Disruption of the metabolism of branched-chain amino acids

Valine, leucine and isoleucine are branched-chain amino acids; deficiency of enzymes involved in their metabolism, leads to the accumulation of organic acids with severe metabolic acidosis.

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Maple Syrup Disease

This is a group of autosomal recessive diseases caused by deficiency of one or more subunits of decarboxylase, active at the second stage of catabolism of branched-chain amino acids. Despite the fact that they are relatively rare, their frequency is significant among Amish and Mennonites (probably 1/200 births).

Symptoms include a characteristic body odor reminiscent of maple syrup (especially strong in earwax), and a serious condition in the first days of life, beginning with the appearance of vomiting and drowsiness and progressing to cramps, coma and death in the absence of treatment. In patients with mild forms of the disease, symptoms can manifest only under stress (for example, infection, surgery).

Biochemical changes include pronounced ketonomy and acidemia. The diagnosis is based on an increase in the level of amino acids with a branched chain in the plasma (especially leucine).

In an acute period, peritoneal dialysis or hemodialysis with simultaneous intravenous hydration and nutrition (including high doses of glucose) may be necessary. Long-term treatment includes limiting the supply of food with amino acids branched chain; at the same time, small amounts of them are necessary for normal metabolism. Thiamine is a decarboxylation co-factor, and some patients respond with an improvement in the administration of high doses of thiamine (up to 200 mg orally once a day).

Isovaleric acidemia

The third stage of leucine metabolism is the conversion of isovaleryl-CoA to 3-methylcrotonyl CoA, the dehydrogenation step. Deficiency of this dehydrogenase leads to an increase in the level of isovaleric acid, the so-called "sweaty feet" syndrome, as the accumulated isovaleric acid smells like sweat.

Symptoms in acute form develop in the first days of life and include a low volume of food eaten, vomiting and respiratory failure that occur with the development of a patient's metabolic acidosis with a deep anion gap, hypoglycemia and hyperammonemia. Often develops oppression of bone marrow function. Chronic intermittent form may not appear for several months or even years.

The diagnosis is based on the detection of an elevated level of isovaleric acid and its metabolites in the blood or urine. In acute form, treatment includes intravenous rehydration and parenteral nutrition (including high doses of glucose) and measures to increase the excretion of isovaleric acid; glycine and carnitine may increase its excretion. If these measures are insufficient, replacement blood transfusion and peritoneal dialysis may be necessary. Long-term treatment includes limiting the intake of leucine with food and continuing the additional administration of glycine and carnitine. The prognosis is excellent for treatment.

Propionic acidemia

Deficiency of propionyl-CoA carboxylase, the enzyme responsible for the conversion of propionic acid to methyl malonate, leads to the accumulation of propionic acid. Symptoms appear in the first days or weeks of life and include low appetite, vomiting and respiratory failure due to metabolic acidosis with a deep anion gap, hypoglycemia and hyperammonemia. Seizures may develop, and bone marrow depression is often noted. Physiological stress can provoke repeated attacks. In the future, patients may have mental retardation and neurological disorders. Propionic acidemia can also be part of a disorder with multiple deficiencies of carboxylases, a biotin or biotinidase deficiency.

The diagnosis is based on an elevated level of propionic acid metabolites, including methyl citrate and tiglate, and their glycine conjugates in urine and blood and are confirmed by measuring the activity of propionyl-CoA carboxylase in leukocytes or fibroblast culture. Treatment for acute manifestations includes intravenous hydration (including high doses of glucose) and parenteral nutrition; can be useful carnitine. If these measures are inadequate, peritoneal dialysis or hemodialysis may be required. Long-term treatment includes limiting the supply of food amino acid precursors and fatty acids with an additional chain, and, possibly, the continuation of additional carnitine administration. Some patients respond to high doses of biotin, since it is a co-factor for propionyl-CoA and other carboxylases.

Methyl malonate acidemia

This disorder is a consequence of a methylmalonyl-CoA mutase deficiency that converts methylmalonyl-CoA (a product of carboxylation of propionyl-CoA) to succinyl-CoA. Adenosylcobalamin, a metabolite of vitamin B12, is a co-factor; its deficiency can also cause methylmalonic acidemia (as well as homocystinuria and megaloblastic anemia). Accumulation of methylmalonic acid occurs. Age of onset, clinical manifestations and treatment are similar to those with propionic acidemia, except that in some patients cobalamin, rather than biotin, can be effective.