Propionic acidemia

OH-butyryl-CoA 3-OH-butyryl-CoA deacylase deficiency deacylase Propionic acidemia Propionyl-CoA carboxylase... 

Tiglylglycine C5 l ILE Propionic acidemia Methylmalonic acidemias Ketothiolase deficiency... 

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...

Roe CR, Millington DS, Maltby DA, Bohan TP, Hoppel CL (1984) L-carnitine enhances excretion of propionyl coenzyme A as propionylcarnitine in propionic acidemia. J Clin Invest 73 1785-1788... 

A closely related disease is caused by a deficiency of propionyl-CoA carboxylase.3 This may be a result of a defective structural gene for one of the two subunits of the enzyme, of a defect in the enzyme that attaches biotin to carboxylases, or of biotinitase, the enzyme that hydrolytically releases biotin from linkage with lysine (Chapter 14). The latter two defects lead to a multiple carboxylase deficiency and to methylmalonyl aciduria as well as ketoacidosis and propionic acidemia. ... 

Propionic acidemia Methylmalonic acidemia Intrinsic factor... 

Propionic acidemia caused by propionyl CoA carboxylase deficiency causes severe ketosis and acidosis, resulting in failure to thrive and mental retardation, and is generally fatal in infancy. Some reports of ketotic hyperglycinemia may also, with hindsight, be attributed to propionyl CoA carboxylase 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. 

An important aspect of metabolite profiles is the study of known inborn errors where the qualitative and quantitative interrelationship of the affected metabolites can be studied. A recent example of this is the comparative study of three diseases, )8-methylcrotonylglycinuria, propionic acidemia and methylmalonic aciduria [362]. The advantage of considering a complete class of compounds in a single experiment is that biochemical markers for a disorder can be detected in the context of any variations in other components. This is particularly important in monitor-... 

Lucke T, Perez-Cerda C, Baumgartner M, et al. (2004) Propionic acidemia Unusual course with late onset and fatal outcome. Metabolism 53 809-810. 

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. 

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are panethnic disorders, but their combined incidence varies considerably, with estimates ranging from 1 2000 to 1 5000 (Saudi Arabia) to 20 times lower. However, there is a general consensus that many patients with this disorder die undiagnosed, being masked by a variety of catastrophic processes (sepsis and intraventricular hemorrhage). In the United States, screening for these disorders by means of MS/MS detection of propionylcarnitine is not offered in 31 states, corresponding to 69% of all babies born... 

Figure 55-14 Plasma profiles of plasma acylcarnitine butyl-ester derivatives. A, Normal control. B, Propionic acidemia. C, Short-chain acyl-CoA dehydrogenase deficiency. D, Isovaleric acidemia. E, Medium-chain acyl-CoA dehydrogenase deficiency. F, Very long-chain acyl-CoA dehydrogenase deficiency. G, Long-chain L-3-hydroxy acyl-CoA dehydrogenase deficiency.The symbol marks internal standards [ Hjj-acetylcarnitine (m/z 263) [ HaJ-propionylcarnitine (m/z 277) fH ]-butyrylcarnitlne (m/z 295) pHal-octanoylcarnitine (m/z 347) [ Haj-dodecanoylcarnltine (m/z 403) [ Haj-palmitoy I carnitine (m/z 459).

Nyhan WL, Ozand PT. Propionic acidemia and methylmalonic acidemia. In Nyhan WL, Ozand PT, eds. Atlas of metabolic diseases. London Chapman 8t Had Medical, 1998 4-23. 

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). 

In the treatment of propionic acidemia, which of the following is contraindicated ... 

DNA analysis is performed on a family because the first child has propionic acidemia. The parents desire prenatal diagnosis, and the fetal DNA is also analyzed. The results are shown below. Which of the following risk figures reflect the risk of the fetus being affected before and after testing ... 

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. 

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. 

The sample is run overnight and reported out to the local metabolic clinic on Friday with elevated propionylcami-tine. The differential diagnosis includes propionic acidemia, methylmalonic acidemias, maternal B12 deficiency, hyperbilirubinemia, and false-positive results. 

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