Paper composed for Molecular Basis of Medicine-602 taught by Professors L. Bill Stillway

Methylmalonic acidemia is a rare autosomal-recessive inborn error of metabolism which is caused by a downstream defect in the propionate metabolic pathway. Methylmalonyl-CoA mutase, the enzyme which converts methylmalonyl-CoA to succinyl-CoA is found to be non-functional in these disorders. The metabolic block in these disorders often leads to severe keto- and organic acidosis, hyperammonemia, hyperglycinemia, and hypoglycemia with marked accumulation of methylmalonate in body fluids and tissues of infants and children. The clinical presentation and pathology is accordingly severe in these disorders: Widespread psychomotor dysfunction, failure to thrive, dystonia, and hepatomegaly are some of the symptoms and the symptoms can extend to long-term neurological and systemic impairment. Hematological abnormalities are also observed, especially in cases where methylmalonic acidemia is accompanied by homocystineuria. The disorder is lethal in its early (neonatal) onset form, and may also manifest as a chronic problem, with episodes of acute decompensation and, in rare cases, the patient may be completely asymptomatic (‘benign’ form). In this article, a comprehensive survey of present literature is presented with an emphasis on the molecular basis of the disease.^1-3 Current methods of diagnosis, treatment, and the prognosis for these patients are discussed and some current areas of investigation explored.

Propionyl-CoA, its parent metabolic compounds, and molecules derived from it (e.g., methylmalonyl-CoA) are important precursors of succinyl-CoA, an important Krebs cycle intermediate. Recently, this metabolic pathway came to the attention of clinicians struggling with disturbing diseases. Researchers reported that adenosylcobalamin (AdoCbl), a metabolic derivative of cobalamin (Cbl; vitamin B₁₂), is an essential coenzyme in the final conversion of L-methylmalonyl CoA to succinyl-CoA.^4-6 Patients with acquired Cbl deficiency excreted large amounts of methylmalonic acid in urine.^7-10 Subsequently, infants not deficient in Cbl were described with similar signs.^11,12 The absence of methylmalonic acid in previously described ketotic hyperglycinemia¹³ suggested a novel disorder which was named methylmalonic acidemia. The former was later ascribed to a defect in propionate metabolism, and named propionic acidemia.^14,15 Methylmalonic acidemia and propionic acidemia are now recognized as the most common inborn errors of organic acid metabolism.

In addition, the Cbl deficient cases of methylmalonic acidemia who responded to Cbl supplements^16,17 had a defect in AdoCbl^18-22 synthesis, the coenzyme of methylmalonyl-CoA mutase,^4-6 the enzyme catalyzing the last step of the propionic acid pathway (Figure 1).^23-25 Also, methylmalonic acidemia patients were described with homocystineuria and hypomethioninimia, who also had methionine synthase³² deficiency owing to defective synthesis of methylcobalamin (MeCbl)^33-35–the Cbl derived coenzyme of methionine synthase, a cytosolic enzyme. Figure 2 to describes the current understanding of cobalamin metabolism in cells.

The study of methylmalonyl-CoA mutase enzyme has advanced significantly. It belongs to the group of enzymes catalyzing unusual 1,2-rearrangements and is the only member of this class found in both bacteria and animals.³⁷ Ledley, et al.³⁸ localized the methylmalonyl-CoA mutase (mcm) gene to the short arm of human chromosome 6. Later the mcm gene was found to span >35 kilobases (comprising 13 exons).³⁹ Jansen and Ledley⁴⁰ found the coding sequence of one subunit to be 718 amino acids in length (» 80 kilodaltons) with a 32 amino acid mitochondrial targeting sequence.^40,41 Mancia, etal.^37,42 solved the protein structure of a homologue of the MCM protein using X-ray diffraction.

The current body of data demonstrates that there are 7 distinct molecular defects in methylmalonate metabolism. Two of them, mut⁰ and mut^-, are a direct result of defect in the mutase apoenzyme: mut⁰ results from complete deficiency; and mut^- results from partial deficiency of methylmalonyl-CoA mutase. The other 5 defects are the cbl defects, so-called because they result from impaired cobalamin metabolism. Two are distinct defects of AdoCbl synthesis (cblA and cblB), and the three others are complicated by MeCbl deficiency in addition to AdoCbl (cblC, cblD, and cblF). The defects leading to isolated mutase deficiency (mut⁰, mut^-, cblA, & cblB) and those leading to combined AdoCbl and MeCbl deficiency (cbl C, D, & F) can be treated as separate groups.

