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Organic Acids
A series of metabolic disorders with prominent neurological accompaniments and serious deleterious effects on the developing central nervous system has 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. Carboxylic acids are the most important organoid acids. Their functional group is the carboxyl group. These compounds would include lactic acid, methylmalonic acid, propionic acid, fatty acids, and a variety of other endogenous and exogenous acids. Disorders of amino acids, which contain both a carboxylic group and an amino group, are discussed in Chapter 31 . Mitochondrial disorders are discussed in Chapters 33 and 37 . 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. Note that we have also included in the tables other more rare causes of metabolic acidosis due to a variety of gene defects.
OVERVIEW OF MAJOR ORGANIC ACID DISORDERS AND NEONATAL METABOLIC ACIDOSIS
The organic acid disorders enumerated in Table 32.1 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. 32.1 . 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 32.1 ) are described briefly at the conclusion of the chapter. The mitochondrial disorders are discussed in Chapters 33 and 37 . The disorders of carbohydrate metabolism listed in Table 32.1 and renal tubular acidosis either manifest clinically only rarely in the neonatal period or exhibit primarily nonneurological syndromes and are not reviewed further.
TABLE 32.1
Major Causes of Metabolic Acidosis in the Neonatal Period
| 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 32.2 ).
TABLE 32.2
Common Features of Disorders of Propionate and Methylmalonate Metabolism
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. 32.2 . 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 methylmalonyl-CoA pathway, succinyl-CoA, is a metabolite in the Krebs cycle.
Certain alternate and minor metabolic pathways are important in understanding the disorders of this pathway (see Fig. 32.2 ). Thus, propionyl-CoA also can be metabolized to lactate and can be used in the synthesis of odd-numbered fatty acids. Methylmalonyl-CoA may 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. 32.2 . 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 often is greater than can be accounted for by these compounds. Other sources of acidemia include a secondary impairment of mitochondrial oxidative phosphorylation leading to lactate accumulation (see Fig. 32.2 ), 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 31 ). Thus these CoA esters have been shown to have a direct inhibitory effect on carbamyl phosphate synthetase 1 and an indirect inhibitory effect at this step by inhibition of the synthesis of N -acetylglutamate, the important activator of carbamyl phosphate synthetase 1. Recent work indicates that the specific CoA metabolite, methylmalonyl-CoA, induces aberrant acylations as posttranslational modifications in proteins such as carbamoyl phosphate synthetase 1 in methylmalonic acidemia (MMA), which results in reduced activity (see Fig. 31.12 in Chapter 31 ). Hyperammonemia and acidosis have major deleterious effects on the brain (see Chapter 31 ) 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 31 because of the association of ketoacidosis (i.e., ketotic versus nonketotic hyperglycinemia) and because the glycine abnormality is a secondary and not a primary metabolic phenomenon. Analogous to the cause of the hyperammonemia in MMA, the cause of the hyperglycinemia is related to an inhibition of the glycine cleavage complex undergoing methylmalonylation.
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 latter 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 (PA) and MMA 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 databases 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. 32.2 ). 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.
Disturbance in Krebs Cycle Metabolism
When propionyl-CoA is present in excessive amounts, it can replace acetyl-CoA in the Krebs cycle enzyme reaction whereby oxaloacetate and acetyl-CoA are converted to citrate, thus yielding 2-methylcitrate. This compound may be toxic. It often is quantified in plasma and urine along with methylmalonic acid.
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’ section), 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 brain 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 32.3 ). Because the fatty acid composition of membrane lipids is important not only for structural integrity but also for 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 the neurological dysfunction and the disturbance of myelination.
TABLE 32.3
Fatty Acid Composition of Brain Lipids With Disorder of Propionate-Methylmalonate Metabolism
Data from Ramsey RB, Scott T, Banik NL. Fatty acid composition of myelin isolated from the brain of patient with cellular deficiency of coenzyme forms of vitamin B 12 . J Neurol Sci . 1977;34:221–232.
Disturbances of Fatty Acid Synthesis
The fatty acid abnormalities described in the previous section are caused presumably by disturbances of fatty acid synthesis. The nature of the disturbances observed in disorders of propionate and methylmalonate metabolism is depicted in Fig. 32.3 . 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. 32.3 ). When propionyl-CoA is present in excessive amounts, it can replace acetyl-CoA with a three-carbon fragment as primer , and, thus, an odd-numbered fatty acid results after the addition of the two-carbon units from malonyl-CoA (see Fig. 32.3 ). When methylmalonyl-CoA is present in excessive amounts, it may replace malonyl-CoA , and, thus, a methyl-branched unit is derived from malonyl-CoA, resulting in methyl-branched fatty acids (see Fig. 32.3 ). 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
PA 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 32.2 ). 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 impaired 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 neurological” deficits. In a recent report, the clinical and outcome data of 55 surviving patients with PA was evaluated retrospectively ( Fig. 32.4 ). The vast majority of patients (>85%) presented with metabolic decompensation in the neonatal period. Approximately 75% of the study population had intellectual disability with a median IQ of 55. Chorea or dystonia has been observed in 20% to 40% of surviving children, and this 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.
Genetics and Antenatal Diagnosis
PA, as just noted, is inherited as an autosomal recessive trait. The propionyl-CoA carboxylase enzyme is composed of two subunits, alpha (PCCA) and beta (PCCB) . The diagnosis can be established by gene sequencing of the two causative subunits. Prenatal diagnosis can be determined by gene sequencing using either chorionic villus tissue or amniotic fluid after the establishment of cells in culture. Carrier testing is available. Biochemical analysis of the critical biomarkers in dried blood spots is at the center of newborn screening.
