A series of metabolic disorders with prominent neurological accompaniments and serious deleterious effects on the developing central nervous system have been described under the designation organic acid disorders . The term organic acid is particularly imprecise but, unfortunately, appears to be firmly entrenched in the medical literature. Strictly speaking, organic acids should include amino acids, fatty acids, ketoacids, and a variety of other endogenous and exogenous acids. Disorders of amino acids are discussed in Chapter 27 . In this chapter, the disorders of organic acids that are associated with prominent neurological phenomena in the neonatal period and that have been reported in more than a few infants are discussed.
Overview of Major Organic Acid Disorders and Neonatal Metabolic Acidosis
The organic acid disorders enumerated in Table 28.1 are important causes of severe neonatal metabolic acidosis. The major acids that accumulate vary according to the site of the metabolic defect, as outlined subsequently. Lactic acidosis is a very frequent accompaniment. A simplified scheme for the differential diagnosis of neonatal lactic acidosis is shown in Fig. 28.1 . In the following sections, the disorders of metabolism of propionate and methylmalonate, pyruvate, and branched-chain ketoacids are discussed. The rare other organic acid disorders and a fatty acid oxidation disorder (see Table 28.1 ) are described briefly at the conclusion of the chapter. The mitochondrial disorders are discussed in Chapter 29 . The disorders of carbohydrate metabolism listed in Table 28.1 and renal tubular acidosis either manifest clinically only rarely in the neonatal period or exhibit primarily nonneurological syndromes and are not reviewed further.
| Disorders of propionate-methylmalonate metabolism |
|
| Disorders of pyruvate and mitochondrial energy metabolism |
|
| Disorders of branched-chain amino acid–ketoacid metabolism |
|
| Disorders of fatty acid metabolism |
|
| Other organic acid disorders |
|
| Disorders of carbohydrate metabolism |
|
| Renal tubular acidosis |
Disorders of Propionate and Methylmalonate Metabolism
Disorders of propionate and methylmalonate metabolism are uncommon but result in serious neonatal neurological disturbances. These disorders are the most common of the so-called organic acid abnormalities. In an earlier large series (105 cases) of patients with organic acidurias with neonatal onset, disorders of propionate and methylmalonate metabolism accounted for 40% of the total. Later reported experiences have been similar. These diseases share certain common features ( Table 28.2 ).
| Clinical features |
|
| Metabolic features |
|
| Other features |
|
| Neuropathological features |
|
Normal Metabolic Aspects
Propionate and methylmalonate are vital intermediates in the catabolism of lipid and protein. The major pathway of the metabolism of propionate and methylmalonate is shown in Fig. 28.2 . Although propionyl–coenzyme A (CoA) formation from isoleucine catabolism is depicted, this organic acid is also the product of the catabolism of valine, methionine, threonine, cholesterol (side chain), and odd-chain fatty acids. Involved in the propionate and methylmalonate pathway are two vitamins, biotin and vitamin B 12 . Biotin is the coenzyme for propionyl-CoA carboxylase, and adenosyl cobalamin (a derivative of vitamin B 12 ) is the coenzyme for methylmalonyl-CoA mutase. Indeed, some of the disorders of this pathway are responsive to large doses of these vitamins (see later section). The product of the pathway, succinyl-CoA, enters the tricarboxylic acid cycle, where pyruvate is formed from reaction with oxaloacetate.
Certain alternate and minor metabolic pathways are important in understanding the disorders of this pathway (see Fig. 28.2 ). Thus, propionyl-CoA also can be metabolized to lactate and can be used in the synthesis of odd-numbered fatty acids. Methylmalonyl-CoA can be used in the synthesis of methyl-branched fatty acids.
Biochemical Aspects of Disordered Metabolism
Enzymatic Defects and Essential Consequences
The enzymes affected in the disorders of propionate and methylmalonate metabolism are shown in Fig. 28.2 . The resulting metabolic consequences (e.g., acidosis, hyperammonemia, and hyperglycinemia) are diverse, and their pathogeneses are now understood to a considerable degree.
Acidosis
The acidosis in disorders of propionate and methylmalonate metabolism results, at least in part, from the accumulation of the acids proximal to the primary enzymatic blocks. However, the degree of acidosis is often greater than can be accounted for by these compounds. Other sources of acidemia include conversion of excessive propionate to lactate by a normally minor metabolic pathway (see Fig. 28.2 ), inhibition of pyruvate dehydrogenase with resulting increased conversion of pyruvate to lactate, and accumulation of ketone bodies by poorly understood mechanisms.
Hyperammonemia
The hyperammonemia that is a nearly consistent feature of the neonatal varieties of propionate and methylmalonate disturbances appears to result from two closely related mechanisms. Both relate to an accumulation of the CoA esters of the acids proximal to the enzymatic blocks (particularly propionyl-CoA, tiglyl-CoA [a metabolite of isoleucine], and methylmalonyl-CoA) and to the effects of these derivatives on the activity of carbamyl phosphate synthetase, the first step in the Krebs–Henseleit urea cycle (see Chapter 27 ). Thus these CoA esters have been shown to have a direct inhibitory effect on carbamyl phosphate synthetase and an indirect inhibitory effect at this step by inhibiting the synthesis of N -acetylglutamate, the important activator of carbamyl phosphate synthetase. Hyperammonemia and acidosis have major deleterious effects on the brain (see Chapter 27 ) and are thought to be major determinants of the acute neurological dysfunction and brain injury that result in the neonatal period.
