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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Organic Acid Metabolism


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Propionate and methylmalonate are derived primarily from catabolism of the BCAA (Fig. 44-1). Additional sources are methionine and threonine, as well as odd-chain fatty acids and cholesterol. Methylmalonic acid (MMA) can be formed also from the catabolism of thymine.

Children with propionic acidemia and methylmalonic acidemia may manifest an intense hyperglycinemia. Indeed, these disorders once were known as “ketotic hyperglycinemia.” As the underlying biochemistry became better understood, this description was discarded in favor of more specific terminology, that is, propionic acidemia and methylmalonic acidemia.

Propionyl-CoA carboxylase deficiency blocks the biotin- and ATP-dependent conversion of propionyl-CoA to methylmalonyl-CoA

The mitochondrial enzyme (Fig. 44-1, reaction 11) is a tetramer of 540 kDa composed of two α and two β subunits. The α subunit has been mapped to human chromosome 13 and the β subunit to chromosome 3. Leader peptides, facilitating transport of the propeptides into the mitochondria, also have been identified. The α subunit contains the biotin-binding site, at which a specific enzyme, holocarboxylase synthetase, mediates binding of this cofactor to the carboxylase.

Patients with a near-total enzyme deficiency become sick as neonates with dehydration, lethargy progressing to coma, vomiting, ketoaciduria and hypotonia. The toxicity may involve the bone marrow, resulting in neutropenia and thrombocytopenia. Hyperammonemia and death from hemorrhage are not unusual. Hyperglycinemia occurs in many cases. Acidosis is not an invariant feature of the syndrome [11].

Infants may relapse, particularly in association with an infection. Permanent brain damage, seizures and mental retardation are frequent. A poor outcome is common even in patients who have enjoyed ostensibly good metabolic control [12]. Some patients remain well until later infancy or childhood, when their developmental retardation and failure to thrive are first discovered.

A variety of neuropathological features have been noted [6], including vacuolization of the white matter and patchy neuronal degeneration. The basal ganglia are a special target of injury. Hemorrhagic lesions have been reported at autopsy in the caudate, putamen, globus pallidus and thalamus. Endothelial cells in these regions tended to be swollen and hyperplastic, perhaps indicating a breakdown of the blood—brain barrier. This type of injury has been termed a metabolic stroke [13].

Various mutations have been described. These were formerly classified into two groups, pccA and pccBC, depending upon the thermostability of the mutant enzyme, its affinity for the effector K+ and the response to addition of avidin. The pccA group, which is more common, has little or no α chain and the pccBC mutants are defective in β chain activity. Inheritance is autosomal recessive.

Presumptive diagnosis requires demonstration of increased excretion of propionate derivatives, including propionylglycine, 3-hydroxypropionate, tiglylglycine and methylcitric acid, a condensation product of propionyl-CoA and oxaloacetate. Definitive diagnosis involves the measurement of enzymatic activity in peripheral blood leukocytes. Prenatal diagnosis is feasible. Hyperammonemia is a more common initial finding than metabolic acidemia.

Treatment entails the restriction of dietary protein to minimize propionate production. Most patients have growth failure. Propionyl-CoA carboxylase is stimulated by biotin, but supplementation with this vitamin is not of documented benefit. Blood carnitine is low, probably because of loss as propionylcarnitine, and some evidence points to clinical improvement with carnitine treatment. An important recent advance is orthotopic liver transplantation, which has been tried with some success in the most severe cases [14].

Methylmalonyl-CoA mutase deficiency prevents the isomerization of methylmalonyl-CoA to succinyl-CoA

The enzyme (Fig. 44-1, reaction 12) is a dimer of approximately 150 kDa made of two identical subunits bound to 1 mol of adenosylcobalamin (vitamin B12). The gene has been mapped to the short arm of human chromosome 6. Patients can have a complete deficiency of the apoenzyme (mut0), partial deficiency (mut) or various defects of vitamin B12 metabolism. The latter patients have homocystinuria and hypermethio-ninemia as well as methylmalonic aciduria.

Patients with the mut0 lesion present as neonates with vomiting, acidosis, hyperammonemia, hepatomegaly, hyperglycinemia and hypoglycemia. Neutropenia and thrombocytopenia can occur. Growth failure is very common in children. Mortality is high and prognosis is poor in children with an early onset (<2 months) of disease. The outlook is somewhat improved in children with a late-onset syndrome, although even in this group morbidity tends to be quite high [15].

