N. G. G. M. Abeling

Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes.

Monoamine oxidase (MAO) exists as two isoenzymes and plays a central role in the metabolism of monoamine neurotransmitters. In this study we compared the neurochemical phenotypes of previously described subjects with genetically determined selective lack of MAO-A or a lack of both MAO-A and MAO-B with those of two subjects with a previously described X chromosome microdeletion in whom we now demonstrate selective MAO-B deficiency. Mapping of the distal deletion breakpoint demonstrates its location in intron 5 of the MAO-B gene, with the deletion extending proximally into the Norrie disease gene. In contrast to the borderline mental retardation and abnormal behavioral phenotype in subjects with selective MAO-A deficiency and the severe mental retardation in patients with combined MAO-A/MAO-B deficiency and Norrie disease, the MAO-B-deficient subjects exhibit neither abnormal behavior nor mental retardation. Distinct neurochemical profiles characterize the three groups of MAO-deficient patients. In MAO-A-deficient subjects, there is a marked decrease in deaminated catecholamine metabolites and a concomitant marked elevation of O-methylated amine metabolites. These neurochemical changes are only slightly exaggerated in patients with combined lack of MAO-A and MAO-B. In contrast, the only biochemical abnormalities detected in subjects with the MAO-B gene deletion are a complete absence of platelet MAO-B activity and an increased urinary excretion of phenylethylamine. The differences in neurochemical profiles indicate that, under normal conditions, MAO-A is considerably more important than MAO-B in the metabolism of biogenic amines, a factor likely to contribute to the different clinical phenotypes.

Simultaneous determination of catecholamines and metanephrines in urine by HPLC with fluorometric detection

A method is described for quantitative analysis of urinary free and conjugated catecholamines and metanephrines. The compounds are isolated from the urine by cation exchange on Amberlite CG 50. Separation is performed by ion-pair reversed-phase high-performance liquid chromatography. For detection of the amines their native fluorescence emitted at 313 nm on excitation at 285 nm was monitored. There was good separation of the compounds of interest, while interference by exogenous compounds other than the catecholamines or metanephrines was minimal. The method is rapid and precise, and it has a broad linear working range for all six DOPA metabolites, making it suitable for clinical analysis. Reference values for children of 0-16 years were established. Examples are shown of excretion patterns of DOPA metabolites from patients with different types of neurogenic tumour.

Deficiency of the adenine nucleotide translocator in muscle of a patient with myopathy and lactic acidosis: a new mitochondrial defect

ABSTRACT: In a patient with a mitochondrial myopathy, presenting with lactic acidosis, 31P-nuclear magnetic resonance spectroscopy in resting muscle showed half the creatine phosphate level of controls. The creatine phosphate resynthesis rate after aerobic exercise was only 18% of that in controls. However, the activities of complexes I to V catalyzing oxidative phosphorylation and the pyruvate and the 2-oxoglutarate dehydrogenase complexes showed a 2- to 20-fold increase. In line with this, the uncoupled mitochondrial respiration rate was significantly higher than in controls. In contrast, the respiration of the mitochondria from the patient was less stimulated by ADP than that of control mitochondria. This finding could point to a defect in complex V, the enzyme directly involved in ATP synthesis. The activity of complex V, measured as the mitochondrial ATPase activity, and its concentration, as judged from Western blots using antisera against the F1 part of complex V, were, however, also greatly increased in the patient. Alternatively, the transport system, importing ADP into and exporting ATP out of the mitochondrial matrix, the ADP/ATP or adenine nucleotide translocator, could be affected. Immunostaining of Western blots revealed a 4-fold decrease in the concentration of the adenine nucleotide translocator in the patient. Because oxidative phosphorylation was not disturbed in fibroblasts and lymphocytes, we conclude that this patient suffers from a muscle-specific deficiency of his mitochondrial adenine nucleotide translocator, a defect unknown so far.

Clinical and biochemical findings in six patients with pyrimidine degradation defects

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Aromatic L-amino acid decarboxylase deficiency : A new case with a mild clinical presentation and unexpected laboratory findings

enzyme in the biosynthetic pathway of both serotonin and the catecholamines. Patients with genetic defects in the metabolism of these biogenic amine neurotrans- mitters have only been detected in recent years. Until now, only one case of patients (twins) with AADC de—ciency has been reported

Vitamin-responsive complex I deficiency in a myopathic patient with increased activity of the terminal respiratory chain and lactic acidosis

