Myoclonus epilepsy with ragged-red fibers
Nov. 06, 2023
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The author provides an overview of the hereditary isolated methylmalonic acidemias, a group of metabolic disorders with varied clinical presentations. This includes the most severe form of L-methylmalonyl-CoA mutase deficiency, termed mut(o) methylmalonic acidemia, which, together with the less severe deficiencies of L-methylmalonyl-CoA mutase, are the most common causes of methylmalonic acidemia, but also the other biochemical differential diagnoses, cblA and cblB deficiency. They review the natural history, clinical phenotypes, and available treatment modalities as well as the metabolic investigations required to establish the diagnosis. The newest advances in molecular genetics are updated.
• Acute metabolic decompensation in a patient with methylmalonic acidemia is a medical emergency.
• “Metabolic stroke” involving the basal ganglia is usually a life-changing event.
• Liver transplantation usually eliminates acute episodes of ketolactic acidosis but is not a cure as CSF levels of methylmalonic acid remain massively elevated.
• Patients with severe mut enzyme (L-methylmalonyl-CoA mutase) deficiency usually develop renal insufficiency/failure in the second-third decade of life.
• Both mut enzyme deficiency and defects in cobalamin (cbl) metabolism lead to methylmalonic acidemia, and some cobalamin defects may also be associated with homocystinuria.
Methylmalonic acidemia and the disease associated with the more proximal defect in the same pathway, propionic acidemia, are the most common clinically significant genetic disorders of organic acid metabolism (44). The key finding in methylmalonic acidemia is the accumulation of methylmalonic acid in body fluids and tissues. The hereditary disease, methylmalonic acidemia, was first described by Oberholzer and colleagues (118) and Stokke and colleagues (150).
Methylmalonic acidemia may be due to several different enzyme defects, some of which primarily involve cobalamin metabolism (44; 95; 49). All are inherited as autosomal recessive traits. In these biochemical genetic disorders, as well as in simple nutritional cobalamin deficiency, the accumulation of methylmalonic acid is secondary to the buildup of mitochondrial methylmalonyl-CoA, an intermediate in the conversion of propionyl-CoA to succinyl-CoA.
There are two isomers of methylmalonyl-CoA, the D- and the L-form. The latter is thought to be derived by the action of D-methylmalonyl-CoA epimerase activity (EC 220.127.116.11). Propionyl-CoA, the immediate precursor of D-methylmalonyl-CoA, is the breakdown product of isoleucine, valine, methionine, threonine, and thymine, as well as cholesterol and odd-chain fatty acids. Subsequently, propionyl-CoA is converted to D-methylmalonyl-CoA via the enzyme propionyl-CoA carboxylase (EC 18.104.22.168). Following racemization, L-methylmalonyl-CoA is converted to succinyl-CoA via the enzyme L-methylmalonyl-CoA mutase (E.C.22.214.171.124), which requires adenosylcobalamin for activity.
The synthesis of this coenzyme, in turn, depends on adequate delivery of vitamin B12 to tissues such as liver and brain; transport into cells through the phagolysosomal system; export and release of cob(III)alamin from lysosomes, cytosolic, and possibly mitochondrial reduction to cob(II)alamin; transport into the mitochondrion; mitochondrial reduction to cob(I)alamin; and conversion to adenosylcobalamin. Methylmalonic acidemia may result from a defect in any of these steps. When it is secondary to an enzymatic block that is proximal in the pathways of cobalamin reduction or lysosomal efflux, it is also associated with homocystinuria because of impaired production of methylcobalamin, in the cytosol, cobalamin cofactor is required for the conversion of homocysteine to methionine (44).