Hyperglycinemia
A striking aspect of propionate and methylmalonate metabolism is hyperglycinemia . This condition is unlike the nonketotic hyperglycinemia described in Chapter 27 because of the association of ketoacidosis (i.e., ketotic vs. nonketotic hyperglycinemia) and because the glycine abnormality is a secondary and not a primary metabolic phenomenon. Analogous to the cause of the hyperammonemia in these disorders of the propionate and methylmalonate pathway, the cause of the hyperglycinemia appears related to an inhibition of glycine cleavage by the accumulation of branched-chain alpha-ketoacids and, more specifically, their CoA derivatives.
A disturbance of glycine cleavage was demonstrated indirectly and directly in studies of patients with ketotic hyperglycinemia caused by deficiencies of propionyl-CoA carboxylase and methylmalonyl-CoA mutase, as well as of isovaleryl-CoA dehydrogenase and beta-ketothiolase (the last two disorders of branched-chain amino acid metabolism are discussed later). Analyses of the individual protein components of the glycine cleavage system of patients with propionic acidemia and methylmalonic acidemia have shown that the H-protein, one of the four proteins of the system, is the component initially inactivated.
That the impairment of glycine metabolism involves the inhibition of the glycine cleavage system by CoA derivatives of accumulated metabolites is suggested by data based on studies of rat liver. In vitro studies of the solubilized hepatic glycine cleavage system show marked inhibition by CoA derivatives found in the catabolic pathway for isoleucine. Such derivatives would be expected to accumulate in the disorders of the propionate and methylmalonate pathway (see Fig. 28.2 ). Coupled with the data referable to the genesis of the hyperammonemia, these observations suggest that the CoA derivatives of the accumulated organic acids are responsible for the major critical secondary metabolic effects that accompany the primary enzymatic disorders.
Myelin Disturbance and Fatty Acid Abnormalities
In the disorders associated with the accumulation of propionic and methylmalonic acids, a disturbance of myelin , detectable by neuropathological examination (see “Neuropathology”), appears to be important in the genesis of the neurological sequelae. Vacuolation of myelin appears in the first months of life and is followed by an apparent disturbance of myelin formation. The magnetic resonance imaging (MRI) correlate of the myelin disturbance, present in many reported cases (see later), is, acutely, diffusely swollen T2-hyperintense cerebral white matter, followed later by white matter atrophy. The genesis of the myelin disturbance is not clear but may be related to changes in the fatty acid composition of oligodendroglial membranes. Distinct changes exist in the composition of fatty acids in the brains of patients with disorders resulting in the accumulation of propionate or methylmalonate, and these changes can be reproduced in cultured rat glial cells. The major alterations are increases in the amounts of odd-numbered and methyl-branched fatty acids (see later). These increases have been demonstrated in phospholipids (i.e., components of all cellular membranes) as well as in myelin lipids (e.g., cerebrosides and sulfatides; Table 28.3 ). Because the fatty acid composition of membrane lipids is important for not only for structural integrity but also the function of a variety of membrane proteins (e.g., enzymes, transport carriers, surface receptors), these alterations may have major implications for the genesis of neurological dysfunction and the disturbance of myelination.
| ODD-NUMBERED FATTY ACIDS | METHYL-BRANCHED FATTY ACIDS | |||
|---|---|---|---|---|
| BRAIN LIPID CLASS | CONTROL (%) | PATIENT (%) a | CONTROL (%) | PATIENT (%) a |
| Choline phospholipid | Trace | 9.8 | — | 2.1 |
| Sphingomyelin | 7.5 | 18.2 | — | — |
| Cerebroside | 18.9 | 29.0 | — | — |
| Sulfatide | 21.7 | 31.1 | — | — |
Disturbances of Fatty Acid Synthesis
The fatty acid abnormalities described in the previous section are presumably caused by disturbances of fatty acid synthesis. The nature of the disturbances observed in disorders of propionate and methylmalonate metabolism is depicted in Fig. 28.3 . Thus, under normal circumstances, de novo synthesis of fatty acids in brain is catalyzed by the multienzyme complex fatty acid synthetase. The first two carbons (i.e., the primer) of the resulting even-numbered fatty acids (primarily the 16-carbon acid, palmitic acid) are derived from acetyl-CoA, whereas the remaining carbons for chain elongation are derived from the two-carbon units obtained from malonyl-CoA (see Fig. 28.3 ). When propionyl-CoA is present in excessive amounts, it can replace acetyl-CoA with a three-carbon fragment as primer ; thus an odd-numbered fatty acid results after the addition of the two-carbon units from malonyl-CoA (see Fig. 28.3 ). When methylmalonyl-CoA is present in excessive amounts, it can replace malonyl-CoA ; thus a methyl-branched unit is derived from malonyl-CoA, resulting in methyl-branched fatty acids (see Fig. 28.3 ). These unusual fatty acids are incorporated into cellular membranes, including myelin, as discussed in the previous section.