Metabolic Features
Major Findings
The constellation of ketoacidosis, PA, hyperglycinemia (and hyperglycinuria), hyperammonemia, neutropenia, anemia, and thrombocytopenia is characteristic and composes the “ketotic hyperglycinemia” syndrome . However, hyperglycinemia with PA 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 31 .
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, and of the various acids that accumulate proximal to propionic acid, as a consequence of continuing degradation of branched-chain and other amino acids) and increased lactate formation.
Increased numbers of odd-numbered fatty acids have been observed in the tissues of infants with PA. 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. 32.3 ).
Neuropathology
A well-studied neonatal case of PA 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 31 ). 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. 32.5 ). 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 PA 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 (see Chapter 22 ). In contrast to MMA (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 31 ) 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 PA. 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. 32.6 ). 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 in chorionic villus samples, by analyzing metabolites in amniotic fluid, and by molecular genetic testing of DNA extracted from fetal cells. The preferred testing modality is molecular genetic gene sequencing (see earlier).
Early Detection
Early diagnosis, particularly in distinguishing this disorder from other causes of severe metabolic acidosis in the neonatal period (see Table 32.1 ), is critical. Plasma acylcarnitine and urine organic acid analysis are critical diagnostic tools that need to be employed as soon as the physician identifies a phenotype compatible with PA. As just noted for antenatal diagnosis, molecular genetic gene sequencing is the preferred testing modality. If the mutation is novel and not previously reported, enzymatic assays may be necessary.
Acute and Long-Term Therapy
Acute episodes should be treated by withdrawing all protein and administering sodium bicarbonate or sodium/potassium citrate parenterally. Hyperammonemia may be severe enough to require specific measures for ammonia removal, such as hemodialysis, as described in Chapter 31 . 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. Carglumic acid (Carbaglu) may also be employed to alleviate the secondary hyperammonemia. Carglumic acid is a synthetic structural analog of N -acetylglutamate, which is produced by the enzyme, N -acetylglutamate synthetase, and functions as an allosteric activator of the carbamyl phosphate synthase 1. Diminished activity of N -acetylglutamate synthetase is considered to be one of the causes of secondary hyperammonemia in organic acidurias and providing a synthetic analog of its product allows proper functioning of the urea cycle by activating carbamyl phosphate synthase.
Biotin
Biotin responsiveness has not been established as an effective treatment modality, but a short therapeutic trial may be considered.
Gene Therapy
Liver transplantation early in infancy may be of value in the management of neonatal-onset PA. Initial mortality rates after transplantation exceeded 50%, and thus the number of infants followed sufficiently long after transplant is small. Moreover, in a recent report of 12 treated patients with PA, mortality was still high (58%). When cardiomyopathy was present before transplantation, it usually resolved, but there are exceptions ; renal failure, present in 50% of the patients before transplantation, worsened in all after transplantation. A beneficial effect on neurological development remains to be defined. Other treatment modalities, such as mRNA therapy, are the subject of current clinical trials.
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 seven discrete metabolic defects (see Fig. 32.2 ): (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; mut 0 enzymatic subtype or mut – enzymatic subtype, respectively), (3, 4, 5) defects in the transport or synthesis of adenosylcobalamin ( cblA, cblB , or cblD-MMA ), (6) deficiency of the enzyme methylmalonyl-CoA epimerase, and (7) defective synthesis of both adenosylcobalamin and methylcobalamin ( Table 32.4 ). Three defects of vitamin B 12 metabolism associated with transport and synthesis of 5-deoxy-adenosyl-cobalamin result in diminished activity of methylmalonyl-CoA mutase, for which adenosylcobalamin is a coenzyme, and thereby results in isolated MMA. Additionally, 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. The result is combined MMA and homocystinuria (cblC, cblD-combined, cblF, cblJ) . In one series of 45 carefully studied patients with MMA (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.
TABLE 32.4
Methylmalonic Acidemias: Biochemical and Metabolic Features a
| 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 32.2 ). Onset of these features in the neonatal period depends on the nature of the enzymatic defect ( Table 32.5 ). 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 32.5 ). 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), the median range of subsequent full-scale IQ score was 100 for the cobalamin responsive, 75 for the early-onset, and 101 for the late-onset noncobalamin 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 PA. Involvement of basal ganglia, similarly, is very common, but in the case of MMA, it involves globus pallidus rather than the caudate/putamen as in PA.
TABLE 32.5
Time of Onset and Outcome in Methylmalonic Acidemias According to Type of Metabolic Defect
Data from Rosenberg LE, Fenton WA. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Metabolic Basis of Inherited Disease . 6th ed. McGraw-Hill; 1989.
| 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% |
cblA , Deficiency of mitochondrial cobalamin reductase; cblB , deficiency of cobalamin adenosyltransferase; mut• , complete mutase deficiency; mut – , partial mutase deficiency.
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 32.4 ) (see ‘Metabolic Features’ section), and onset in the first month of life also had a generally unfavorable neurological outcome (not shown in Table 32.5 ). The clinical and neuroradiological features were similar, albeit milder, than those observed in patients with the mutase deficiencies, and the metabolic features included homocystinuria and MMA. 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, MMA, 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 that resulted 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. 32.2 ).
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 32.4 ). 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. 32.2 . 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 one-half of the neonatal cases and, secondarily, to increased catabolism of lipid, with resultant ketosis and acidosis. The cause of the hyperammonemia and hyperglycinemia in MMA is related, at least in part, to the inhibition of the CPS1 and the glycine cleavage complex undergoing methylmalonylation (see discussion earlier).
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. 32.3 ). 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. 32.2 ). 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.
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