Most cases of methylmalonic acidemia are secondary to a complete or partial deficiency of L-methylmalonyl-CoA mutase, termed mut methylmalonic acidemia (44). The deficiency of L-methylmalonyl-CoA mutase as a cause of methylmalonic acidemia was first reported by Morrow and Barness (111). The mut(o) and mut(-) designations refer to complete and partial deficiencies, respectively, determined by in vitro studies with cultured cells (44). Some patients with primary defects in cobalamin metabolism such as impaired reduction of cobalamin (II) to cobalamin (I) or adenosylcobalamin synthase deficiency are responsive to cobalamin megatherapy (99). Thus, methylmalonic acidemia in more than a third of patients is a vitamin-responsive inborn error of metabolism (99). Although the residual enzyme activity in the mut(-) state may be stimulated by high concentrations of hydroxycobalamin and adenosylcobalamin in vitro, most patients with L-methylmalonyl-CoA mutase deficiency do not respond to pharmacologic doses of cobalamin (99).
The expression of disease in methylmalonic acidemia is varied (73; 74). Most dramatic is the phenotype with presentation in the first week of life, ie, the catastrophically ill newborn infant, moribund and requiring ventilatory assistance. These babies are full term, and although their condition mimics sepsis, they have an overwhelming ketolactic acidosis, frequently display hyperammonemia, and can die despite supportive therapy including dialysis.
The most common phenotype is presentation during infancy. The signs are variable, and their clinical recognition may be as early as the first few weeks of life or as late as the second year. Almost all of these infants will present with poor growth, feeding problems, developmental delay, and intermittent episodes of lethargy during which the clinical and laboratory findings are essentially those of metabolic acidosis except that the degree of obtundation may be out of proportion to the magnitude of acidemia. In some, intermittent emesis may be so pronounced as to suggest a primary gastrointestinal disorder. Seizures may occur but are more likely during episodes of metabolic decompensation with coma. Some infants never display clearly recognizable episodic illness but nevertheless have a mild chronic metabolic acidosis with ketosis. Hypoglycemia has been reported. Hepatomegaly due to fatty infiltration is not uncommon and correlates with metabolic control.
Less common is an intermittent phenotype. This form is also seen in other types of inborn errors of organic or fatty acid metabolism. Probably most of these patients come to clinical attention during early childhood. The hallmark of this form is that there was no evidence of clinical disease before the first episode of vomiting, dehydration, lethargy, or coma associated perhaps with respiratory distress, hepatomegaly, and seizures. As with the other phenotypes and other metabolic diseases, an intermittent episode may mimic sepsis or Reye syndrome. During one of these episodes of metabolic decompensation, the patient may die despite intensive intervention. A review summarizes aspects of care for adults with methylmalonic acidemia (155).
Outcome in the methylmalonic acidemias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset, and birth decade. The prognosis is still unfavorable in patients with neonatal metabolic crises and nonresponsiveness to cobalamin, in particular mut(o) patients (57). In the first review of outcome by Matsui and colleagues, 60% of mut(o) patients had died, and the majority of survivors were growth retarded and had intellectual disabilities (99). In contrast, 69% of individuals with cobalamin A were alive and well, and 91% were cobalamin-responders. The prognosis is best for those who are detected early in life and treated appropriately, for those who have a partial enzyme deficiency, and especially for those who are cobalamin responsive. A retrospective, survey-based study indicated that outcomes for methylmalonic acidemia had improved since the study of Matsui and colleagues and highlighted the fact that renal disease is prevalent among affected patients and can occur even in patients with more mild enzymatic defects (56). Another study compared the long-term outcomes of 28 cblA and 95 mut patients. Although the initial clinical presentations of the two groups were similar, cblA patients responsive to hydroxycobalamin treatment showed a significantly milder clinical course regarding growth, neurologic complications, and chronic renal failure. In these patients, renal function can be preserved even as adults (58). For the patients with cobalamin-unresponsive forms, there is currently no satisfactory therapy (156). For these patients, even on a strict low-protein diet, the concentrations of methylmalonic acid remain elevated in body fluids. Many patients so treated manifest poor appetite, intermittent emesis, gastroesophageal reflux, disease, poor growth, osteopenia, and signs of renal insufficiency even in the absence of intellectual