Propionic acid acidemia

Duran M> Ketting D, Wadman SK, Trijbels JM, Bakkeren JA, Waelkens JJ. Propionic acid, an artefact which can leave methylmalonic acidemia undiscovered. Clin Chim Acta 1973 49 177-9. 

The answer is d. (Murray, pp 238-249. Scriver, pp 2165-2194. Sack, pp 121-144. Wilson, pp 287-324.) Propionic acidemia (232000) results from a block in propionyl CoA carboxylase (PCC), which converts propionic to methylmalonic acid. Excess propionic acid in the blood produces metabolic acidosis with a decreased bicarbonate and increased anion gap (the serum cations sodium plus potassium minus the serum anions chloride plus bicarbonate). The usual values of sodium (-HO meq/L) plus potassium ( 4 meq/T) minus those for chloride (-105 meq/L) plus bicarbonate (—20 meq/L) thus yield a normal anion gap of -20 meq/L. A low bicarbonate of 6 to 8 meq/L yields an elevated gap of 32 to 34 meq/L, a gap of negative charge that is supplied by the hidden anion (propionate in propionic acidemia). Biotin is a cofactor for PCC and its deficiency causes some types of propionic acidemia. Vitamin B deficiency can cause methylmalonic aciduria because vitamin Bn is a cofactor for methylmalonyl coenzyme A mutase. Glycine is secondarily elevated in propionic acidemia, but no defect of glycine catabolism is present. 

Methylmalonic acid (MMA) is a metabolic intermediate in the biosynthesis of succinic acid from propionic acid, a step that involves the enzyme Methylmalonyl Coenzyme A mutase and a vitamin B12-derived cofactor. MMA concentrations increase when vitamin B12 is deficient hence, MMA can be used as a clinical biomarker of vitamin B12 status. In addition, mutations in the genes encoding the enzyme responsible for MMA metabolism or the enzymes responsible for vitamin B12 metabolism can lead to heritable disorders, known as methylmalonic acidemias. 

Ando, T., Nyhan, W.L., Connor, J.D., Rasmussen, K., Donnell, G., Barnes, N., Cottom, D. and Hull, D. (1972a), The oxidation of glycine and propionic acid in propionic acidemia with ketotic hyperglycinemia. Pediatr. Res., 6,576. 

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...

In known metabolic states and disorders, the nature of metabolites excreted at abnormal levels has been identified by GC-MS. Examples of this are adipic and suberic acids found in urine from ketotic patients [347], 2-hydroxybutyric acid from patients with lactic acidosis [348], and methylcitric acid (2-hydroxybutan-l,2,3-tricarboxylic acid) [349] in a case of propionic acidemia [350,351]. In the latter instance, the methylcitric acid is thought to be due to the condensation of accumulated propionyl CoA with oxaloacetate [349]. Increased amounts of odd-numbered fatty acids present in the tissues of these patients due to the involvement of the propionyl CoA in fatty acid synthesis, have also been characterised [278]. A deficiency in a-methylacetoacetyl CoA thiolase enzyme in the isoleucine pathway prevents the conversion of a-methylacetoacetyl CoA to propionyl CoA and acetyl CoA [352,353]. The resultant urinary excretion of large amounts of 2-hydroxy-3-methylbutanoic acid (a-methyl-/3-hydroxybutyric acid) and an excess of a-methylacetoacetate and often tiglyl glycine are readily detected and identified by GC-MS. 

Figure 1.19 shows a typical normal acid profile [358] and for comparison one from a patient with propionic acidemia [362]. Greatly improved separations are possible by using open tubular capillary columns [40] and it is likely that such columns will be widely used for this purpose in future. 

Lactic acidosis occurs in two clinical settings (1) type A (hypoxic), associated with decreased tissue oxygenation, such as shock, hypovolemia, and left ventricular failure and (2) type B (metabolic), associated with disease (e.g., diabetes melUtus, neoplasia, liver disease), drugs and/or toxins (e.g., ethanol, methanol, and salicylates), or inborn errors of metabolism (e.g., methylmalonic aciduria, propionic acidemia, and fatty acid oxidation defects). Lactic acidosis is not uncommon and occurs in approximately 1% of hospital admissions. It has a mortality rate greater than 60%, which approaches 100% if hypotension is also present. Type A is much more common. 

Carbamoyl phosphate synthesis requires amino acid acetyltransferase (N-acetylglutamate synthase, mitochondrial) and carbamoyl-phosphate synthase I (CPSI). N-Acetylglutamate (NAG) is an obligatory positive effector of CPSI. NAG synthase is under positive allosteric modulation by arginine and product inhibition by NAG. Depletion of CoA-SH decreases NAG synthesis and ureage-nesis. This situation can occur in organic acidemias (e.g., propionic acidemia Chapter 18), in which organic acids produced in excess compete for CoA-SH for formation... 