Propionic Acidemia and Propionyl–Coenzyme A Carboxylase Deficiency
Propionic acidemia is caused by a defect in the first step of the pathway from propionyl-CoA to succinyl-CoA, a step catalyzed by the enzyme propionyl–CoA carboxylase.
Clinical Features
Onset is in the first days of life, with a dramatic clinical syndrome consisting primarily of vomiting, stupor, tachypnea, and seizures (see Table 28.2 ). The usual time of onset is the second to fourth days of life. Infants whose condition is not diagnosed and treated properly rapidly lapse into coma and die. Indeed, in earlier studies, approximately 75% of patients died in early infancy. More recent improvements in management have resulted in improved survival rates. In one series of six infants, all survived the neonatal period. Lethal cerebellar hemorrhage, occurring in association with thrombocytopenia and hyperosmolar bicarbonate therapy, has occasionally been observed in the neonatal period. Survivors of the neonatal period are prone to episodic attacks of vomiting and stupor, with severe ketoacidosis, often precipitated by infection, and to subsequent retardation of neurological development. Of 11 infants reported in one series, no survivor had an intelligence quotient (IQ) higher than 60. In a later series of 38 infants, 95% had “cognitive and neurologic” deficits. In a recent report, the clinical and outcome data of 55 surviving patients with propionic acidemia was evaluated retrospectively ( Fig. 28.4 ). The vast majority of patients (>85%) presented with metabolic decompensation in the neonatal period. Approximately 75% of the study population was mentally retarded, with a median IQ of 55. Chorea or dystonia has been observed in 20% to 40% of surviving children, and such extrapyramidal involvement is common in this disorder (see later discussion of neuropathology). The genetic data for this disorder indicate autosomal recessive inheritance. This conclusion is based in part on the pattern of familial occurrence, partial disturbance of enzymatic activity in parents, and complementation testing of cells in culture.
Metabolic Features
Major Findings.
The constellation of ketoacidosis, propionic acidemia, hyperglycinemia (and hyperglycinuria), hyperammonemia, neutropenia, anemia, and thrombopenia is characteristic and composes the ketotic hyperglycinemia syndrome . However, hyperglycinemia with propionic acidemia and propionyl-CoA carboxylase deficiency has occurred in the neonatal period without consistent ketonuria. This finding is important because patients with disorders of propionate and methylmalonate metabolism should be managed differently from those with the more common nonketotic hyperglycinemia described in Chapter 27 .
Enzymatic Defect.
The enzymatic defect involves propionyl-CoA carboxylase. Structural alterations of the two nonidentical subunits (alpha and beta) of the carboxylase molecules account for the enzymatic defect. The enzyme contains four copies each of the alpha and beta subunits, with the gene for the alpha subunit encoded on chromosome 13 and the gene for the beta subunit encoded on chromosome 3. Because this enzyme requires biotin for activity, the possibility of a defect in activation or binding of biotin to the carboxylase apoprotein as the basis of the disturbed activity in certain patients must be considered. The initial observation of a beneficial response of one patient to large amounts of biotin suggested that such an additional defect may occur. The delineation of impaired activity of propionyl-CoA carboxylase (as well as of other carboxylases) in two disorders of biotin metabolism, holocarboxylase synthetase deficiency and biotinidase deficiency, corroborated this suggestion (see later discussion). However, only one of these disorders (holocarboxylase synthetase deficiency) consistently causes prominent clinical phenomena in the newborn, as discussed later.
Pathogenesis of Metabolic Features.
The genesis of the various metabolic consequences of this disorder is now understood to a considerable degree. The origins of the hyperglycinemia and the hyperammonemia relate to the secondary effects of the CoA derivatives of certain of the accumulated metabolites on the pathways of glycine cleavage and ammonia detoxification by the urea cycle (see earlier discussion). The acidosis must relate to several factors (i.e., accumulation of the propionic acid proximal to the primary enzymatic block, of lactate produced by the alternate pathway of propionate degradation, and of the various acids that accumulate proximal to propionic acid as a consequence of continuing degradation of branched-chain and other amino acids).
Increased numbers of odd-numbered fatty acids have been observed in the tissues of infants with propionic acidemia. The genesis of the odd-numbered fatty acids relates to the utilization of propionyl-CoA as a primer for the fatty acid synthetase reaction, as described previously (see Fig. 28.3 ).
