Summary The clinical and biochemical features of a case of methylmalonic acidemia, a newly described inborn error of metabolism, are reported. The cardinal feature was chronic metabolic acidosis which was controlled by restriction of the protein intake. Periodically, exacerbations with vomiting, dehydration, lethargy, coma, and even peripheral circulatory failure have appeared. The crisis have been induced by trivial acute infections and by overloading with protein. Mild symptoms appeared in the neonatal period, crises after an age of 4 months. When the protein intake was high, there was marked muscular hypotonia, developmental retardation, and neutropenia. When acidosis was controlled by protein restriction and treatment with bicarbonate the baby made marked progress. At 23/12 years of age the development was normal. The patient excreted large amounts of methylmalonic acid in the urine and the blood level was elevated. Other biochemical abnormalities were hyperglycinemia, hyperglycinuria, and hyperlactatemia. The hypothesis that the basic metabolic defect in methylmalonic acidemia and the ketotic type of hyperglycinemia is the same is discussed, as are the similarities between methylmalonic acidemia and infantile lactic acidosis.

Methylmalonic acidemia (8) or aciduria (5) is a newly described inborn error of metabolism. Clinically, the disease is characterized by metabolic acidosis, vomiting, dehydration, muscular hypotonia, and retarded psychomotor development. Life-threatening crises of acidosis may develop during the course of even mild acute infections or during periods of high protein intake (3). The main biochemical features are methylmalonic acidemia, high urinary excretion of methylmalonic acid and intermittent ketosis.The accumulation of methylmalonic acid is caused by a block in the two-step conversion of methylmalonyl-CoA to succinyl-CoA (4, 6, 7). In the first step the enzyme methylmalonyl-CoA racemase (EC 5.1.99.1) catalyzes the reversible conversion of D-methylmalonyl-CoA to L-methylmalonyl-CoA, and in the second step methylmalonyl-CoA mutase (EC 5.4.99.2) catalyzes the reversible conversion of L-methylmalonyl-CoA to succinyl-CoA. The last enzyme has cobamide coenzyme as a co-factor.The metabolic block in methylmalonic acidemia may thus be explained by a deficiency of one or both of the two enzymes. Since patients with pernicious anemia are This work has been supported by a grant from the Swedish Medical Research Council (2583). Acta Pcediat Scand 58known to excrete up to 1 g of methylmalonic acid in the urine per day (1, 2) the possibility exists that there is, in methylmalonic acidemia, an abnormally high requirement of cobamide coenzyme, i.e. a so-called dependency condition. In order to test the validity of this hypothesis, the metabolic effect of a large dose of cobamide coenzyme has been studied in two patients with methylmalonic acidemia.The first patient (case E. B.) is a girl of 2 9/12 years of age, and whose clinical history has been reported in detail previously (3). The second patient (case S. B.) is a 2-year-old boy with a history of mild to moderate attacks of metabolic acidosis sinct the neonatal period. When 1 7/12 years of age he got an acute upper respiratory tract infection and during the course of this disease he developed a severe ketosis and a pronounced metabolic acidosis and went into shock. Following intensive medical treatment, including the administration of large doses of sodium bicarbonate, he recovered from the acute episode. However, when the protein intake was increased after another week, the patient relapsed. Since it was then found that the urinary excretion of methylmaIonic acid ranged between 3 and 4 g per day and that the serum concentration of this compound was 23 mg per 100 ml, he was diagnosed as a case of methylmalonic acidemia. When the patient had recovered from the second severe attack of acidosis he was put on a low protein diet providing him with 2 g of protein per kg body weight per day. Since then he has been free of severe attacks of acidosis although he has continued to excrete large quantities of ketone bodies in the urine. There has never been any symptoms of vitamin B12 deficiency and the serum concentration of vitamin BE has been found to be 690 pg per ml.