Isolated dehydrogenase deficiency

Roe CR, Cederbaum SD, Roe DS, Mardach R, Galindo A, Sweetman L. Isolated isobutyryl-CoA dehydrogenase deficiency an unrecognized defect in human valine metabohsm. Mol Genet Metab. 1998 Dec 65(4) 264-71. PubMed citation... 

Isolated isobutyryl-CoA dehydrogenase deficiency an unrecognized defect in human valine metabolism. 

Fig. 3.2.5 Profiles of acylcarnitines as their butyl esters in plasma (precursor of m/z 85 scan) of a normal control (a) and patients with various organic acidemias. Propionylcarnitine (C> m/z 274 peak 3) is the primary marker for both propionic acidemia (b) and methylmalonic acidemias (c). Note that an elevation of methylmalonylcarnitine (C4-UC m/z 374) is not typically found in patients with methylmalonic acidemias. In the three cases of ethylmalonic encephalopathy (d) analyzed in our laboratory, elevations of ,- (m/z 288 peak 4) and C5-acylcarnitine (m/z 302 peak 5) species were noted. Isolated C5-acylcarnitine elevations are encountered in patients with isovaleric acidemia (e), where it represents isovalerylcarnitine. Cs-Acylcarnitine is also elevated in patients with short/branched chain acyl-CoA dehydrogenase deficiency, where it represents 2-methylbutyrylcarnitine (see Fig. 3.2.4), and in patients treated with antibiotics that contain pivalic acid, where it represents pivaloylcarnitine [20, 59, 60]. Patients with /3-ketothio-lase deficiency (f) present with elevations of tiglylcarnitine (C5 i m/z 300 peak 6) and C5-OH acylcarnitine (m/z 318 peak 7). In most cases of 3-methylcrotonyl-CoA carboxylase deficiency (g) Cs-OH acylcarnitine is the only abnormal acylcarnitine species present. The differential diagnosis of C5-OH acylcarnitine elevations includes eight different conditions (Table 3.2.1). Also note that C5-OH acylcarnitine represents 3-hydroxy isovalerylcarnitine in 3-methylcrotonyl-CoA carboxylase deficiency (g), and 2-methyl 3-hydroxy butyrylcarnitine in / -ketothiolase deficiency...

A new case of short-chain acyl-CoA dehydrogenase deficiency with isolated ethylmalonic aciduria. 

High incidence of glucose-6-phosphate dehydrogenase deficiency in Croatian island isolate example from Vis island, Croatia. 

High clinical suspicion for organic acid disorders with possibly isolated elevations of pathological metabolites in CSF ( cerebral lactic addemiasj glutaryl-CoA dehydrogenase deficiency disorders of biotin metabolism)... 

The inborn errors of L-leucine catabolism present biochemically with branched-chain amino and/or organic aciduria [1]. These disorders include maple syrup disease (MSD branched-chain a-ketoacid dehydrogenase (BCKD) deficiency), isovaleric acidemia (isovaleryl-coenzyme A (CoA) dehydrogenase deficiency), isolated 3-methylcrotonyl-CoA carboxylase deficiency, the 3-methylglutaconic acidurias (3-methylglutaconyl-CoA hydratase deficiency, Barth syndrome, and other disorders in which the primary defect has not been demonstrated), and 3-hydroxy-3-methylglutaric aciduria (3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency). 

Andresen, B. S., Christensen, E., Corydon, T. J. et al. (2000) Isolated 2-methylbutyryl-glycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency Identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism. Am. J. Hum. Genet,67, 1095. 

Several diseases are known that result in elevations in tissues and fluids of various esters of carnitine and reduce the availability of free carnitine, which is normally synthesized by humans and is necessary for the transport of long-chain fatty acids into mitochondria for oxidation. In several disorders arising from acyl-CoA dehydrogenase deficiencies, the accumulation of the acyl-CoA substrate frequently sequesters coenzyme A and reduces its availability for other unrelated but important and otherwise competent pathways. Carnitine administration can displace and make available much of the coenzyme A that had been isolated, and stimulate the excretion of the accumulating acidic metabolites now esterified to carnitine. Detection of reduced levels of serum or urinary free carnitine and elevations of esterified carnitine is therefore useful for diagnosis of a variety of metabolic disorders, among them congenital inability to synthesize carnitine. In this disorder, carnitine must be supplied by a carnitine-enriched diet as it is, in effect, a vitamin. 

In the 1930s, Peters and co-workers showed that thiamine deficiency in pigeons resulted in the accumulation of lactate in the brainstem [ 15]. Furthermore, they showed that the addition of small quantities of crystalline thiamine to the isolated brainstem tissue from thiamine-deficient birds in vitro resulted in normalization of lactate levels. These findings led to the formulation of the concept of the biochemical lesion in thiamine deficiency. Subsequent studies showed that the enzyme defect responsible for the biochemical lesion was a-KGDH rather than pyruvate dehydrogenase (PHDC), as had previously been presumed. a-KGDH and PHDC are major thiamine diphosphate (TDP)-dependent enzymes involved in brain glucose oxidation (Fig. 34-4). 

Yoshiki (29) has studied the biosynthetic pathways of vitamin Bg, including the discovery of the precursor glycolaldehyde, glycolaldehyde dehydrogenase, and isolation of microorganisms deficient in regulation mechanism of Bg biosynthesis. 

In experimental animals and with isolated tissue preparations and organ cultures, the test can be refined by measuring the production of G02 from [ C]histidine in the presence and absence of added methionine. If the impairment of histidine metabolism is the result of primary folate deficiency, the addition of methionine wUl have no effect. By contrast, if the problem is trapping of folate as methyl-tetrahydrofolate, the addition of methionine will restore normal histidine oxidation as a result of restoring the inhibition of methylene-tetrahydrofolate reductase by S-adenosylmethionine and restoring the activity of 10-formyl-tetrahydrofolate dehydrogenase, thus permitting more normal folate metabolism (Section 10.3.4.1). 

The CO dehydrogenase reaction has been extensively studied in Rho-dospirillum rubrum and C. thermoaceticum. For studying this reaction, R. rubrum offers the advantage that it lacks Cluster A and the entire acetyl-CoA synthase subunit, which also contains Ni. In addition, a Ni-deficient protein eontaining all Fe components of the holoenzyme ean be isolated. Furthermore, the erystal structure of this protein will be known in the next few months. 

Patient 1 suffered from an isolated deficiency of the 3-hydroxyacyl-CoA dehydrogenase component of D-bifunctional protein and has been fully described elsewhere."" The clinical and biochemical characteristics of patient 2 have been described previously by Watkins and cowoikers."... 

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