Methylmalonic Acidemia (MMA)

Heterogeneous inborn error of metabolism affecting amino acid metabolism, leading to metabolic acidosis and accumulation of methylmalonic acid (MMA) and its by-products.

Methylmalonic Aciduria, Methylmalonic-Coenzyme A Mutase Deficiency; MMA.

First reported in 1967 by Oberholzer and Stokke.

Approximately 1:25,000-50,000 (all types of MMA included). Consanguinity is a risk factor. No gender predilection has been reported.

Autosomal recessive (for all types). The gene encoding the enzyme methylmalonyl-CoA mutase has been mapped to 6p12-21.1. Two forms of this mutase deficiency exist: the mut0 form with complete absence of mutase activity, and the mut- form with reduced mutase activity. The mutase defect accounts for approximately 50% of patients with MMA. The defect in adenosylcobalamin synthesis has been mapped to chromosome 4q31.1-2.

Methylmalonic-coenzyme A mutase is a vitamin B12-dependent enzyme involved in the catabolism of leucine, isoleucine, and valine; its deficiency leads to increased amounts of MMA in plasma and urine. Because of secondary inhibition of propionyl-CoA carboxylase, propionic acid also accumulates, as do other organic acids. Accumulation of propionyl-CoA results in inhibitory effects on various pathways of intermediary mitochondrial metabolism and secondary carnitine deficiency, thus explaining hypoglycemia, hyperammonemia, and hyperlactacidemia and the synthesis of odd-numbered abnormal fatty acids. Moreover, gut bacteria produce approximately 25% of the propionate to be metabolized.

Neonatal screening for inborn errors of metabolism should detect all genetic variants of MMA. Large amounts of MMA, methylcitrate, propionic acid, and 3-hydroxy propionic acid can be detected in the urine by gas chromatography-mass spectrometry. However, once other causes for neonatal or infantile ketoacidosis have been ruled out, simple colorimetric assays for urinary MMA for suspected MMA are also available. Enzyme analysis in fibroblasts is used to detect the specific enzyme abnormality and finalize the diagnosis. Cultured amniotic cells are used for prenatal diagnosis.

The clinical picture has a high variability, and asymptomatic children with mutase apoenzyme deficiency have been identified through newborn screening. Although the signs in symptomatic children are basically similar to those of Propionic Acidemia, complications and prognosis are worse in MAA. In 80%, manifestation of mut0 patients occurs in the first week of life and the remainder by 6 months of life. In contrast, mut- and cobalamin disorder patients most often present after the first month of life. The most common signs and symptoms at onset after a period of normal feeding are lethargy or coma, poor feeding with failure to thrive, recurrent vomiting with dehydration, hepatosplenomegaly, respiratory distress, and muscular hypotonia. MMA caused by a cobalamin-related defect usually has onset later in childhood or adolescence, starting with decreased lower leg sensitivity, thrombosis secondary to persistent homocystinuria, and progressive myopathy leading to chronic gait disturbances, which may not be irreversible. The majority of patients present with metabolic acidosis with a blood pH less than 6.9 and bicarbonate concentrations as low as 5 mmol/l. Ketonemia and ketonuria, hyperammonemia, anemia, leukopenia, and thrombocytopenia are found in more than 50% and hypoglycemia in 40% of the patients at presentation. Hyperglycinemia has been reported in some patients. All patients with isolated MMA have in common the high plasma and urine concentrations of MMA, with urine concentrations up to 1000 times higher than normal. Infections and high-protein diet are known triggers for acute exacerbation, and many children with MMA may die in the first weeks of life, often before a diagnosis has been established secondary to ketoacidosis and/or hyperammonemia. The risk is significantly lower in MMA resulting from cobalamin deficiency. The median life expectancy for mut0 patients is approximately 6 years. Mental retardation, seizures, and stroke are common features in MMA. The reasons for increased risk for stroke remain to be determined, but several hypotheses exist: severe acidosis may result in reduced cerebral blood flow secondary to hypocapnia or direct toxicity to the brain (glial and neuronal cells) from MMA and odd-chain fatty acids, or iatrogenic by treatment with high doses of cyanocobalamin, which is metabolized to the highly toxic cyanide. A stroke should always be excluded in MMA patients with acute onset of dystonia, dysarthria, dysphagia, or choreoathetosis. Acute exacerbation requires symptomatic treatment (rehydration, acid-base correction) and parenteral hyperalimentation with minimal amounts of proteins and high doses of vitamin B12 and l-carnitine. Hemoor peritoneal dialysis may be required to correct hyperammonemia effectively. Long-term treatment consists of a low-protein diet and supplements of vitamin B12 and l-carnitine. Often chronic bicarbonate supplements are required to correct the metabolic acidosis. High forehead, epicanthal folds, broad nasal bridge, long philtrum, and a triangular mouth are the features responsible for facial dysmorphism. Skin lesions similar to acrodermatitis enteropathica have been described repeatedly. Chronic tubulointerstitial nephritis with progressive decline of renal function is a frequent long-term complication (20-60% of adolescents with MMA) and may require either hemodialysis or kidney transplantation.