More than 100 children with isolated mutase deficiency have been documented.¹ The four known etiologies which result in such patients present with similar clinical findings. Matsui, et al.⁴³ surveyed the natural histories of 45 patients with these etiologies: 15 mut⁰, 5 mut^- 14 cblA, and 11 cblB. Equal numbers of males and females were in each group. The most common signs and symptoms at the onset of clinical difficulty (usually brought about in children by an infection or excessive protein intake²) are listed in Table 1 and were similar in all etiologies. Patients in mut⁰ class presented earlier than those in other groups. Whereas 80 percent of children in the mut⁰ class became ill in the first week of life, less than half the children in the three other groups were ill during this interval.⁴³ Furthermore, clinical onset occurred in 90 percent of the mut⁰ patients before the end of the first month, whereas onset beyond the first month was observed in an appreciable fraction of patients the other three groups. Another survey reached similar conclusions.⁴⁴

The laboratory findings in affected patients also show marked similarity between the etiologies. Serum Cbl concentrations were routinely normal. The findings are listed in Table 2. Earlier case reports⁴⁵ indicated that hypoglycemia, a parameter not assessed in this survey,¹ occurs in about 40% of patients.

A number of pathologic signs involving various organ systems have been documented and characterized to some degree. These are presented in Table 3.

Mutase deficiency may sometimes be asymptomatic.⁶⁸ Presumably, these patients have an enzyme defect which retains just enough activity that homeostasis is maintained.¹ Another report describes patients with methylmalonic aciduria urine levels of approximately 1400 mmoles/mmole creatinine, who had normal somatic and cognitive outcomes.⁶⁹ Levy, et al.⁷ followed closely a child who suffered several acute episodes in childhood but afterwards remained asymptomatic, with an outstanding academic performance. Interestingly, one study reports that children with methylmalonic acidemia have an increased resting energy expenditure (REE) in spite of being asymptomatic.⁷⁰

On the otherhand, other groups appear to have a puzzlingly mild methylmalonic acidemia without demonstrable defect in methylmalonyl-CoA mutase activity or in Cbl metabolism.^71,72 The patients in at least one report⁷² presented with psychomotor delay, no metabolic acidosis and methylmalonic semialdehyde dehydrogenase deficiency.

The most prominent chemical abnormality observed in patients with the isolated mutase deficiency is large amounts of methylmalonic acid in urine and blood, as indicated in Table 4.^7,45

Importantly patients with mild, late-onset, or "benign"⁶⁸ disease may have much lower levels of methylmalonate, particularly when clinically asymptomatic.^8,68 Propionate and some of its upstream precursors also accumulate in blood and urine of these patients,^{14, 73-76} thus accounting for the great similarity observed in the presentation of propionic and methylmalonic acidemias.^2,77

Lastly, research has shown that administration of protein and amino acid precursors of propionate (and methylmalonate), such as methionine, threonine, valine, and isoleucine, augments methylmalonate accumulation and, in some instances, ketosis or acidosis. ^11,12,14,16 When Cbl-responsive patients are given supplements vitamin B₁₂, such augmentation by methylmalonate precursors is lessened.⁷⁸

All studies in vivo and in vitro in patients with methylmalonic acidemia indicate that the primary block in the conversion of methylmalonyl-CoA to succinyl-CoA explains the methylmalonate accumulation and accompanying biochemical changes.¹ However, primary block does not explain several important physiologic disturbances such as acidosis, hypoglycemia, hyperglycinemia, and hyperammonemia. Oberholzer, et al.¹¹ suggested an explanation for the observed acidosis that methylmalonyl-CoA might be "trapping" the cellular supply of coenzyme A, leading to impaired carbohydrate metabolism. Alternatively, methylmalonyl-CoA might interfere with gluconeogenesis,⁷⁹ leading directly to hypoglycemia, and the subsequent increase in lipid catabolism could cause ketoacidosis. Halperin, et al.⁸⁰ showed that methylmalonate inhibited the transmitochondrial shuttle of malate and argued that impairment of this key step in gluconeogenesis could lead to hypoglycemia. Treacy, et al.⁸¹ have suggested that a deficiency of glutathione may also contribute to lactic acidosis in these patients.