SummaryAn 11-year-old gril with exercise intolerance, fatiguability from early childhood, had high blood lactate levels. Histochemistry showed increased activity of succinate dehydrogenase at the periphery of the muscle fibres, whereas aggregates of mitochondria were seen by electron microscopy. Biochemical investigation of isolated mitochondria and homogenate from muscle showed evidence of a severe complex I deficiency. In contrast, succinate dehydrogenase, complex II + III and complex IV were increased in activity. Therapy with biotin, riboflavin, nicotinamide, carnitine and amino acids resulted in an improvement of her endurance.31P NMR spectroscopy of her forearm muscle showed a decreased ratio of phosphocreatine (PCr) over ATP. After exercise the PCr recovery rate was 26% of the average rate in 20 healthy untrained controls. When the therapy was suspended the PCr/ATP ratio at rest decreased from 2.60 to 2.34, and the PCr recovery rate after exercise decreased to 21% of the average control rate. The therapy was reinstituted but only riboflavin and carnitine were given. The PCr/ATP ratio increased to 2.60 and the PCr recovery rate increased to 32% of the control rate. Improvement of the energy metabolism in patients with defects in the oxidative phosphorylation may add to the quality of life;31P NMR spectroscopy can measure these improvements.

1H NMR spectroscopy of body fluids in patients with inborn errors of purine and pyrimidine metabolism

1H NMR spectroscopy of body fluids has been used in the diagnosis of many inborn errors of metabolism (Lehnert and Hunkler 1986; Iles and Chalmers 1988). To our knowledge there is no systematic study available of body fluids from patients with inborn errors in the purine or pyrimidine metabolism. The main advantage of the technique over others that are used diagnostically in the screening for inborn errors of metabolism is the minimal sample pretreatment required for NMR spectroscopy. Fractionation, extraction or derivatization of metabolites is not required. A further advantage is the overall view of proton-containing metabolites. Quantification of metabolites is possible. An obvious disadvantage is the substantial cost of high-field NMR spectrometers that are required for this work. This paper demonstrates that NMR spectroscopy can be used in diagnosing inborn errors in purine and pyrimidine metabolism. Examples are given of NMR spectra of body fluids from patients with dihydropyrimidine dehydrogenase deficiency (McKusick 274270) and with dihydropyrimidinase deficiency (McKusick 222748).

Prolidase deficiency among an Israeli population: prenatal diagnosis in a genetic disorder with uncertain prognosis

Prolidase deficiency is an autosomal recessive disorder that is characterized by considerable inter‐ and intrafamilial variability in its clinical presentation, ranging from asymptomatic to severe and fatal illness. We report here, for the first time, prenatal diagnosis of prolidase deficiency in a family whose first child was severely affected since birth and died at an early age. However, unexpectedly, the parents decided to continue the second pregnancy, which produced a full‐term, healthy‐appearing baby. The diagnosis of severe prolidase deficiency was confirmed in the babys leukocytes. At age 4 months the baby is asymptomatic. Since the clinical severity of the disorder cannot be predicted, genetic counselling remains problematic despite the feasibility of prenatal diagnosis. Copyright

L-2-Hydroxyglutaric aciduria and lactic acidosis

present a case of L-2-hydroxyglutaric aciduria (McKusick 236792) di†erent from We the common proÐle of L-2-hydroxyglutaric aciduria et al et al (Duran 1980 ; Barth et al et al with respect to the age of clinical 1992, 1993 ; Larnaout 1994 ; TopcÓ u 1996) onset, severity of symptoms, presence of excess lactic acid in plasma and CSF, and absence of L-2-hydroxyglutaric acid elevation in the CSF. CASE REPORT

Inhibition of beta-ureidopropionase by propionate may contribute to the neurological complications in patients with propionic acidaemia

Propionic acidaemia is due to a primary deficiency of propionyl-CoA carboxylase (EC 6.4.1.3) activity. The clinical picture is characterized by repeated relapses and neurological sequelae are common. Among the neurological complications, focal and general seizures as well as EEG abnormalities are often observed. During relapse substantial accumulation of propionate occurs in all body fluids. β-Ureidopropionase (UP, EC 3.5.1.6) is the third enzyme in the degradation pathway of uracil and thymine. It catalyses the degradation of both β-ureidopropionic acid and β-ureidoisobutyric acid to β-alanine and β-aminoisobutyric acid, respectively. A deficiency of UP or one of the other enzymes of pyrimidine degradation leads to a diminished production of β-alanine, a neurotransmitter amino acid. Diminished production of β-alanine also occurs in other pyrimidine degradation defects and is presumed to be a contributing factor in the neurological abnormalities seen in the patients with those defects (Van Gennip et al 1997). Propionate has been reported to inhibit UP in Euglena gracilis (Wasternack et al 1979). We wondered whether inhibition of UP by propionate or β-hydroxypropionate could be demonstrated in vitro in human liver and in vivo in patients with propionic acidaemia.