disability, motor handicaps, overt acidosis, or episodes of severe decompensation. Various degrees of neurologic disease may be seen (144; 114; 120; 116). The development of bilateral optic neuropathy as a chronic complication in patients with mut(o) disease (166; 129; 154; 98), megamitochondria in a patient with mut(o) disease (173), and the demonstration of widespread mitochondrial morphological lesions in the kidney and liver of knockout mice with methylmalonic acidemia (24) lend credence to the hypothesis that the mechanism of disease in methylmalonic acidemia may be due to a secondary defect in mitochondrial oxidative phosphorylation (72; 52; 37). The bilateral destruction of globus pallidus (75; 54; 152; 101; 172; 85; 132; 09), one of the vulnerable areas in brain, during an acute episode of metabolic decompensation may be due to underlying MMA-CoA- and/or MMA-induced perturbations in mitochondrial metabolism or respiratory chain function. Altered thiol status in patients with organic acidemias has been noted (140). This type of brain injury only involving other areas may even develop in patients after successful liver transplantation (20; 70; 117; 69). This may be caused by continued elevated concentrations of methylmalonic acidemia in the CNS. Cardiomyopathy has just been recognized in individuals with methylmalonic acidemia (07; 131), chronic liver disease, and different hepatic neoplasias (61; 45). Some patients with severe L-methylmalonyl-CoA mutase deficiency require daily alkali therapy to buffer the excess acid production. Renal disease is primarily of the tubulointerstitial variety (161; 108; 139). The majority of patients with mut(o) disease have severe renal insufficiency or failure by the second to third decade of life (56; 30). The pathogenesis is unknown. There is suspicion that a component may involve congenital disease, perhaps renal hypoplasia or dysplasia (118; 77). Early manifestations include renal tubular acidosis (167), particularly type IV, and concentrating defects. Hyporeninemic hypoaldosteronism can be seen in some patients (161). Renal disease may also occur in cobalamin A disease if not sufficiently treated with hydroxycobalamin (51). Hyperkalemia after acute metabolic decompensation has been noted (125).
Any patient may succumb to an episode of ketolactic acidosis. Other complications, particularly as a consequence of decompensation, include damage to the basal ganglia (75; 54; 35; 137; 09), which may be bilateral and associated with an acute extrapyramidal syndrome (54), and pancreatitis (65; 96). Basal ganglia disease may be of the acute or chronic variety (105; 145; 16; 17; 169; 158; 09). The latter, as in propionic acidemia, may only consist of radiologic findings not associated with clinical signs. A variety of radiological abnormalities have been detected in children with methylmalonic acidemia; ventricular dilation and cortical atrophy are the most common (132). Patients who are not diagnosed until late infancy or early childhood are often growth retarded and delayed with motor handicaps. Severe cognitive impairment, however, although often the complication of chronic untreated disease, appears less common than neuromuscular disabilities (120). Patients may have hypotonia, spasticity, and, less commonly, choreoathetosis or dystonia. Aspects of epilepsy in methylmalonic acidemia were reported (92). Some patients with mut(o) defects or treatment since early infancy may have normal growth and development during the toddler years. Nevertheless, the likelihood of such a patient not surviving a future episode of metabolic decompensation is great. Even the patient with a variant late-onset phenotype due to cobalamin B disease may succumb (27).
Neuropathologic findings may include demyelination, spongiosus of the globus pallidus, hemorrhage, and possible evidence of prenatal damage (138; 122).
A full-term male infant was born after an uncomplicated pregnancy to nonconsanguineous parents. Birth parameters were proportionate and age appropriate. The infant became progressively obtunded during the first week of life, with decreased feeding, diminished arousability, and intermittent vomiting. He was brought to the local emergency room for evaluation. No odors were detected. Physical examination was remarkable for lethargy without focal signs. The fontanelle was flat. There were diminished movements of the extremities, and the infant could not be aroused. Laboratory values were significant for pancytopenia, severe metabolic acidosis (anion gap=25), and plasma ammonium concentration of 700 uM. The urine had a specific gravity of 1010 with 3+ ketones. An inborn error of metabolism was suspected, specifically an organic aciduria. A stat urine organic acid analysis using GC with MS confirmation revealed an enormous peak of MMA and large quantities of methylcitrate. Plasma amino acid analysis showed hyperglycinemia without elevated homocysteine. Free carnitine was diminished, and propionylcarnitine was elevated. Plasma vitamin B12 concentrations were normal.
