are deficient for homogentisate 1,2 dioxygenase (HGO); this deficiency causes homogentisic aciduria, ochronosis, and arthritis. We cloned the human HGO gene and characterized two loss-of-function mutations, P230S and V300G, in the HGO gene in AKU patients. Here we report haplotype and mutational analysis of the HGO gene in 29 novel AKU chromosomes. We identified 12 novel mutations: 8 (E42A, W97G, D153G, S189I, I216T, R225H, F227S, and M368V) missense mutations that result in amino acid substitutions at positions conserved in HGO in different species, 1 (F10fs) frameshift mutation, 2 intronic mutations (IVS9-56G-->A, IVS9-17G-->A), and 1 splice-site mutation (IVS5+1G-->T). We also report characterization of five polymorphic sites in HGO and describe the haplotypic associations of alleles at these sites in normal and AKU chromosomes. One of these sites, HGO-3, is a variable dinucleotide repeat; IVS2+35T/A, IVS5+25T/C, and IVS6+46C/A are intronic sites at which single nucleotide substitutions (dimorphisms) have been detected; and c407T/A is a relatively frequent nucleotide substitution in the coding sequence, exon 4, resulting in an amino acid change (H80Q). These data provide insight into the origin and evolution of the various AKU alleles.

Alkaptonuria↗
PubMed1997

Persistent hyperinsulinaemic hypoglycaemia of infancy: therapy, clinical outcome and mutational analysis.

UNLABELLED: Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is an autosomal recessive disorder characterized by irregular insulin secretion leading to hypoglycaemia. Recently, mutations in the sulphonylurea receptor (SUR) have been described in association with PHHI. We studied clinical symptoms, therapy, long-term outcome and mutational analysis in 14 patients with PHHI. In 8 patients subtotal pancreatectomy was performed whereas 6 responded to conservative treatment with diazoxide. Psychomotor retardation was found in 6 patients, most of them after a delayed diagnosis. A G-to-A point mutation in one allele of the SUR gene was detected by loss of a MspI restriction site in only one patient. CONCLUSION: Early diagnosis and therapy in PHHI is essential to prevent brain damage. In one patient mutational analysis suggested compound heterozygosity for a known and an as yet unidentified mutation in the SUR gene.

ATP-Binding Cassette Transporters↗