Neuropathology
A well-studied neonatal case of propionic acidemia involved a 1-month-old patient. The dominant neuropathological findings involved myelin and consisted of marked vacuolation , with a less striking diminution of the amount of myelin. Similar pathological findings have been described in other affected cases. The disturbance of myelin is similar to that noted in nonketotic hyperglycinemia and other aminoacidopathies (see Chapter 27 ). Vacuolation appears to be the early change, occurring principally in systems actively myelinating at the time of the illness (e.g., medial lemniscus, superior cerebellar peduncle, posterior columns, and peripheral nerve in the 1-month-old patient of Shuman and coworkers ) ( Fig. 28.5 ). The impaired myelination appears to occur subsequent to the vacuolation. Vacuolation has been observed in oligodendrocytes in areas just before myelination. The cause of this defect in myelination in ketotic hyperglycinemia may relate to the disturbance of fatty acid synthesis and the resultant altered fatty acid composition of myelin (see earlier discussion). Thus the odd-numbered fatty acids may alter the stability of the oligodendroglial-myelin membrane, thereby impairing oligodendroglial differentiation and rendering the newly formed myelin unstable. Vacuolation and the subsequent deficit of myelin would result. Other possibilities, such as disturbance of synthesis of myelin proteins because of the amino acid imbalance (e.g., the elevated glycine levels) must be considered as well.
An interesting additional feature of the neuropathology of propionic acidemia is the prominence of involvement of the basal ganglia in patients who survive for several or more years. Thus neuronal loss and gliosis are prominent and, in one case, the addition of aberrant myelin bundles caused a marbled appearance, reminiscent of status marmoratus of perinatal asphyxia. In contrast to methylmalonic acidemia (see later), caudate and putamen, rather than globus pallidus, are preferentially involved. The importance of excitotoxicity in the basal ganglia neuronal injury and the potential role of glycine in the genesis of excitotoxic neuronal injury (see discussion of nonketotic hyperglycinemia in Chapter 27 ) are of interest in this context. The involvement of basal ganglia in older infants and children has been documented repeatedly by brain imaging. Finally, this derangement of basal ganglia may underlie the relative frequency of extrapyramidal movement disorders observed subsequently in infants with propionic acidemia. Cerebral cortical atrophy is noted in survivors of several years or more.
As with several other metabolic disorders in which the enzymatic defect is present in brain (see later), agenesis or hypoplasia of the corpus callosum may result ( Fig. 28.6 ). Indeed, the presence of callosal abnormalities without an obvious syndromic or other cause should raise the possibility of a metabolic disorder.
Management
Antenatal Diagnosis.
Antenatal diagnosis has been accomplished by measuring propionyl-CoA carboxylase activity chorionic villus samples, by analyzing metabolites in amniotic fluid, and by molecular genetic testing of DNA extracted from fetal cells. Thus the possibility of preventing the disorder is real.
Early Detection.
Early diagnosis, particularly in distinguishing this disorder from other causes of severe metabolic acidosis in the neonatal period (see Table 28.1 ), is critical. Identification of the accompanying metabolic features is particularly valuable in this regard. Organic acid analysis of urine by tandem mass spectrometry is especially useful. Recent evidence suggests that heptadecanoylcarnitine (C17) is a novel biomarker specific for the identification of patients with propionic acidemia and methyl malonic aciduria. Thus 21 out of 23 neonates (22 with methymalonic aciduria, and 1 with propionic acidemia) exhibited significantly higher levels of C17 compared with controls. Definitive diagnosis is established by measurement of propionyl-CoA carboxylase activity in leukocytes or cultured fibroblasts.
Acute and Long-Term Therapy.
Acute episodes should be treated by withdrawing all protein and administering sodium bicarbonate parenterally. Hyperammonemia may be severe enough to require specific measures for ammonia removal, such as hemolysis, as described in Chapter 27 . Subsequently, a low-protein diet (restricted especially in isoleucine, valine, methionine, and threonine) is administered. The use of gastrostomy feeding to guarantee nutritional intake has been valuable. Supplementation with l -carnitine may be indicated, because the excretion of carnitine as propionyl carnitine may lead to decreased plasma levels of free carnitine, and supplementation with carnitine has produced beneficial clinical and metabolic responses in isolated patients. Oral antibiotic therapy to reduce propionate production by bacteria in the gastrointestinal tract may also be useful later.
Biotin.
Because some biochemical benefit was observed in an infant treated with biotin, large doses of this vitamin are worthy of a trial in affected patients. Biotin responsiveness should be assessed by observation of changes in metabolite levels in blood and urine and in enzyme activity in white blood cells. The effect of biotin in vitro on the enzyme in cultured fibroblasts may be useful in determining the likelihood of a beneficial response in vivo. Marked biotin responsiveness is characteristic of multiple carboxylase deficiency (see later discussion).
Gene Therapy.
Liver transplantation early in infancy may be of value in the management of neonatal-onset propionic acidemia. Initial mortality rates after transplantation exceeded 50%; thus the number of infants followed sufficiently long after transplant is small. Moreover, in a recent report of 12 treated patients with propionic acidemia, mortality was still high (58%). When cardiomyopathy was present before transplantation, it resolved; but renal failure, present in 50% of the patients before transplantation, worsened in all following transplantation. A beneficial effect on neurological development remains to be defined.