The constellation of findings in this case suggested that the infant had a severe enzyme deficiency associated with an isolated methylmalonyl-CoA mutase deficiency, likely mut(o) MMA. Cobalamin B and cobalamin A deficiencies were also possibilities, but statistically, a mutase deficiency was more common.
In this disease, the clinical and laboratory abnormalities are ultimately the consequence of the accumulation of L- or D-methylmalonyl-CoA within mitochondria that are hydrolyzed to methylmalonic acid. As a consequence, other metabolites, such as D-methylmalonyl-CoA, propionyl-CoA, and propionate build up within cells (174; 72). In both methylmalonic acidemia and propionic acidemia there is an accumulation of propionyl-CoA, propionate, and other minor metabolites of propionyl-CoA, such as methylcitrate and propionylglycine, some of which are the result of activity of seldom used alternate pathways. Secondary impairments in cellular metabolism in both diseases lead to increased concentrations of lactic acid and ketone bodies. It is important to remember that quantitatively lactate, 3-hydroxybutyrate, and acetoacetate are much more important contributors to the anion gap of the metabolic acidosis than methylmalonic acid or related metabolites. Clearly, many of the clinical signs and symptoms of acute, as well as even chronic, disease are related to acidemia per se. It is thought, however, that methylmalonic acid itself serves as a toxin in certain cells in target organs such as the brain and kidney. Even in the “well” state, resting energy expenditure may be decreased (43). Provision of optimal daily calories is not always straight-forward (53). Additional secondary biochemical abnormalities include hyperammonemia, hyperglycinemia, and L-carnitine deficiency. Occasionally, the degree of elevation in plasma ammonia may be severe. Hyperglycinemia, secondary to an impairment in the function of the glycine cleavage enzyme complex, previously led to the use of the term "ketotic hyperglycinemia." Hypoglycemia is an uncommon finding. States of metabolic decompensation may also affect the hematopoietic and lymphoid systems. Patients may develop leukopenia, thrombocytopenia, and anemia, especially during or after a ketoacidotic crisis. This is related to impaired maturation of hematopoietic precursors in bone marrow (62; 29). Patients may also have chronic mucocutaneous infections with Candida albicans. This may be related to T-cell dysfunction.
Mitochondrial matrix L-methylmalonyl-CoA mutase is a homodimer. Each 78.5-kd subunit is catalytically active, binds one molecule of adenosylcobalamin, and must be imported into the mitochondria for assembly. Many disease-producing mutations are found in the L-methylmalonyl-CoA mutase gene, which has been characterized and mapped to chromosome 6p12-21.1 (113), have been identified (83; 32; 63; 84; 04; 05; 102; 02; 03; 12; 13; 127; 47). In the mut(o) form, mutations in the amino-terminal or carboxy-terminal half of the protein eliminating enzyme activity, methylmalonyl-CoA, and adenosylcobalamin binding mutations associated with reduced concentrations of L-methylmalonyl-CoA mutase mRNA, including a splice site mutation, as well as a mutation in the mitochondrial leader sequence leading to defective mitochondrial importation of L-methylmalonyl-CoA mutase have been described (82; 119; 84; 04; 102; 13). A deletion-insertion mutation was reported (50). Although there is significant variation among mutations seen in patients, some pathogenic changes are seen in diverse populations, such as R369C (64). Mutations involving the putative adenosylcobalamin binding domain in the carboxyl-terminal portion have been detected in the mut(o) and mut forms (33; 04); some of the mut cell lines used for mutation analysis also showed an increased Km for adenosylcobalamin. Interallelic complementation (133) between mutant alleles can occur in mut MMA, which complicates genotype-phenotype predictions. A large collection of mut patient cell lines have been studied by molecular genetics and the spectrum of mutations identified (168). The mutations are spread throughout the gene, and although several mutations may be more common in selected ethnic groups, most are unique to a family. Abramowicz and colleagues reported an interesting case of a newborn infant with methylmalonic acidemia and agenesis of pancreatic beta-cells, causing diabetes mellitus associated with isodisomy of chromosome 6 (01); Corazza described an unusual cytopenia seen in one patient (29).