Examination of the brain with magnetic resonance imaging shows some white matter attenuation during the first month of life. This progresses to a failure of myelination as the infant grows. The globus pallidus may display a disproportionate degree of injury, although this may regress to a variable degree following institution of therapy to lower the toxic concentration of methylmalonic acid (MMA) [5].

The urine contains excessive MMA, even when patients are well. The concentration in the CSF equals or even exceeds that in the blood.

Treatment involves a diet that is low in the amino acid precursors to MMA. Medical attention should be sought whenever the patient develops an acute infection. There may be a role for l-carnitine supplementation.

High concentrations of MMA, or propionate, adversely affect oxidative metabolism, resulting in a depletion of ATP. Several enzyme systems, for example, pyruvate carboxylase, are inhibited by these organic acids. In addition, the sequestration of CoA as methylmalonyl-CoA or propionyl-CoA probably causes a depletion of the free CoA pool, which would adversely affect the synthesis of myelin, urea and glucose.

Vitamin B12 is ineffective in patients with either the mut0 or mut lesions, but it may help infants with defects of cobalamin synthesis and/or transport (see below). There is no hazard associated with giving 1 to 2 mg per day of vitamin B12, and this approach is warranted until the results of enzymatic studies are available.

Methylmalonic aciduria may be secondary to defects of cobalamin metabolism

Vitamin B12 is a cofactor for the MMA-CoA mutase reaction. Increased urinary methylmalonate is a common finding in patients with cobalamin deficiency, such as in pernicious anemia or congenital defects of cobalamin metabolism. Homocystinuria also is frequent because methylcobalamin is necessary for the remethylation of homocysteine to methionine (Fig. 44-2, reaction 4; also see below, section on disorders of sulfur-containing amino acids). Neurological symptoms, frequently severe and presenting in early infancy, are common to most of these syndromes.

Intestinal absorption of cobalamin requires intrinsic factor, a glycoprotein that is synthesized in the gastric parietal cells. The cobalamin—intrinsic factor complex is taken up by cells in the ileum, where the complex dissociates. Cobalamin enters the circulation bound to transcobalamin II (TC-II), which also abets uptake into tissues. Methylcobalamin is the major circulating form, but the major intracellular species, including in the brain, appears to be adenosylcobalamin. The cobalamin—TC-II complex is broken down by a specific lysosomal protease. The free cobalamin then is methylated in the cytoplasm, or it enters the mitochondrion, where, as adenosylcobalamin, it serves as cofactor for the MMA-CoA mutase reaction.

Several genetic defects have been identified, including anomalies involving either cobalamin absorption, cellular uptake or intracellular handling. Transport defects are represented by inherited deficiency of intrinsic factor in juvenile pernicious anemia, cobalamin malabsorption syndrome and TC-II deficiency. These patients usually have megaloblastic anemia, methylmalonic aciduria and homocystinuria. Neurological signs, especially in infants with TC-II deficiency, tend to be quite severe. The pathogenesis of the CNS lesions probably involves a failure to generate an adequate amount of S-adenosylmethionine, the major methyl donor in the developing brain. This pivotal compound is formed from methionine, which is regenerated from homocysteine in a reaction that is dependent upon methylcobalamin (see below, section on disorders of sulfur amino acid metabolism).

Primary defects in the synthesis of methylcobalamin and adenosylcobalamin have been described. Patients with methylmalonic aciduria secondary to deranged vitamin B12 metabolism can be distinguished from those with the mutase deficiency by their response to pharmacological doses of cyanocobalamin or adenosylcobalamin, which sharply reduce methylmalonate excretion. At least two distinct inherited forms of faulty adenosylcobalamin synthesis, known as cblA and cblB, have been identified from clinical findings and complementation analysis in skin fibroblasts. Unlike infants with the mutase deficiency, who present in the first 1 to 2 weeks of life, these patients do not become clinically ill until after the first month of life. They may have ketonuria and metabolic acidemia, as well as a severe neurological syndrome involving coma and convulsions. Survivors commonly have mental retardation and microcephaly. Evidence of pathology to the cerebellum and the dorsal columns of the spinal cord is common.