Additionally, in methylmalonic acidemia the accumulated organic acids or their CoA esters inhibit intramitochondrial glycine cleavage and an enzyme associated with the urea cycle.^82-88 These are probable causes of hyperglycinemia and hyperammonemia in affected children. Carnitine deficiency results from decreased renal handling of filtered carnitine and the excretion of acylcarnitine derivatives formed from organic acids.^2,89,90 This deficiency may contribute to muscle hypotonia and other clinical findings (Tables 1 & 3).

Each of the four etiologies for isolated methylmalonyl-CoA mutase deficiency are inherited as autosomal-recessive traits, as a number of studies demonstrate.^40,43,91-98

The prevalence of methylmalonic acidemia is difficult to define precisely. One survey in Massachusetts suggested an occurrence of 1:48,000 infants,⁹⁹ while another in Quebec suggested 1:61,000 infants.¹⁰⁰ Others have suggested a figure of 1:29,000.^99,68 A much greater prevalence of between 1:1,000 and 1:2,000 has been reported in Middle Eastern populations.⁶⁰

Evidence for defect in methylmalonyl-CoA mutase apoenzyme came from in vitro studies showing instances where mutase enzyme activity could not be restored at saturating AdoCbl concentrations, whereas, in other cases, the activity was restored to normal.^101,102 Subsequently, much has been learned about the mut⁰ and mut^- defects.

The mut⁰ defect, constituting two-thirds of the mut group, shows mutase activity which is undetectable in cultured fibroblasts (<0.1% of control), even in the presence of excess AdoCbl.^96,102 The molecular flaws in mut⁰ patients range from no enzyme synthesis at all, to unstable and rapidly degraded enzyme, to highly reduced enzyme levels–and a problem with mitochondrial targeting in one case.^103-105

The other defect, mut^-, involves a structurally abnormal mutase apoenzyme. The mutated enzymes in extracts from these cells retain 2 to 75% of normal activity, bind AdoCbl 200 to 5000 times less well than normal enzyme, and exhibit increased thermolability.^96,106,108 Since individuals who appear to be mut⁰/mut^- compound heterozygotes are affected, both defects must reflect abnormalities of the same locus (i.e., the mut gene).^96,106

Moreover, considerable information exists on the molecular abnormalities underlying the mut group of defects in methylmalonic acidemia. Ledley, et al.⁹⁸ initially found reduced mRNA levels in some lines. Table 5 lists many of the mutations identified to date. To date, about 34 mutations and 2 benign sequence changes have been identified.^{40,91,92,105,109-121} A number of mutations have been characterized which are common among people from different racial or ethnic groups.^{111,113,116,117} Figure 3 shows a linear representation of the structure of human mutase,¹⁰⁸ based on the crystal structure of a bacterial homologue.^37,42 On it are indicated the locations of a number of the missense mutations in mutase identified so far. The effects of some of these have been rationalized in terms of the predicted three dimensional structure.^{92,108,110,118,122}

The molecular abnormality of adenosylcobalamin synthesis–i.e., the Cbl-responsive forms of the disease (i.e. the cbl- defects)–are associated with functional deficiency of specific mitochondrial enzymes of AdoCbl synthesis (Figure 2).^23,24 In particular, two mutant classes have been differentiated among patients defective only in AdoCbl synthesis, that is, cblA and cblB.^93-95,123 The cblA defect is associated with a deficiency of a mitochondrial Cbl reductase.¹²⁴ There is some evidence indicating a possibility of interallelic complementation in this defect.¹²⁵ The second defect designated cblB, results from deficiency of cob(I)alamin adenosyltransferase.⁹⁷

The defects in this category differ from isolated mutase deficiency in that they demonstrate both methylmalonic acidemia and homocystineuria. Many patients with the inherited combined disorder have been subject of individual case reports.^{126, 127-143} Cells from these children comprise three biochemically and genetically distinct complementation groups, designated cblC, cblD, and cblF. ^{93,94,125,144} Of these, the cblC defect is inherited as an autosomal-recessive trait,⁹³ but the mode of inheritance of cblD and cblF defects is not yet known.

Among the more than 100 patients characterized with cblC defect, clinical findings have varied widely, and some cases diagnosed only in adult life. In a review of 50 patients,¹⁴⁴ 44 had onset in the first year of life and 6 had onset after 6 years of age, and 13 early-onset patients died. The clinical presentation and laboratory findings of cblC patients are given in Table 6.

Neither of the two brothers in the cblD group¹²⁶ had any clinical problems until the older brother presented with severe behavioral pathology and moderate mental retardation. The 2-year-old sibling was asymptomatic, although biochemically affected, and neither had any hematologic abnormalities.