Two other genes, MMAA and MMAB, cause methylmalonic aciduria when mutated. Using the same technique that was employed for the identification of the human methylmalonyl-CoA racemase gene, the genes responsible for cobalamin A or cblA (39) and cobalamin B or cblB deficiencies (40; 81) have been identified. The MMAA gene is mutated in some patients with cblA class MMA (39; 87), but the function of the putative gene awaits definitive biochemical analysis. Although this gene was originally predicted to encode a mitochondrial B12 transporter (39), it more likely is a protein that protects the methylmalonyl-CoA mutase enzyme from catalytic inactivation (76), probably through a chaperone-like function (124). Studies suggest loss of functional interaction between MMAA and MUT as a disease-causing mechanism that impacts processing and assembly of a cofactor to its destination enzyme (130). The MMAB gene is mutated in cblB class MMA (40; 81) and encodes an ATP: Cob(I)alamin adenosyltransferase (81). Several mutations have been identified in each gene, including deletions, splice site mutations, and point mutations (39; 40; 170; 97; 88). Forny and colleagues reported different disease-causing variants and corresponding functional data in 97 individuals affected by cblB-type MMA (46). They reported the variant p.(Arg234*) that is associated with late-onset disease and cobalamin responsiveness. The deficit in mitochondrial handling of methylmalonyl-CoA that is common to the mut, cblA, and cblB forms of methylmalonic acidemia can be demonstrated in vivo by administration of the precursor, [1-13C]propionate, with measurement of 13CO2 in expired air (10). All of these defects that result in methylmalonic acidemia are inherited in an autosomal recessive manner. Genetic complementation studies using biochemical analyses and cultured skin fibroblasts have allowed for the separation of the disorders of methylmalonic acidemia and cobalamin metabolism into distinct classes: (1) cobalamin A, discussed above; (2) cobalamin B, discussed above; (3) cobalamin C, discussed elsewhere; (4) cobalamin D, an unknown cobalamin defect leading to methylmalonic acidemia and homocystinuria; (5) cobalamin F, defective lysosomal metabolism of cobalamin; (6) cobalamin E and G, both with reduced synthesis of methyl-cobalamin leading to homocystinuria alone; and (7) cobalamin H (163), cobalamin D variant 2. The cobalamin D group is itself heterogeneous with the variant 2 subclass exhibiting isolated methylmalonic acidemia due to defective adenosylcobalamin synthesis and the variant 1 subclass exhibiting isolated homocysteinemia (151). A complex encephalomyopathic mtDNA depletion syndrome is also associated with methylmalonic aciduria and caused by deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1 (121; 18).
The different forms of methylmalonic acidemia have been detected in different ethnic groups. It is thought that the frequency of methylmalonic acidemia is higher than 1 in 48,000 reported for Massachusetts newborn screening (31) and 1 in 61,000 for Quebec (86). Not unexpectedly, the frequency is greater in a population with a high rate of consanguinity (123). Details on a large Chinese cohort have been published (67).
Prenatal diagnosis is available for most of the forms of methylmalonic acidemia (109; 11). Therapy with cobalamin has been initiated in utero (06; 42). Gene therapy remains an interesting possibility of future treatment and is under development (141; 165). Several mouse models have been developed meanwhile (128); a human L-methylmalonyl-CoA mutase gene has been overexpressed in mice following in vivo gene transfer (149). Adeno-viral as well as adeno-associated virus-mediated gene delivery rescues a neonatal lethal murine model of mut(o) methylmalonic aciduria (23; 143). Another clinically relevant mouse model of MMAuria was developed using a constitutive Mut knock-in (KI) allele based on the p.Met700Lys patient mutation that is rescued by cobalamin treatment (47). Even partial correction of hepatic enzyme deficiency would dramatically alter the nature of the disease. It is unclear, however, whether some patients would be at risk for some manifestation of CNS disease, as methylmalonic acid is also generated de novo within certain brain cells. This may also apply to the kidney and its complications in methylmalonic acidemia. New genomic technologies under investigation have been reviewed (159).