Methylmalonic Acidemias
Methylmalonic acidemias constitute the single most frequent group of organic disorders. The accumulation of large quantities of methylmalonic acid in blood and urine is associated with at least five discrete metabolic defects (see Fig. 28.2 ): (1 and 2) defects of methylmalonyl-CoA mutase (two different defects of the mutase apoenzyme, one resulting in complete deficiency and the other in partial deficiency of the mutase), (3 and 4) defects in the synthesis of adenosylcobalamin, and (5) defective synthesis of both adenosylcobalamin and methylcobalamin ( Table 28.4 ). The last three defects of vitamin B 12 metabolism result in diminished activity of methylmalonyl-CoA mutase, for which adenosylcobalamin is a coenzyme. In addition, the last of these defects also results in diminished activity of the methyltransferase required for methylation of homocysteine; the formation of the methyltransferase requires methylcobalamin. In one series of 45 carefully studied patients with methylmalonic acidemia (without homocystinuria), 15 had complete mutase deficiency, 5 had partial mutase deficiency, 14 had deficient mitochondrial cobalamin reductase, and 11 had deficient cobalamin adenosyltransferase (the latter two defects resulting in defective synthesis of adenosylcobalamin). These disorders are discussed collectively.
| METABOLIC ACCUMULATION | ||
|---|---|---|
| DEFECTIVE ENZYME | METHYLMALONIC ACID | HOMOCYSTEINE |
| Methylmalonic acid mutase | + | − |
| Mitochondrial cobalamin reductase ( cblA ) | + | − |
| Mitochondrial cobalamin adenosyltransferase ( cblB ) | + | − |
| Abnormal lysosomal or cytosolic cobalamin metabolism ( cblC, cblD, cblF ) | + | + |
Clinical Features
The clinical features are similar to those noted for disorders of propionate metabolism (i.e., vomiting, stupor, tachypnea, and seizures; see Table 28.2 ). Onset of these features in the neonatal period depends on the nature of the enzymatic defect ( Table 28.5 ). Neonatal onset is most likely with complete mutase deficiency, and nearly all neonates with this severe enzymatic lesion present in the first 7 days of life. Fewer than half of all patients with the other three metabolic defects present in the first 7 days. The outcome also is related to the type of metabolic defect (see Table 28.5 ). The gravity of outcome correlates approximately with the frequency of neonatal onset. Thus infants with complete mutase deficiency nearly invariably die or exhibit subsequent neurological impairment. In earlier series, mortality rates for such patients were approximately 60%, although in more recent series, approximately 30% of infants have died. In a series of 35 infants, of whom 6 were cobalamin-responsive and 29 were cobalamin-nonresponsive (20 were early-onset and 9 late-onset cases), the median range of subsequent full-scale IQ score was 100 for the cobalamin-responsive, 75 for the early-onset cases, and 101 for late-onset non–cobalamin responsive patients, respectively. One infant with severe mutase deficiency detected at 3 weeks of age by neonatal screening was reported to be normal at the age of 5 years after treatment with a low-protein diet. Patients with methylmalonic acidemias who survive are subject to episodic decompensation, especially with minor intercurrent infections. Brain imaging reveals the abnormalities of myelin, as noted earlier for propionic acidemia. Involvement of basal ganglia, similarly, is very common, but in the case of methylmalonic acidemia, it involves the globus pallidus rather than the caudate/putamen, as in propionic acidemia.
| METABOLIC DEFECT | ||||
|---|---|---|---|---|
| ONSET OR OUTCOME | mut• | mut – | cblA | cblB |
| Age at onset | ||||
| 0–7 days | 80% | 40% | 42% | 33% |
| 8–30 days | 7% | 20% | — | 22% |
| >30 days | 13% | 40% | 58% | 55% |
| Outcome | ||||
| Dead | 60% | 40% | 8% | 30% |
| Impaired | 40% | 20% | 23% | 40% |
| Well | — | 40% | 69% | 30% |
The smaller number of infants, approximately 35, reported with a defect in cobalamin metabolism characterized by impaired synthesis of both methylcobalamin and adenosylcobalamin (see Table 28.4 ) (see the next section, “Metabolic Features”) and onset in the first month of life also had a generally unfavorable neurological outcome (not shown in Table 28.5 ). The clinical and neuroradiological features were similar, albeit milder than those observed in patients with the mutase deficiencies, and the metabolic features included homocystinuria as well as methylmalonic acidemia. At least 80% subsequently exhibited major developmental deficits, and completely normal intellectual functioning was very unusual. Available genetic data indicate that these disorders all exhibit autosomal recessive inheritance.
Metabolic Features
Major Findings.
The constellation of severe ketoacidosis, methylmalonic acidemia, hyperglycinemia, hyperammonemia, neutropenia, and thrombopenia is characteristic. Approximately 40% of neonatal patients have also exhibited significant hypoglycemia with their attacks of ketoacidosis.
As noted earlier, approximately 35 infants were observed with a genetic defect resulting in impaired synthesis of both methylcobalamin and adenosylcobalamin and the additional metabolic feature of homocysteinemia/homocystinuria. However, unlike the classic homocystinuria resulting from cystathionine synthase deficiency (which is associated with elevated levels of methionine and depressed levels of cystathionine), this type is associated with hypomethioninemia and cystathioninuria (the product of homocysteine and serine) (see Fig. 28.2 ).
Enzymatic Defects.