Obtain a full neurologic status and ask particularly about strokes, seizures pattern and frequency (and efficacy of treatment), and degree of mental retardation. Laboratory investigations should include a complete blood count (anemia, thrombocytopenia, leukopenia), blood glucose, electrolytes, acid-base status (blood gas analysis), and urine analysis for ketones. Renal function should be checked. For elective surgery, patients must be optimized as much as possible. Muscular hypotonia may require prolonged postoperative mechanical ventilation, and appropriate arrangements should be made in advance. During periods of increased catabolism, patients with MMA are at increased risk for metabolic decompensation (e.g., stress, intercurrent infections, trauma, surgery). The appropriate treatment is directed toward stopping catabolism and promoting anabolism. This can be achieved by intravenous administration of dextrose-containing solutions and maintenance of normovolemia. Provision of a stress-free anesthetic helps prevent acute exacerbations. Careful sedative and/or anxiolytic premedication may be helpful in the absence of lethargy and/or muscular hypotonia.

Dehydration, arterial hypotension, hypoxia, inappropriate caloric intake (catabolism, high-protein diet), and inadequate anesthesia technique can result in severe metabolic acidosis. Lactate-containing solutions (e.g., Ringer lactate, Hartmann or Stocker [swiss modification of Hartman solution]) should be avoided because they may not be metabolized appropriately in the presence of dysfunctional mitochondria and therefore contribute to the acid load. The regular bicarbonate requirements of the patients should be replaced intravenously in the perioperative period. Depending on the length of the procedure, an arterial line may be inserted to facilitate mandatory perioperative monitoring of acid-base status, blood glucose, ammonia, and lactate levels. Often, patients show lethargy and muscle hypotonia preoperatively. If there is risk of nasal, pharyngeal, or gastric bleeding, a gastric tube should be inserted to remove swallowed blood, which may otherwise provide a significant protein load and trigger an acute metabolic decompensation. Perioperative gastroduodenal ulcus prophylaxis with an H2 antagonist or proton pump inhibitor may be indicated. Osteoporosis (secondary to malnutrition resulting from low-protein diet) requires careful positioning. Prolonged postoperative metabolic monitoring for early diagnosis of acute decompensation is recommended.

Nitrous oxide inhibits vitamin B12-dependent enzymes and so should be avoided in these patients. Drugs containing or metabolized to MMA, odd-chain organic acids, odd-chain fatty acids, odd-chain alcohols, or acrylic acids must be avoided because they can be metabolized to MMA, inhibit citric acid cycle enzymes, and result in ketoacidosis. These drugs include muscle relaxants metabolized by ester hydrolysis (succinylcholine, atracurium, cis-atracurium, mivacurium). Furthermore, propionic acid-derived nonsteroidal antiinflammatory drugs (e.g., naproxen, ketoprofen, ibuprofen) should be avoided. Propofol contains polyunsaturated fat (soybean oil) and should not be used. Avoid potentially epileptogenic drugs such as methohexital, ketamine, enflurane, atracurium, and meperidine (the last two in large quantity because of their respective metabolites of laudanosine and normeperidine) in patients with known seizures.

Propionic Acidemia: Inborn error of metabolism affecting mitochondrial catabolism of valine and isoleucine that left untreated results in ketoacidosis, lethargy, coma, and finally death.

Homocystinuria (HCU): Genetically transmitted error of metabolism of the amino acid methionine characterized by severe myopia, Marfan-like stature with pectus excavatus, slight mental retardation, and tendency to develop spontaneous generalized arterial and venous thromboses under stress.

Maple Syrup Urine Disease (MSUD): Autosomal recessive transmitted inborn error of metabolism caused by a defect in the branched-chain α-ketoacid dehydrogenase resulting in the characteristic smell of the urine. Untreated, this disorder leads to mental retardation, seizures, and most often death.

Multiple Carboxylase Deficiency: Inborn error of metabolism characterized by defective activity of all biotin-dependent carboxylases. Characterized by seizures, developmental delay, eczema, and hearing loss when left untreated.

Argininemia: Urea cycle disorder that leads to hyperammonemia and neurologic symptoms, which are less severe than in other forms of urea cycle abnormalities. Clinical features include spastic paraplegia, seizures, and severe mental retardation. The triad of hyperammonemia, encephalopathy and respiratory alkalosis may be present.

Citrullinemia: Syndrome arising from argininosuccinate synthetase deficiency leading to hyperammonemia and neurologic consequences. Severe vomiting spells beginning in infancy and the presence of mental retardation are characteristic features.

HHH Syndrome: Genetically transmitted inborn error of metabolism resulting from a defect in the transport of ornithine into the mitochondrial matrix, clinically characterized by early growth retardation, learning disabilities, periodic confusion, and ataxia.

N-Acetylglutamate Synthetase Deficiency: Congenital mitochondrial disorder affecting the metabolism of ammonium and resulting in hyperammonemia. Clinical features include cerebral edema, raised intracranial pressure, lethargy, heavy and rapid breathing, irritability, and coma leading to death if untreated.

Ornithine Carbamoyltransferase Deficiency (OTCD): Rare genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase. The lack of this enzyme results in excessive hyperammonemia, which is a known neurotoxin. Clinically, patients present with vomiting, refusal to eat, progressive lethargy, and coma.

Carnitine Deficiency: Disorder resulting from decreased carnitine concentrations in plasma and tissues preventing mitochondria from adequate beta oxidation. Primary and secondary defects have been described. The manifestations are cardiomyopathy, encephalopathy, and myopathy.

Isovaleric Acidemia: Genetic disorder affecting the branched-chain organic acids, the most frequent form of leucine metabolism disorders. It results in accumulation of isovaleric acid (and its metabolites), leading to vomiting, dehydration, severe metabolic acidosis, and neurologic manifestations.