Orthotopic liver transplantation can be considered in some infants with the mut(o) phenotype (70; 59; 69; 110; 26; 115; 15). This treatment can eliminate the occurrence of overt metabolic decompensation with metabolic acidosis and ketonuria and can also improve protein tolerance, but it does not correct the elevated concentrations of methylmalonic acid in cerebrospinal fluid or eliminate the elevation of methylmalonic acid in serum and urine (68). Similar findings have been reported in an older patient following combined liver and kidney transplantation (157). Kidney transplantation alone for the treatment of methylmalonic acidemia deserves further study (91; 28; 14). The effect of pregnancy in a patient with methylmalonic acidemia and kidney transplant was reported (90), but there is growing evidence that only liver transplantation (alone or combined) led to markedly lower plasma methylmalonic acid concentrations and is associated with a better preservation of kidney function (34). The current evidence on posttransplantation outcomes has been summarized (171), and new recommendations by the American College of Medical Genetics and Genomics (ACMG) have been published (142).
The role of newborn screening remains to be elucidated. In a first analysis of a European registry, E-IMD, newborn blood spot is an effective intervention to reduce time until diagnosis, especially for late-onset patients, and to prevent irreversible cerebral damage in methylmalonic acidemia patients who are not responsive to cobalamin treatment (55).
The differential diagnosis obviously is dependent on the phenotype in a particular patient. Not unexpectedly, the same genotype may give rise to different clinical syndromes depending primarily on environmental factors, ie, protein intake, the number or severity of episodes of fasting or infections, etc. The differential diagnosis may include:
(1) idiopathic developmental delay or mental retardation (cognitive impairment)
(2) cerebral palsy
(3) gastroesophageal reflux
(4) food allergy
(5) growth failure due to liver, renal, or endocrine disease
(6) Reye syndrome
(7) other defects in the metabolism of ammonia, amino acids, organic acids, and fatty acids
The diagnosis of the specific type of methylmalonic acidemia requires the measurement of enzyme activity, usually via the indirect assessment of radio-labeled propionate incorporation into protein in cultured skin fibroblasts, or the identification of an abnormal disease-producing gene mutation. Guidelines have been published (11). Analysis of cultured cells will also permit assignment to a particular complementation group (mut(o), mut(-), cblA, cblB, cblC, cblD, and variants), which is especially important if the abnormality is not in the L-methylmalonyl-CoA mutase gene. Patients with cobalamin C and D abnormalities also have homocystinuria. Patients with cobalamin E and G abnormalities do not have methylmalonic acidemia but homocystinuria due to impaired methyl-cobalamin synthesis. The rare cobalamin F deficiency is due to impaired release of cobalamin from lysosomes, is similar in general to nutritional cobalamin deficiency, and is associated with a megaloblastic anemia (164). Diagnosis of methylmalonic acidemia in general can be performed by analyzing a urine sample by gas-liquid chromatography with peak confirmation by mass spectrometry. Accurate quantization requires the use of a stable isotopically-labeled methylmalonic acid standard in isotope dilution analysis by gas-liquid chromatography/mass spectrometry (25). Elevated concentrations of methylmalonic acid can also be detected in serum and CSF (146; 19). The measurement of free methylmalonic acid in serum by gas-liquid chromatography is not usually employed in the initial diagnostic workup. Serum propionic acid may also be increased in patients with methylmalonic acidemia but extreme elevations suggesting the primary diagnosis of propionic acidemia may be the result of artifactual ex vivo decomposition of methylmalonate to propionate in prepared samples (41; 146). Serum propionate has also been misidentified in a gas chromatography-based toxicological screening test as ethylene glycol in a patient with methylmalonic acidemia leading to a false charge of child abuse (146). The urine of any patient suspected of having methylmalonic acidemia should be analyzed without delay by gas-liquid chromatography. Because propionyl-CoA accumulates secondarily in methylmalonic acidemia, there is increased production of propionylcarnitine and 2-methylcitrate, which may be detected in serum and urine samples. Increased concentrations of propionylcarnitine in serum may be detected using a tandem mass-spectrometry. In the past, newborn screening for methylmalonic acidemia has been performed by detecting methylmalonate in urine. It is now possible to detect some forms of methylmalonic acidemia by analysis of propionylcarnitine in blood spots on filter paper by tandem mass spectrometry (134). Analysis of urine by 1H-NMR spectroscopy can also be utilized to demonstrate increased methylmalonate concentrations in methylmalonic acidemia (60; 71) or by high-performance liquid chromatography for propionylcarnitine (100; 103; 104).