The enzymatic defects in methylmalonic acidemias involve the methylmalonyl-CoA mutase apoenzyme (two major defects) and the metabolism of vitamin B 12 (three major defects), as noted in the introduction to this section (see Table 28.4 ). The defects have been demonstrated primarily in liver and in cultured fibroblasts.
The two major defects of the mutase apoenzyme result, as noted earlier, in either complete or partial deficiency of enzyme activity. In most reported examples of complete deficiency of mutase activity, little or no immunoreactive enzyme protein was present. In the cases with partial deficiency of activity, a presumably altered enzyme with defective catalytic function was present, because the amount of immunologically reactive protein varied from 20% to 100% of control values.
The three major sites of the defects in vitamin B 12 metabolism are shown in Fig. 28.2 . Under normal circumstances, vitamin B 12 , bound to a carrier protein, is internalized by the cell through endocytosis; the endosome is taken up by the lysosome, proteases of which degrade the carrier protein, and the cobalamin is released into the cytosol, where reduction and methylation take place. A portion of the cobalamin released into the cytosol enters the mitochondrion for reduction and adenosylation. The defect that results in impaired synthesis of both methylcobalamin and adenosylcobalamin involves an event after binding and internalization (i.e., after cellular uptake). The defects of vitamin B 12 metabolism have been defined through studies of cultured fibroblasts from affected patients.
Pathogenesis of Metabolic Features.
The causes of the various metabolic consequences of the methylmalonic acidemias are similar in many ways to those described for other disorders in the propionate and methylmalonate pathway, especially regarding the hyperglycinemia and the hyperammonemia . The ketoacidosis is not as readily accounted for because it is more severe than would be expected from the accumulation of methylmalonic acid. Methylmalonyl-CoA is an inhibitor of pyruvate carboxylase, and its product, succinyl-CoA, is involved in gluconeogenesis by conversion to pyruvate (see earlier discussion). Together, these effects could lead to an impairment of gluconeogenesis to account for the hypoglycemia in nearly half of the neonatal cases and, secondarily, to increased catabolism of lipid, with resultant ketosis and acidosis.
The accumulation of odd-numbered and methyl-branched fatty acids in neural and other tissues of affected patients relates, respectively, to substitution of propionyl-CoA for acetyl-CoA as primer for the fatty acid synthetase reaction and to the substitution of methylmalonyl-CoA for malonyl-CoA for chain elongation in the same reaction (see Fig. 28.3 ). The genesis of the defects of sulfur amino acid metabolism in the disorder with impaired synthesis of both methylcobalamin and adenosylcobalamin relates to a disturbance of the methylation of homocysteine to form methionine; the enzyme for this reaction, methionine synthase, requires methylcobalamin (see Fig. 28.2 ). The consequences of the disturbance of homocysteine methylation, as noted earlier, are homocystinuria, hypomethioninemia , and cystathioninuria , the last resulting because some of the accumulated homocysteine is converted to cystathionine.
Neuropathology
The neuropathological features of the methylmalonic acidemias suggest a derangement of myelination. An abnormality of myelin with features similar to those described for propionic acidemia has been observed. Particular involvement of spinal nerve roots rather than central myelin was noted in one premature infant studied. Whether the myelin defect relates to the abnormal accumulation of odd-numbered and methyl-branched fatty acids in glial membranes, as discussed earlier, remains to be established.
A carefully studied infant of 36 weeks of gestation (death at 4 days of age) exhibited selective death of immature neurons (i.e., residual neuronal cells in germinal matrix), migrating neuroblasts, and neurons of the external granule cell layer of cerebellum ( Fig. 28.7 ). The cytological characteristics, marked karyorrhexis, were compatible with apoptotic cell death and suggested that the toxic effect of the metabolites of methylmalonic acidemia particularly involved provocation of apoptosis of immature neuronal cells. Involvement of the external granule cell layer of cerebellum may be related etiologically to the occasional occurrence of cerebellar hemorrhage with methylmalonic acidemia.
As noted earlier, as with propionic acidemia, evidence for basal ganglia lesions has been obtained by brain imaging later in infancy and childhood. In methylmalonic acidemias, the globus pallidus is preferentially affected. This finding is consistent with the occurrence of dystonia and extrapyramidal features on follow-up in approximately 20% to 25% of cases of methylmalonic acidemia of neonatal onset.
Management
Antenatal Diagnosis.
Antenatal detection of the methylmalonic acidemias has been accomplished primarily by detecting elevated methylmalonate content in the amniotic fluid and maternal urine and by enzymatic assay of cultured amniotic fluid cells (mutase activity and adenosylcobalamin synthesis). The possibility of prenatal therapy with cobalamin supplements was shown initially by demonstrating a decrease in maternal excretion of methylmalonic acid after administration of such supplements to the mother of an affected fetus. A subsequent case, treated similarly in utero and postnatally, had normal growth and development in early infancy. However, because at least 60% of neonatal cases are not cobalamin-responsive, this approach may not be highly useful for the majority of affected fetuses.