Additionally, six patients have been reported in the cblF group. The clinical and laboratory findings from patients in this category are presented in Table 7.

A variety of experiments have revealed that in cblC and cblD forms of the disease, the cellular metabolism of cobalamin (Cbl, vitamin B₁₂) becomes deranged such that the coenzymes for both methylmalonyl-CoA mutase and methionine synthase (AdoCbl and MeCbl, respectively) are improperly synthesized.^33,127 Experiments have indicated lower Cbl content in liver and kidney fibroblasts,^{33,128,148,149} and inability of cells to retain radioactively labeled CN-Cbl or convert it to either MeCbl or AdoCbl.^24,94,150 The two enzymatic deficiencies improve with OH-Cbl supplementation of growth medium.^{24,33,94,95,151} cblC is unable to convert CN-Cbl to OH-Cbl, a necessary prerequisite for MeCbl and AdoCbl synthesis, indicating a defective cytosolic cob(III)alamin reductase.^152,153,154 This is indeed the case for both cblC and cblD.^155,156 Glutathionyl Cbl intermediate in the reductive pathway may also be mutated in these groups.¹⁵⁷

Although the cblF defect results in impaired AdoCbl and MeCbl synthesis, affected cells accumulate unmetabolized CN-Cbl in lysozomes, indicating a deficiency in the process by which cobalamin metabolites exit from lysozomes after being taken up (Figure 2).

In general the two groups of combined methionine synthase and methylmalonyl-CoA mutase deficiency and isolated methylmalonyl-CoA mutase share more in common than not. But important differences set these categories of methylmalonic acidemia apart which should be noted. A comparison of the two groups of disorders is presented in Table 8. One should also note that homocystinuria present in the combined disease form may not always be detectable although methione synthase activity is reduced.^140-143

A number of techniques exist for the diagnosis of methylmalonic acidemia and these are indicated in Table 9. Other sources of ketoacidosis must also be ruled out. Confirmation and etiologic designation (i.e., mut or cbl defect) depend on studies with cultured cells and extracts therefrom (see Table 9).^159,160 Prenatal detection of methylmalonic acidemia has also been accomplished as indicated in Table 9.

Based on current understanding, the presence of methylmalonic aciduria, homocystinuria, and normal serum Cbl concentrations is the combination needed to distinguish patients in the combined deficiency groups from those with isolated mutase deficiency, and one of several other causes of homocystineuria. Such distinctions can be confirmed by cell studies. Thus, patients in this category can be expected to present with a combination of symptoms from both the isolated mutase deficiency (Tables 1-3) and those attributable to the methionine synthase deficiency (Tables 6-7).^146,158

The acute management of methylmalonic acidemia^2,60 involves (1) protein elimination with provision of adequate calories to suppress gluconeogenesis using intravenous fluids with glucose, (2) administration of intravenous bicarbonate to correct acidosis, and (3) pharmacologic doses of hydroxocobalamin (OH-Cbl) (1 mg) in the new or undefined patient. Dialysis may be necessary in some cases. Carnitine supplementation is useful, not only to reverse the deficiency of free carnitine that regularly occurs in these conditions, but also to form carnitine esters of accumulated toxic CoA esters; these carnitine esters are subsequently excreted in the urine.^3,168

Two treatment regimens for children with methylmalonic acidemia exist for chronic therapy and should be used in tandem. A diet restricted in protein (or a special formula restricted in precursors of methylmalonate) should be instituted as soon as life-threatening problems such as ketoacidosis, hypoglycemia, or hyperammonemia have been addressed;^2,60 and supplementary Cbl (1-2 mg CN-Cbl or, preferably, OH-Cbl intramuscularly daily for several days) should be given as soon as the diagnosis of methylmalonic acidemia is seriously considered. Such measures should decrease the circulating concentrations of methylmalonate and propionate. Even Cbl-unresponsive children with delayed development have been shown to improve markedly when treated with careful dietary protein restriction.^169,170 Table 10 lists several other treatment options that may be successful.