The therapeutic approach to the patient with mut(o) disease who requires strict control and a meticulous attention to detail is the prime consideration in this section (11; 48). The guidelines for the diagnosis and management of methylmalonic acidemia have been revised thoroughly (45). A protocol to test for cobalamin responsiveness has been proposed (11). Cobalamin is a powerful therapeutic tool, which is an important prognostic factor; therefore, cobalamin responsiveness has to be tested cautiously (57; 58). For cobalamin nonresponders, treatment primarily consists of a low-protein diet. In general, the goal is to provide enough protein of a high biological quality, such as egg protein, to allow for normal growth while maintaining methylmalonic acid concentrations at a minimum (112). For most patients, this eliminates signs of severe disease. From a practical vantage point, this is often not possible, as some patients with severe phenotypes will achieve methylmalonic acid concentrations that are associated with the absence of overt disease only when protein restriction is so severe as to cause essential amino acid concentrations in plasma to drop below the normal range, a condition obviously not compatible with normal growth. The use of supplemental amino acid mixtures that are free of isoleucine, valine, methionine, and threonine to enhance nitrogen intake is controversial. Many investigators believe its utility in stimulating anabolism is limited, and its use may simply enhance the waste nitrogen burden and perhaps the propensity for further renal deterioration in certain susceptible patients (89; 93; 94; 106). Antibiotics for sterilization of gut bacteria may be useful in therapy (148; 08; 11). Using metronidazole, it was estimated that approximately one quarter of daily methylmalonic acid production is derived from propionate synthesized in the large colon by anaerobic bacteria (153). This or related agents may be particularly helpful during metabolic decompensation. Chronic administration, however, may not be warranted because of the problem of drug resistance. The experience of many centers is that the majority of patients with neonatal-onset methylmalonic acidemia or a severe phenotype have serious problems with poor feeding and vomiting that they cannot maintain adequate nutritional intake without the use of gastrostomy tube feedings. A nasogastric tube is a useful temporary measure. A gastrostomy tube placed prophylactically in early infancy may represent the safest mode of therapy for those babies, the majority of whom have cobalamin-unresponsive disease. In some instances, total parenteral nutrition may be necessary to reestablish metabolic balance (11), particularly in those with nutritional deficiencies in whom chronic anorexia, vomiting, upper gastrointestinal bleeding, pancreatitis, dermatitis, and anorexia are coexistent (96).