In the rare infants with the combined defect resulting in both methylmalonic acidemia and homocystinuria, large doses of hydroxycobalamin also are important. Betaine, another methyl donor, may also be beneficial. Follow-up data are too sparse to assess effects on neurological development. It is likely that both prenatal and postnatal therapy will be critical.
Early Detection and Acute and Long-Term Therapy.
Early detection in the neonatal period and the importance of acute and long-term therapy are essentially as described for propionic acidemia. Therapy consists of a low-protein diet or a diet low in the amino acid precursors of methylmalonate, supplemented with cobalamin (see next section) and l -carnitine. The possible role of antibiotic therapy to reduce the production of methylmalonate by bacteria in the gastrointestinal tract may also be relevant in this condition.
Vitamin B 12 .
Because some patients with isolated methylmalonic acidemias respond to vitamin B 12 (see earlier discussion), a trial of this vitamin as hydroxycobalamin in high doses is indicated in such patients. In a series of 21 infants with neonatal-onset methylmalonic acidemia, of the 11 who responded to vitamin B 12 , 3 were normal on follow-up, whereas of the 10 who did not respond to vitamin B 12 , none was normal.
Gene Therapy.
As with propionic acidemia, liver transplantation has been used in infants with methylmalonic acidemia. Initial results in transplanted infants were not clearly beneficial. However, recent reports suggest some optimism. First, in a report of 12 infants transplanted at a mean age of 8.2 years, all survived through 3.2 ± 4.2 years and after transplantation had no episodes of hyperammonemia, acidosis, or metabolic decompensation. A second report of two patients, both of whom survived through ages 2 and 12 years, reported similar improvement. Early transplantation is important, but the youngest infants have the highest risk for graft loss, largely related to technical surgical issues.
Outcome.
The long-term outcome of 80 patients with organic aciduria (see earlier) included 38 with methyl malonic acidemia (MMA). Patients with MMA were less likely to have an abnormal neurological examination (24%), a lower abnormal psychometric evaluation at age 3 years (26%), and basal ganglia lesions (i.e., 36%) as compared with patients with propionic acidemia (PA). The prognosis of MMA patients with mutations involving the MMAA (methylmalonic acidemia cblA type) gene has been better than that of patients with mutations involving the MUT (methylmalonyl CoA mutase) gene.
Disorders of Pyruvate and Mitochondrial Energy Metabolism
Disorders of pyruvate and mitochondrial energy metabolism have been the topic of active research in the past several decades and constitute uncommon but serious neonatal neurological disorders. Together with disorders of propionate and methylmalonate metabolism and of branched-chain ketoacid metabolism, these disorders are important examples of organic acid disturbances. In large part because of the difficulties in studying the complex enzyme systems involved, the elucidation of abnormalities of pyruvate and mitochondrial energy metabolism has been relatively recent.
Disorders of pyruvate and mitochondrial energy metabolism may lead to striking metabolic acidosis with lactic acidemia in the neonatal period. Disorders related to pyruvate metabolism may involve either the Krebs citric acid cycle or the electron transport system. Disorders of the citric acid cycle with neonatal onset include deficiencies of alpha-ketoglutarate decarboxylation (dihydrolipoyl dehydrogenase deficiency), succinate dehydrogenase, or fumarase. However, because only a few well-studied neonatal cases have been documented, these disorders are not discussed in detail. Fumarase deficiency with fumaric acidemia is the most common of these conditions with a neonatal presentation. Reports delineate a rare neonatal or early infantile syndrome of hypotonia, seizures, dysmorphic facial features, frontal bossing, microcephaly, neonatal polycythemia, diffuse polymicrogyria, dysgenetic corpus callosum, hypomyelination, and ventriculomegaly. Disorders of the electron transport chain are more common. In addition to the metabolic abnormalities, the prominent features of these disorders include manifestations of encephalopathy, myopathy, or both; thus they are discussed in Chapters 29 and 33 . The focus in this chapter is on disorders of pyruvate metabolism, because the metabolic manifestations, particularly lactic acidemia , tend to dominate the neonatal clinical presentation.
Normal Metabolic Aspects
Pyruvate occupies a central position in intermediary metabolism ( Fig. 28.8 ). It is formed primarily from glucose through the process of glycolysis in brain as in other tissues. The major metabolic fates of pyruvate are shown in Fig. 28.8 and summarized in Table 28.6 .
| Transamination |
|
| Reduction |
|
| Carboxylation |
|
| Decarboxylation |
|
Transamination results in the formation of alanine, used partly for protein synthesis. The reverse reaction is particularly important in liver for gluconeogenesis from alanine.
Reduction to lactate is catalyzed by lactate dehydrogenase. Lactate can be used for gluconeogenesis through the reversal of this reaction.
Pyruvate carboxylation , catalyzed by the biotin-dependent enzyme pyruvate carboxylase, results in the formation of oxaloacetate. This step is critical in gluconeogenesis in liver and in several other tissues (but not to any significant extent in brain). Oxaloacetate is also an important intermediate in the citric acid cycle, and this reaction plays a role in priming the cycle. Oxaloacetate transamination results in the formation of aspartate, an excitatory neurotransmitter in brain, a precursor for protein synthesis and an important component of the urea cycle.