Patients with cblA disease have defective adenosylcobalamin synthesis. The precise biochemical lesion is not yet known, although patients have normal activity of the adenosyltransferase enzyme, which mediates the formation of adenosylcobalamin from ATP and hydroxocobalamin (Fig. 44-2, reaction 16). Patients may lack a specific mitochondrial cobalamin reductase (Fig. 44-2, reactions 14 and 15). Patients with cblB disease are missing a functional adenosyltransferase enzyme (Fig. 44-2, reaction 16).

The diagnosis of defective adenosylcobalamin synthesis is suggested by methylmalonic aciduria without megaloblastic changes, homocystinuria or hypomethioninemia. The blood vitamin B12 concentration is normal. Prenatal diagnosis is feasible, either through study of the mutase reaction in amniocytes or by quantitation of MMA in amniotic fluid.

More than 90% of patients with the cblA disease respond favorably to the administration of hydroxycobalamin, which reduces MMA excretion. They have a good prognosis, with most surviving into adulthood in an intact state. Only 40% of individuals with cblB disease show a positive response. Their prognosis is less sanguine, with neurological impairment often noted among youngsters who survive the initial insult. Protein restriction, which minimizes production of MMA, is also indicated.

Glutaryl-CoA dehydrogenase deficiency blocks oxidation of glutaryl-CoA and produces degeneration in basal ganglia and white matter

Glutaric acid is an intermediate in the formation of crotonyl-CoA from α-ketoadipic acid, which is derived from the catabolism of lysine, hydroxylysine and tryptophan (Fig. 44-3). Patients with a congenital absence of glutaryl-CoA dehydrogenase (Fig. 44-3, reaction 3) seem normal at birth, although they may manifest macrocephaly. Normal development is common for the first 1 to 2 years, when they develop hypotonia, opisthotonus, seizures, rigidity, dystonia, facial grimacing and seizures. These signs may develop very abruptly, following an intercurrent illness, or in a more gradual manner. Developmental assessment is difficult because of severe motor involvement, but mental retardation may not occur. The neurological syndrome may be progressive, and death may occur during the first decade of life. The diagnostic hallmark is excretion of glutaric acid and 3-hydroxyglutaric acid. Imaging of the brain shows atrophy of the caudate and putamen and a loss of white matter in both frontal and occipital horns. Pathological examination of the brain also shows degenerative changes in the basal ganglia and the cortical white matter. A special diet low in tryptophan and lysine will reduce excretion of glutaric acid, but it may not improve the clinical status.

Type II glutaric aciduria results from a deficiency in electron transfer proteins involved in mitochondrial respiration

Oxidation of glutaric acid (Fig. 44-3, reaction 3) involves transfer of electrons to FAD, in the process forming FADH2. Glutaric aciduria type II usually is caused by a congenital deficiency of either ETF or ETF:ubiquinone reductase. These proteins, which are encoded by nuclear genes, mediate the transfer of electrons from flavoproteins to the respiratory chain in mitochondria. Other substrates that donate electrons to these proteins are dimethylglycine dehydrogenase and sarcosine dehydrogenase.

Patients often present as neonates with hepatomegaly, hypoglycemia without significant ketonemia, lipid storage myopathy with hypotonia, metabolic acidosis and a rancid urine odor similar to that of isovaleric acidemia (see above). The kidneys commonly are enlarged. Cystic changes of both the liver and kidney are frequent. Facial dysmorphism also can occur. Magnetic resonance imaging of brain typically suggests a leukodystrophy. The outlook is almost uniformly fatal, and the few babies who survive have severely compromised development and a cardiomyopathy that usually proves fatal. In rare cases, a patient stays asymptomatic until after the neonatal period, when hepatomegaly, vomiting, metabolic acidosis, hypoglycemia and a proximal myopathy become evident.

Pathological examination of the brain reveals dysplasias and other evidence of aberrant neural migration. The gyri of the cortex generally are reduced. 1H-Magnetic resonance spectroscopy of the brain shows an increase of lactic acid concentration and of the choline:creatine ratio, suggesting dysmyelination. 31P-Spectroscopy of muscle shows a severe compromise of energy metabolism [16]. Occasionally, patients have responded to riboflavin therapy [17], but there is no effective therapy.

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK27933