Patients usually develop a secondary deficiency of free L-carnitine (21; 36). This is associated with increased concentrations of propionylcarnitine as the esterified form of L-carnitine (103). Several investigators have administered oral L-carnitine (50 to 200 mg/kg per day) to reduce toxicity of methylmalonic acid in either the acute or chronic state (136; 22; 126). Biochemical studies support the concept that patients with methylmalonic acidemia have a deficiency of mitochondrial L-carnitine. Acute severe metabolic decompensation in a patient with methylmalonic acidemia constitutes a medical emergency. These patients are at risk for the development of necrosis of the basal ganglia, pancreatitis, a bleeding diathesis, irreversible shock, and death. Diagnostic clinical or laboratory findings are varied and include anorexia, vomiting, dehydration, moderate to severe ketosis, acidosis, and hyperammonemia. In a retrospective analysis aiming to identify the most frequent and reliable clinical and biochemical abnormalities that aid in determining when to start emergency treatment, the authors identified vomiting and metabolic acidosis with partial respiratory compensation and hyperammonemia as the most reliable (174). Patients are usually lethargic but do not need to be stuporous or in a coma. Because the long-term neurodevelopmental outcome is strongly influenced by the duration of coma and peak blood ammonia concentrations, therapy must not be delayed and, therefore, the diagnostic workup and the initial medical treatment should proceed simultaneously. Emergency management has been outlined in one guideline and consists of the following major elements: 1) stabilize the patient; 2) stop protein intake; 3) start intravenous glucose according to age-dependent requirements; 4) seek expert metabolic advice; 5) initiate first-line treatment of L-carnitine and ammonia scavenging drugs, as outlined in the guideline (11).
Despite optimal dietary and drug treatment, there remains a large burden of disease associated complications, especially in mut(o) patients (56; 30). Chronic renal failure and associated complications, such as anemia, metabolic acidosis, and hyperparathyroidism, can only be postponed, but not prevented in these patients. Therefore, the role of organ transplantation in the treatment of methylmalonic and propionic acidemia is currently evolving (11). Transplantation in methylmalonic acidemia is considered in patients with frequent metabolic decompensations where the clinical condition is difficult to stabilize with dietary/pharmacological treatment. Previously, liver transplantation was associated with high mortality rates. This problem has diminished more recently, and there have been several reports of successful liver transplantations with a drastic decrease of hospital admissions and improvement in quality of life. The most important concerns, particularly in methylmalonic acidemia, are neurologic complications, such as basal ganglia, cerebellar stroke, movement disorders, tremor, and sensorineural hearing loss, occurring even after liver or combined liver and kidney transplantation (160; 15). Thus, transplantation can only be considered as a symptomatic treatment directed at improving quality of life, but not as a definitive cure of the disease. The role of kidney transplantation remains even less clear.
Chronic therapy of the patient with mut disease via a low-protein diet with an adequate amount of calories and nitrogen and/or alkali, L-carnitine, and intermittent metronidazole may allow for normal growth and development, prevent severe progressive brain damage, and decrease the frequency and/or severity of acute episodes of metabolic decompensation with ketolactic acidosis (11). However, it cannot prevent cognitive impairment, language delay, speech defects, and brain atrophy in certain patients, nor can it prevent the development of renal insufficiency, especially in patients with mut(o) disease (78; 147). A liver and/or kidney transplantation may be appropriate for certain patients depending on the severity of the enzyme deficiency or gene defect and organ failure (14; 11; 115; 147; 15; 107). However, depending on the timing of this procedure and the severity of organ dysfunction, there may be postoperative complications and even death (160). In addition, the details of pre-operative preparation to avoid acute metabolic complications still need to be established (66; 160).
Diss and colleagues reported the first case of a 23-year-old woman with methylmalonic acidemia who became pregnant, withstood the rigors of labor, and delivered an apparently healthy newborn infant (38).
Other reports also support that mothers with methylmalonic acidemia can deliver successfully (162; 80; 135).
Prenatal diagnostic testing is available for several of the subtypes of methylmalonic acidemia (109).
Patients with methylmalonic acidemia are at risk for intraoperative and postoperative metabolic decompensation with ketoacidosis because of the effect of stress, etc., on muscle protein catabolism. Fasting should be avoided, and the patients should receive intravenous fluids consisting of 10% glucose and appropriate electrolytes at all times if enteral feeds are not tolerated. For patients with severe enzyme defects, preadmission for hydration and glucose should be considered. Propofol administration to patients with methylmalonic acidemia may impose a risk (79). A protocol has been suggested within a treatment guideline (11).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Friederike Hoerster MD
Dr. Hoerster of University Children's Hospital in Heidelberg, Germany, has no relevant financial relationships to disclose.See Profile
Barry Wolf MD PhD
Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.See Profile
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