Pyruvate decarboxylation , catalyzed by the thiamine-dependent pyruvate dehydrogenase complex, is an exceedingly important reaction in all tissues, including brain, in view of the nature of its product, acetyl-CoA. The reaction thereby plays a major role in citric acid cycle function, in adenosine triphosphate synthesis, and in the syntheses of acetylcholine and lipids (i.e., fatty acids and cholesterol).
Biochemical Aspects of Disordered Metabolism
Enzymatic Defects and Essential Consequences
Of the four major fates of pyruvate, impairment of two, decarboxylation and carboxylation, has been described (see later discussion). Defects in the pyruvate dehydrogenase complex and in pyruvate carboxylase have been the enzymatic defects for these disorders. Both defects cause accumulation of pyruvate, lactate, and alanine proximal to the enzymatic block, but obviously the consequences distal to the enzymatic blocks differ to some degree.
Relation to Acute Neurological Dysfunction and to Neuropathology
The mechanisms for brain injury in defects of the pyruvate dehydrogenase complex or of pyruvate carboxylase include acute and more long-lasting effects. The common metabolic feature of these disorders, lactic acidosis , may be very important in causing the acute neurological dysfunction. Moreover, an irreversible structural deficit is a likely consequence when the acidosis is severe and prolonged.
A second metabolic feature, important in the genesis of the acute neurological dysfunction associated with disturbances in pyruvate metabolism, is impairment of the synthesis of factors important in neurotransmission . Thus, a deficiency of pyruvate dehydrogenase complex activity may be expected to lead to a diminution in the synthesis of acetylcholine (an established and important neurotransmitter). A deficiency of pyruvate carboxylase activity, with resulting decreased synthesis of oxaloacetate and function of the citric acid cycle, could lead to a disturbance of the excitatory amino acid transmitters, aspartate (a transamination product of oxaloacetate) and glutamate (a transamination product of the citric acid cycle intermediate alpha-ketoglutarate).
A third metabolic feature, probably important in the genesis of both acute and chronic effects, is impairment of energy production . This impairment would be expected with a disturbance of acetyl-CoA synthesis by pyruvate dehydrogenase complex deficiency, but the disturbance of oxaloacetate synthesis by pyruvate carboxylase deficiency may also have a similar consequence.
A fourth metabolic feature, which may be of particular importance in the genesis of the long-term irreversible structural deficits, is a disturbance in the synthesis of brain lipids and proteins . Disturbed activity of the pyruvate dehydrogenase complex would be expected to lead to impairment in the synthesis of fatty acids and cholesterol, critical constituents of neural membranes, including myelin, by impairment of acetyl-CoA formation. Experimental support for this notion is available. Deficits of pyruvate dehydrogenase complex and of pyruvate carboxylase also would lead to an alteration in levels of certain amino acids (e.g., alanine and aspartate) and perhaps thereby to a secondary disturbance of protein synthesis. The relative roles of these several factors remain to be defined in the inborn errors of pyruvate decarboxylation and carboxylation.
Pyruvate Dehydrogenase Complex Deficiency
Clinical Features
In general, deficiency in the pyruvate dehydrogenase complex is associated with three major categories of clinical phenotype, divisible according to age of onset: (1) neonatal types, (2) infantile form (onset, 3 to 6 months), and (3) later-onset benign forms with episodic ataxia. The infantile form is characterized particularly by hypotonia, cranial nerve signs (especially ophthalmoplegia), ataxia, delayed development, ventilatory disturbance, and other features, and it is most often (≈85% of cases) associated with the neuropathological features of Leigh syndrome (see Chapter 29 ). The later-onset forms may be punctuated by transient episodes of ataxia or paraparesis, but overall development is normal or only mildly disturbed.
The clinical features of the neonatal forms of pyruvate dehydrogenase complex deficiency consist of two basic syndromes: (1) marked lactic acidosis, often with dysmorphic craniofacial features and brain anomalies, and (2) Leigh syndrome. Newborns with Leigh syndrome overlap with those with the infantile forms of pyruvate dehydrogenase complex deficiency with slightly later onset of Leigh syndrome, noted in the previous paragraph and discussed in Chapter 29 . In this group, the onset of symptoms is generally in the first week of life and is often within the first 24 hours.
The major clinical features of the more common of the two neonatal forms (i.e., marked lactic acidosis) include stupor, tachypnea, hypotonia, and seizures ( Table 28.7 ). The infant’s course may be fulminating, with coma evolving in hours to a day or so. Most of the infants with this severe presentation have died in the first year of life. Newborns with pyruvate dehydrogenase complex deficiency may exhibit prominent craniofacial dysmorphic features ( Fig. 28.9 ) and signs of cerebral dysgenesis. The features of dysgenesis include partial or total agenesis of the corpus callosum, ventricular dilation, gyral abnormalities, subependymal heterotopias, hypoplasia of hindbrain structures (brain stem and cerebellum), and ectopic olivary nuclei. Severe impairment of neurological development, often with microcephaly, is the rule in survivors. Encephaloclastic lesions (see later) often coexist.
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