Organic Acidemias

Summary

Isovaleric acidemia and the inherited disorders of propionate metabolism, which include propionic and methylmalonic acidemias (PA, MMA), constitute the most commonly encountered abnormal organic acidemias in pediatrics. More than 100 patients have already been described in each category.

Isovaleric acidemia (IVA) results from a defect in isovaleryl-CoA dehydrogenase (IVCoADH), which metabolizes IVCoA produced by the oxidative decarboxylation step of leucine, to methylcrotonyl-CoA. Biochemically, the disease is characterized by a greatly increased excretion of 3-hydroxyisovaleric acid, isovalerylglycine, and isovalerylcarnitine, whereas the concentration of isovaleric acid itself can be normal. Regardless of the clinical phenotype, residual IVCoADH has been found to be very low (0%–3%). No complementation groups have been defined, while at the molecular level different types of mutation have been detected.

PA and MMA share many characteristic features due to accumulation of propionyl-CoA. Isoleucine, valine, methionine, and threonine are essential amino acids which are metabolized to propionyl-CoA. Although leucine is catabolized to acetyl-CoA, there is evidence for its potential toxicity in PA and IVA. The β-oxidation of odd-numbered carbon fatty acids, which are minor components of dietary fats, and the side chain of cholesterol are also minor precursors of propionyl-CoA. In addition, the potential importance of propionate synthesis by gut bacteria has recently been reemphasized. Propionyl-CoA is further metabolized to succinyl-CoA through propionyl-CoA carboxylase (PCC), MMCoA racemase, and MMCoA mutase.

PA is secondary to a defect of PCC. It is characterized by high plasma and urinary propionate levels and by excretion of multiple organic acid byproducts, of which methylcitrate and 3OH-propionate are major diagnostic metabolites. At the molecular levels, there are two major complementation groups pcc A and pcc BC which correspond to the genes coding for the alpha and the beta chain, respectively.

Inherited MMA is secondary to either a MMCoA mutase mutation or to a defect of adenosylcobalamin (AdoCbl), synthesis. Impairment of mutase activity leads to accumulation of MMCoA and propionylCoA, which is reflected by the presence of greatly increased amounts of methylmalonic and propionic acid and other organic byproducts in blood and urine. Nine classes of MMA are defined on the basis of complementation studies. About one half of patients have a vitamin B₁₂-unresponsive mutase apoenzyme defect divided into mut° and mut⁻ groups, the latter corresponding to a defective apoenzymecoenzyme affinity. The remaining patients are cobalamin variants (registered CblA to CblG). CblA is due to a mitochondria) cobalamin reductase deficiency and CblB to defective AdoCbl transferase. All CblA patients and 40% of CblB are B₁₂ responsive in vivo. MMCoA mutase has recently been cloned, and several mutants have been already investigated at the gene level.

Children with IVA, PA, and MMA have many symptoms in common. Although several patients are asymptomatic, most of them present with one of the three clinical onset types:

• In the severe neonatal form, babies, after an initial symptomfree period, undergo relentless deterioration which has no apparent cause and does not respond to symptomatic therapy. Major features include poor sucking, vomiting, anorexia, lethargy, generalized hypertonic episodes, large amplitude tremors, truncal hypotonia, dehydration, and at a more advanced state, respiratory distress, bradycardia, and hypothermia. A strong odor of sweaty feet in urine and skin is present in IVA. Metabolic acidosis, ketonuria, hyperammonemia, hypocarnitinemia, moderate hypocalcemia, neutropenia, thrombocytopenia, and macrocytic anemia are almost constant findings. Hyperglycinemia is present in PA and MMA. The final diagnosis of all these organic acidemias is made by identifying specific abnormal metabolites by GLC-MS.

• One third of patients present with a late onset form. Recurrent attacks of coma or lethargy with ataxia are frequent, precipitated by infections, excessive protein intake, or catabolism, but sometimes without apparent cause. In between the child may seem to be entirely normal. The most frequent varieties of comas are those presenting with ketoacidosis with normo-, hypo-, or hyperglycemia. Some patients may mimic diabetic coma. Neurologic signs such as hemiplegia, hemianopsia, and metabolic stroke can be observed, simulating a cerebrovascular accident or cerebral tumor. Few patients with MMA developed acute extrapyramidal disease.

Acute ataxia, unexplained dehydration, persistent anorexia, failure to thrive, hypotonia, myopathy, progressive developmental delay, neutropenia, recurrent infections, and chronic mucocutaneous candidiasis are other common chronic presentations. Generalized staphylococcal cutaneous epidermolysis is a possible complication. Chronic renal impairment with tubulointerstitial nephritis is a frequent long-term complication in MMA and may be also a revealing symptom.

The emergency management of organic acidurias in the neonate has two main goals: toxin removal and promotion of anabolism. Toxin removal is achieved with blood exchange transfusions and peritoneal dialysis in PA, hydration and exchange transfusions in IVA and MMA. Additionally, glycine 500 mg/kg/day in IVA, biotin in PA, and vitamin B₁₂ in MMA should be tried in all cases, although the neonatal forms of these defects are rarely vitamin responsive. l-Carnitine (200 mg/kg) is systematically given in all three disorders. Additional treatment such as insulin or growth hormone may be considered. Anabolism is met by early effective continuous enteral nutrition with a protein-free diet. A special amino acids mixture free of precursors can be added to the formula as soon as ammonia levels are below 80 μmol/l.

Long-term dietary treatment is aimed at reducing accumulated toxic metabolites, while maintaining normal development and nutrition status and preventing catabolism. In IVA, leucine intake can be increased up to 800 mg/day during the 1st year and then most children can tolerate 20–30 g/day of vegetable protein if associated with oral l-glycine and l-carnitine therapy. In most PA and MMA early onset forms, the intake of valine must be rigidly restricted to 250–500 mg/day for the first 3 years of life, subsequently slowly increased to 600–800 mg/day by the age of 6–8 years. Supplementation with a synthetic mixture of amino acids containing none of the amino acid precursors is generally recommended, although still controversial. In general, these infants are severely anorectic, and the entire diet must be delivered through a nocturnal gastric drip feeding using a peristaltic pump. Long-term carnitine treatment may be considered. Metronidazole has been recently found to be very effective in reducing excretion of propionate metabolites because of its activity against gut anaerobic bacteria.

Most of late onset forms are easier to manage, tolerate up to 1.5–2 g/kg per day of protein, and amino acid mixtures are no longer necessary. In all CblA and 40% of Cb1B patients, hydroxocobalamin at a dose of 1 mg/day IM is very efficient. Some patients have gradually interrupted chronic B₁₂ therapy without apparent discomfort. These late onset forms, as well as the vitamin-responsive forms, have an excellent long-term prognosis although they may decompensate at any age and in unpredictable situations.

All forms of IVA, PA, and MMA can be diagnosed early in pregnancy by measuring the defective enzyme activity in uncultured chorionic villi and by directly measuring abnormal metabolites accumulated in amniotic fluid as early as the 12th week of gestation.