Acidemia, metabolic

Hauser NS, et al. Variable diettuy management of methylmalonic acidemia metabolic and eneigetic correlations. Am J Chn Nutr. 2011 93(l) 47-56. 

The catabolism of leucine, valine, and isoleucine presents many analogies to fatty acid catabolism. Metabolic disorders of branched-chain amino acid catabolism include hypervalinemia, maple syrup urine disease, intermittent branched-chain ketonuria, isovaleric acidemia, and methylmalonic aciduria. 

As with the treatment of metabolic acidosis, the role of NaHC03 therapy is not well defined for respiratory acidosis. Realize that administration of NaHC03 can paradoxically result in increased C02 generation (HC03 + H+ —> H2C03 —> H20 + C02) and worsened acidemia. Careful monitoring of the pH is required if NaHC03 therapy is started for this indication. The use of THAM in respiratory acidosis (see metabolic acidosis, above) has unproven safety and benefit. 

Arterial blood gases are measured to determine oxygenation and acid-base status (Fig. 74-1). Low pH values (less than 7.35) indicate acidemia, whereas high values (greater than 7.45) indicate alkalemia. The PaC02 value helps to determine if there is a primary respiratory abnormality, whereas the I IC( )3 concentration helps to determine if there is a primary metabolic abnormality. Steps in acid-base interpretation are described in Table 74-2. 

The manifestations of acute severe metabolic acidemia (pH less than 7.15 to 7.20) involve the cardiovascular, respiratory, and central nervous systems. Hyperventilation is often the first sign of metabolic acidosis. Respiratory compensation may occur as Kussmaul s respirations (i.e., deep, rapid respirations characteristic of diabetic ketoacidosis). 

Table 3.1.1 Disorders of organic acid metabolism (in alphabetical order). This table does not include disorders with primary accumulation of amino acids, disorders of mitochondrial fatty acid oxidation, or primary lactic acidemias. Co A Coenzyme A, FAD flavin adenine dinucleotide...

Urine is collected from patients suspected to have an organic acidemia preferably during an acute metabolic decompensation. As this is often not possible, an early morning specimen should be collected. The sample should be sent frozen and without preservatives. 

Morel CF, Watkins D, Scott P, Rinaldo P, Rosenblatt DS (2005) Prenatal diagnosis for methylmalonic acidemia and inborn errors of vitamin B12 metabolism and transport. Mol Genet Metab 86 160-171... 

Thus, physiological changes in blood flow through organs, such as shunting, may occur. Peripheral vasodilation due to hypoxia may exceed the cardiac output and hence fainting and unconsciousness can occur. Lactic acidemia will also result from impaired aerobic metabolism. 

The propionyl-CoA derived from these three amino acids is converted to succinyl-CoA by a pathway described in Chapter 17 carboxylation to methylmalonyl-CoA, epimerization of the methylmalonyl-CoA, and conversion to succinyl-CoA by the coenzyme B independent methylmalonyl-CoA mutase (see Fig. 17-11). In the rare genetic disease known as methylmalonic acidemia, methylmalonyl-CoA mutase is lacking—with serious metabolic consequences (Table 18-2 Box 18-2). 

BOX 17-F LACTIC ACIDEMIA AND OTHER DEFICIENCIES IN CARBOHYDRATE METABOLISM... 

But many metabolic processes are likely to influence amino acid blood levels and urinary excretion both ways, some of which may be genetically controlled specifically or else may be influenced by a variety of body functions. Endocrine factors have for instance been taken into consideration in the case of histidinuria (S22). It seems, however, that in our present state of knowledge we are still altogether insufficiently informed about amino acid blood levels and on their possible fluctuations. As long as the data published in the literature on amino acidemia remain as scarce as they are at the present time, we feel that our knowledge of the... 

Figure 20.20 Pathways of branched-chain amino acid metabolism. A, B, C, D, E, and F indicate defects in valinemia, maple syrup urine disease, isovaleric acidemia, /3-hydroxyisovaleric aciduria, a-methyl-j3-hydroxybutyric aciduria, and methylmalonic aciduria, respectively.

Throughout this chapter, we have had occasion to refer to genetic diseases associated with amino acid metabolism. Such defects are characterized by amino acidemias and amino acidurias. The former indicate elevated amino acid levels in serum, whereas the latter indicate their excretion in the urine. A patient may have an amino aciduria without an amino acidemia. This is the case with amino acid transport disorders. It is unusual, however, to have an amino acidemia without amino aciduria. 

Some children with profound biotinidase deficiency exhibit symptoms, such as seizures, but do not have metabolic acidemia or elevations of the characteristic organic acids in their plasma or blood. What is a possible explanation for this observation ... 

Carnitine deficiency complicates HMG-CoA lyase deficiency and other inborn errors of metabolism, which results in organic acidemia. L-Camitine or P-hydroxy-y-trimethylammonium butyrate is a carrier molecule that transports long-chain fatty acids across the inner mitochondrial membrane for subsequent P-oxi-dation. L-Carnitine also facilitates removal of toxic metabolic intermediates or xenobiotics via urinary excretion of their acyl carnitine derivatives. Indeed, individuals with HMG-CoA lyase deficiency have been shown to excrete 3-methylgluatarylcamitine (Roe et al., 1986). In the absence of ketogenesis, the formation of the acyl carnitine derivative of 3-hydroxy-3-methylglutarate from HMG-CoA also serves to regenerate free CoA in the mitochondria and permits continued P-oxidation of fatty acids. 

Isovaleric acidemia. This is believed to be a defect in the step from isovaleryl Co A to beta-methyl cro-tonyl Co A, in the metabolism of leucine. Rather than a maple syrup odor, there is an odor of sweaty feet . The patient has various neurologic disturbances and mental retardation. Isovaleric acid is elevated in the plasma. It is treated by restricting dietary intake of leucine. 

Therapeutic glycine. Isovaleric acidemia is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl CoA dehydrogenase. Many infants having this disease die in the first month of life. The administration of large amounts of glycine sometimes leads to marked clinical improvement. Propose a mechanism for the therapeutic action of glycine. 

---