In addition, the successful treatment of cblC, cblD, or cblF patients may demand administration of very large amounts of Cbl.^{126,129,131-133,140,180} Such treatment has resulted in dramatic decreases in methylmalonate (less dramatic changes in urinary homocysteine) in patients who have received it.¹⁸¹ Additionally, supplementation with betaine, methionine, and carnitine can reduce homocysteine and organic acid levels, while alleviating many associated symptoms.^180,182

The prognosis of patients with methylmalonic acidemia–either owing to isolated mutase deficiency (mut⁰, mut^-, cblA, or cblB) or the forms with an additional methionine synthase deficiency (cblC, cblD, or cblF) depends on (a) early diagnosis and (b) the ability to effect good long-term metabolic control.¹ However some defects are less severe than others in terms of the outcome. Both the response to Cbl supplements and the long-term outcome in affected patients depend considerably on the nature of the biochemical lesion causing methylmalonic acidemia:⁴³ None of the children designated mut⁰ or mut^- responded to Cbl supplements with a distinct decrease in blood and urinary methylmalonate, whereas over 90% of the cblA and about 40% of the cblB patients showed a response. Moreover, one must alleviate the enzyme deficiency just slightly to see a positive response as studies suggest that raising enzyme activity to only 10 percent of normal via growth medium supplementation with OH-Cbl distinctly augments propionate pathway activity.^95,159 The use of AdoCbl instead of CN-Cbl or OH-Cbl is ineffective.^183,184

Owing to complete methylmalonyl-CoA mutase deficiency the mut⁰ group has the poorest prognosis, with approximately 60% deceased and 40% distinctly impaired developmentally.^43,44 In contrast, cblA patients (i.e., the group biochemically most responsive to Cbl supplements) had the best outcome: 70% were alive and well at ages up to 14 years. The cblB and mut^- groups were intermediate, with about equal fractions in each group being found in the alive and well, alive and impaired, or the deceased category.⁴³

Additionally, a long-term complication of methylmalonic acidemia patients is chronic renal failure.^50-56 One report indicated that 8 of 12 non-Cbl responsive patients (1-9 years of age) had a reduced glomerular filtration rate, with five severely affected.⁵¹ In one of these, "greatly improved metabolic control" over a period of 18 months led to increased, but still impaired, renal function.⁵¹ It is not known what impact better metabolic control and Cbl supplementation may have in this and similar cases.¹

Finally, early diagnosis and prompt institution of therapy with Cbl supplements (and betaine) may be the only way to change the outcome of cblC, cblD, and cblF patients which has mostly been dismal thus far.^126,127-143 At least one recent study reports on more favorable outcomes for eight cblC patients subjected to aggressive therapy with intramuscular OH-Cbl, carnitine, and oral betaine.¹⁸²

Methylmalonic acidemias are a group of rare but severe inborn errors of metabolism caused by non-functional methylmalonyl-CoA mutase. The resulting accumulation of organic and ketotic acid compounds precipitates a constellation of biochemical and pathologic problems which are often debilitating and fatal in infants and young children. Owing to the severity of the metabolic disorders of methylmalonic acidemia much work remains to be done towards the development of more effective treatments, and several paths toward doing so are being carved out.

Not surprisingly, liver transplantation has been attempted in a limited number of early-onset patients, who have the worst prognosis.^185-188 Although liver transplantation appears to protect against acute metabolic decompensation, biochemical correction is incomplete and it is not certain that there will be complete protection against the renal and neurologic complications.¹ In one case, combined liver-kidney transplantation led to marked improvement, but the precise mechanism of its effectiveness remains to be worked out.¹⁸⁹

Preliminary steps have also been taken toward somatic gene therapy for mutase deficiency.^190,191 Besides all the usual questions of safety and long-term stability of response that surround somatic gene therapy, two important issues remain unanswered for mutase: How much activity must be restored in vivo to normalize the biochemical hallmarks of the disease? And, does correction of the defect in the liver, for example, lead to reversal or amelioration of the pathologic changes in other organ systems and overall clinical improvement?

Another interesting concept involves the study of the molecular defects through an understanding of the enzyme structure.^37,121,122 For example, it is known that certain mutations at the cobalamin binding site, sterically block the docking of the AdoCbl coenzyme, thus preventing holoenzyme formation.¹²² If one could chemically modify a Cbl derivative such that it could now fit into the binding site, then it would be possible to design specific pharmacologic agents against known structural defects of methylmalonyl-CoA mutase. In other words, such wonder drugs could restore compromised activity to methylmalonyl-CoA mutase in affected individuals to a significant degree, alleviating many symptoms of the disease. Approaches of this kind are important reasons for researchers to continue the molecular characterization of defects in methylmalonic acidemia.¹²¹

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