Inborn errors of metabolism may be due to propionyl-CoA carboxylase deficiency, defects in biotin transport or metabolism, methylmalonyl-CoA mutase deficiency, or defects in adenosylcobalamin synthesis. The former two defects result in propionic acidemia, the latter two in methylmalonic acidemia. All cause metabolic acidosis and developmental retardation. Organic acidemias often exhibit hyperammonemia, mimicking ureagenesis disorders, because they inhibit the formation of N-acetylglutamate, an obligatory cofactor for carbamoyl phosphate synthase (Chapter 17). Some of these disorders can be partly corrected by administration of pharmacological doses of the vitamin involved (Chapter 38). Dietary protein restriction is therapeutically useful (since propionate is primarily derived from amino acids). Propionic and methylmalonyl acidemia (and aciduria) results from vitamin B12 deficiency (e.g., pernicious anemia Chapter 38). 

Because persons may be bom with defects in almost any gene, a variety of other problems leading to accumulation of organic acids are also known. Methylmalonic aciduria and propionic acidemia are discussed in Box 17-B. Lactic acidemia (Box... 

Sometimes a test for more than one protein is needed and mass spectrometry is the method of choice for that purpose. A good example for this would be the use of tandem mass spectrometry to screen neonates for metabolic disorders such as amino acidemias (e.g., phenylketonuria—PKU), organic acidemias (e.g., propionic acidemia—PPA), and fatty acid oxidation disorders (e.g.. Medium-chain acyl-CoA Dehydrogenase deficiency—MCAD) [9]. Although the price of this capital equipment could be high, costs of using it as a sensor is quite low (usually < U.S. 50.00 to screen for more than 20 metabolic disorders), and many states in the United States provide the service to newborns during the first week of life. 

In patients with organic acidemias and urea cycle disorders, approximately 50 % of total protein is consumed in amino acid-based formulas. The amount of total protein and percentage of amino acid-based formulas is variable [44, 72]. Reported clinical outcomes based on dosage of amino acid-based medical foods are variable. Touati et al. [72] reported near-normal growth velocity in patients with propionic acidemia in total protein intakes lower than recommended [72]. The amount of... 

They are defects in the degradation pathways of leucine, isoleucine, and valine. These conditions are usually diagnosed by examining organic acids in urine with abnormal metabolites also notable on acylcamitine profile. Organic acidemias comprise a variety of disorders and include methylmalonic acidemia (MMA), propionic acidemia (PROP), isovaleric acidemia (IVA), glutaric acidemia type 1 (GA-1), 3-methylcrotonyl carboxylase deficiency (3-MCC), 3-methylglutaconic acidemia (3-MGA), and vitamin B12 uptake, transport, and synthesis defects. 

Propionic acidemia (PROP) and methylmalonic acidemia (MMA) are inherited disorders of the metabolism of the propiogenic amino acids valine, isoleucine, threonine, and methionine and odd-chain fatty acids (Figs. 20.1 and 20.2,... 

A typical example of the use of GC/MS is in the detection of acidemia (defined as an accumulation of organic acids in cells or body fluids), which can manifest in infants. Propionic acidemia can induce lethargy, vomiting, acidosis, hypoglycemia, and possibly death in infants. To diagnose these disorders, organic acids are extracted from body fluids, derivatized by trimethylsilylation, and profiled by GC/MS [46]. 

Unlike many routine clinical chemistry tests, clinical analyses of lEM almost always involve a multiple metabolite analysis. The results form the basis of a metabolic profile in which both individual concentrations of metabolites and their relationship to each other can be viewed either in tabular form or in a graphical display. Perhaps the most comprehensive and historically significant test in lEM studies is gas chromatography/mass spectrometry (GC/MS) of a derivatized extract of urine. Figure 2 is a chromatogram from an infant with propionic acidemia, an organic acid disorder of leucine metabolism. Hundreds of volatile compounds of carbohydrate, amino acid, fatty acid, and nucleic acid metabolism are separated in 40 min using capillary GC. Addition... 

Method for Determination of Volatile Organic Acids in Aqueous Solutions and Urine, and the Results Obtained in Propionic Acidemia, 3-Methyl-crotonyglycinuria, and Methylmalonic Acidemia... 

Note that MS/MS is unable to distinguish between isomeric acylcarnitines. Therefore, elevations of C4 can be either from accumulation of butyr-yl or isobutyryl carnitine, C5 can be either isovaleryl or 2-methylbutyryl and so on. Some individual metabolites are characteristic of more that one disease. Propionylcarnitine is markedly elevated in both propionic and methylmalonic acidemia. 3-Hydroxyisovalerylcarnitine (OH-C5) is associated with both 3-MCC deficiency and HMG-CoA-lyase deficiency. Minor elevations in either or both of these metabolites are also consistent with ho-locarboxylase deficiency or with deficiency of the cofactor biotin (or bioti-nidase). The differential diagnosis of each of these conditions is generally made from a careful analysis of urinary organic acids, performed by capillary column GC/MS in a reputable facility. This is especially important in the follow-up of abnormal newborn screening acylcarnitine results. 

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