Adrian C. Sewell

The cblD Defect Causes Either Isolated or Combined Deficiency of Methylcobalamin and Adenosylcobalamin Synthesis

Intracellular cobalamin is converted to adenosylcobalamin, coenzyme for methylmalonyl-CoA mutase and to methylcobalamin, coenzyme for methionine synthase, in an incompletely understood sequence of reactions. Genetic defects of these steps are defined as cbl complementation groups of which cblC, cblD (described in only two siblings), and cblF are associated with combined homocystinuria and methylmalonic aciduria. Here we describe three unrelated patients belonging to the cblD complementation group but with distinct biochemical phenotypes different from that described in the original cblD siblings. Two patients presented with isolated homocystinuria and reduced formation of methionine and methylcobalamin in cultured fibroblasts, defined as cblD-variant 1, and one patient with isolated methylmalonic aciduria and deficient adenosylcobalamin synthesis in fibroblasts, defined as cblD-variant 2. Cell lines from the cblD-variant 1 patients clearly complemented reference lines with the same biochemical phenotype, i.e. cblE and cblG, and the cblD-variant 2 cell line complemented cells from the mutant classes with isolated deficiency of adenosylcobalamin synthesis, i.e. cblA and cblB. Also, no pathogenic sequence changes in the coding regions of genes associated with the respective biochemical phenotypes were found. These findings indicate heterogeneity within the previously defined cblD mutant class and point to further complexity of intracellular cobalamin metabolism.

N-carbamylglutamate enhances ammonia detoxification in a patient with decompensated methylmalonic aciduria

In patients with methylmalonic aciduria (MMA), the accumulating metabolite propiony-CoA results in an inhibition of the urea circle via the decreased synthesis of N-acetylglutamate, an essential activator of carbamylphosphat synthetase (CPS). This results in one of the major clinical problems which is hyperammonaemia. In a patient with decompensated MMA, the CPS activator carbamylglutamate was tested for its ability to antagonize the propionyl-CoA-induced hyperammonaemia. Oral carbamylgutamate administration resulted in an impressive increase in ammonia detoxification compared to peritoneal dialysis. Safe, fast and easy to administer, carbamylglutamate improves the acute therapy of decompensated MMA by increasing ammonia detoxification and avoiding hyperammonaemia.

4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone)--the odour of maple syrup urine disease.

Maple syrup urine disease is an autosomal recessive inherited disorder of branched-chain amino acid metabolism due to deficiency of the branched-chain α-keto acid dehydrogenase complex. The disease was originally named after the characteristic sweet aroma, reminiscent of maple syrup, present in the body fluids of affected patients. Until now, the substance responsible for the odour has not been positively identified. Using enantioselective multidimensional gas chromatography-mass spectrometry (enantio-MDGC-MS), we could demonstrate that 4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone), a well-known flavour impact compound present in fenugreek and lovage, was present in urine from seven patients with maple syrup urine disease. Urine samples from healthy control persons lacked sotolone. We have shown that sotolone is responsible for the characteristic odour of maple syrup urine disease and, since maple syrup also contains sotolone, the naming of this disease appears to be correct.

Hyperinsulinaemic hypoglycaemia—Leading symptom in a patient with congenital disorder of glycosylation Ia (phosphomannomutase deficiency)

AbstractA male infant is described who presented with persistent hyperinsulinaemic hypoglycaemia, responding to diazoxide treatment. However, this therapy was discontinued because of seizures as a consequence of disturbed water and electrolyte balance. Glucose homeostasis could only be maintained by subtotal pancreatectomy, which was performed at 3n

Maternal plasma homocysteine, placenta status and docosahexaenoic acid concentration in erythrocyte phospholipids of the newborn

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The spectrum of free neuraminic acid storage disease in childhood: clinical, morphological and biochemical observations in three non-Finnish patients.

n years of age. He developed a severe thrombosis, whereon a congenital disorder of glycosylation (CDG) was suspected. An abnormal transferrin isoelectric focusing pattern was found and the diagnosis of CDG Ia was confirmed by enzyme and molecular genetic analysis. This is the first patient with phosphomannomutase deficiency (McKusick 601785) described presenting with severe hyperinsulinaemic hypoglycaemia.

L-2-Hydroxyglutaric aciduria presenting as status epilepticus

Enantioselective multidimensional gas chromatography-mass spectrometry is a valuable tool for the enantioselective analysis of compounds from complex matrices. Samples are separated initially on a precolumn and selected substances then transferred on-line to a main-column coated with suitable chiral stationary phase for enantioselective analysis with subsequent mass selective detection. In this paper the method is used as an adjunct to urinary organic acid analysis to provide information in patients with suspected inborn errors of metabolism. Lactic acid, alpha-hydroxyisocaproic acid, 3-phenyllactic acid and 3-(4-hydroxyphenyl)-lactic acid are separated in a single run. In addition, the enantioselective analysis of pyroglutamic acid is presented. D-Enantiomers of amino acids and alpha-hydroxycarboxylic acids derived from amino acids, point to a bacterial origin whereas the L-enantiomer is predominantly of endogenous origin. Therefore the enantiomeric ratio of chiral metabolites is an important parameter for the understanding of metabolic processes.

Simultaneous enantioselective analysis of chiral urinary metabolites in patients with Zellweger syndrome.

Abstract The enhanced transport of long-chain polyunsaturated fatty acids, in particular docosahexaenoic acid (22:6 ω-3) (DHA), to the fetus is a placental function important for adequate membrane phospholipid formation and herewith decisive for the quality of fetal CNS myelination. A compromised placental function is correlated with signs of vascular pathology. As elevated plasma total homocysteine (tHcy) concentrations are considered an independent risk for premature occlusive vascular disease, the influence of maternal plasma tHcy concentrations on placental function was indirectly studied, determining the DHA content in erythrocyte membrane phospholipids of the newborn. A total of 60 unselected pregnant women (age range: 21 to 39 years) were investigated at delivery. Gestational age ranged from 26 to 41 weeks. Prior to delivery a placental ultrasound scan was performed. Complete sets of data could be obtained from 43 mothers and their offspring. tHcy concentrations were determined in the plasma of cord and maternal blood. The fatty acid pattern of erythrocyte membrane phospholipids was determined in the mothers and their newborns. Z-scores of the birth weights ranged from −3.4 to 2.1 and of the placental weights from −3.8 to 4.7. The mean maternal plasma tHcy concentration was 6.29u2009±u20093.34u2009μmol/l ranging from below our limit of detection up to 15u2009μmol/l. These maternal concentrations were correlated with those of their infants (ru2009=u20090.71; Pu2009<u20090.0001). The tHcy concentrations were significantly higher in mothers with pregnancies complicated by gestosis or placental calcifications. The Z-scores of birth weights as well as placental weights showed a significant negative correlation with maternal plasma tHcy concentrations. The mean DHA percentage of total fatty acids in erythrocyte phospholipids was 3.2u2009±u20092.2% in the mothers and 3.4u2009±u20092.3% in their newborns. Most importantly the maternal plasma tHcy levels and the erythrocyte phospholipid DHA concentrations of their offspring were significantly correlated (ru2009=u2009−0.51; Pu2009<u20090.0003).nConclusion In this study, total homocysteine concentrations were elevated in the plasma of pregnant women with signs of placental vasculopathy. Maternal plasma total homocysteine concentrations were positively correlated with erythrocyte phospholipid docosahexaenoic acid of their offspring and may be an indicator for the integrity of placental vascular function. The nutritional status as well as predisposing genetic factors of pregnant mothers need to be investigated more thoroughly.