Arch Dis Child: first published as 10.1136/adc.42.225.492 on 1 October 1967. Downloaded from Arch. Dis. Childh., 1967, 42, 492. Methylmalonic Aciduria An Inborn Error ofMetabolism Leading to Chronic Metabolic Acidosis V. G. OBERHOLZER, B. LEVIN, E. ANN BURGESS, and WINIFRED F. YOUNG From Queen Elizabeth Hospital for Children, Hackney Road, London E.2 Although metabolic acidosis from a variety of and constipation. At first he was hungry but later causes is very frequent in infancy, congenital refused feeds. acidosis appears to be extremely rare. Two In 1957 he was admitted to hospital aged 8 months, unrelated cases of a new syndrome are now des- weighing 5 8 kg. (121 lb.), unable to sit up, and with cribed with a congenital metabolic acidosis resulting generalized hypotonia, but no cause for his symptoms was found. He had persistent hepatomegaly but liver from a block in the conversion of methylmalonic function tests were normal. acid to succinic acid. The vomiting, associated with upper respiratory tract The first had persistent mild acidosis with acute infections recurred, and he had a raised blood urea and a episodes of severe metabolic acidosis during the first metabolic acidosis. He was treated by alkali supple- year of life. He was thought to have renal tubular ments, sodium citrate, and potassium acetate, to his milk acidosis, albeit atypical, and died during an acute feeds, but after an initial improvement, the acidosis episode at 2 years of age in 1959. His disorder was recurred, and this was now attributed to renal tubular always considered to have been similar to that of the dysfunction. He was given a low protein diet and he later case, and this was confirmed 7 years after death began to gain weight on this treatment, the blood urea copyright. fell and the plasma CO2 level was normal and continued by an examination of his stored plasma. so after the alkali administration had been discontinued. The second child, born in 1960, had persistent He was discharged weighing 7 kg. (154 lb.), having acidosis with acute exacerbations from the first week been in hospital for 3 months. of life. She was found to have renal tubular One month later he was readmitted, respiratory acidosis, confirmed by the hydrogen ion clearance infection having precipitated a recurrence of symptoms. index, and treatment with alkalis was instituted, but The constitutional disturbance then failed to respond so her course was atypical. In one severe episode of well to symptomatic treatment. He had a persistent moderately raised blood urea with low urea clearances acidosis it was noted that she was excreting a very http://adc.bmj.com/ acid urine in of a normal and some degree of metabolic acidosis, with an acid during treatment, spite urine. However, he could concentrate his urine to a blood pH and plasma bicarbonate. An analysis of specific gravity of 1017, and the pyelogram showed no the urine for organic acids revealed that she was abnormality of the renal tract. excreting large amounts of methylmalonic acid, an From the age of 15 months, he was always on supple- intermediate in the metabolism of some amino acids ments of sodium citrate and potassium acetate and also and of fatty acids with an odd number of carbon on a restricted protein intake, but this treatment did not atoms. prevent recurring episodes of dehydration and metabolic The effect of the metabolic block on protein and acidosis, and progressive renal tubular dysfunction was on October 1, 2021 by guest. Protected carbohydrate metabolism has also been studied, and postulated. When 1 i years old he weighed 9 kg. (20 lb.), to elucidate the metabolic and his condition was considered stable enough for him preliminary investigations to be looked after at home. defect are presented. Reappraisal at 21 months showed that the acidosis and increase in blood urea were present despite alkali Case Reports administration, and the urine was acid. The dosage of alkalis was therefore increased and a higher fluid intake Case 1. K.F., a boy, was the second born infant of prescribed. Clinical improvement was now well healthy parents and has two normal sibs. His progress sustained. When 2 years of age he developed respira- was satisfactory while on the breast for 7 weeks, but tory infection and was admitted already in peripheral thereafter he began to suffer from intermittent vomiting circulatory failure after vomiting for only 1 day, having been without alkalis and the high fluid intake on which Received December 29, 1966. he depended. Despite intravenous fluid and alkali 492 Arch Dis Child: first published as 10.1136/adc.42.225.492 on 1 October 1967. Downloaded from Methylmalonic Aciduria 493 administration, the blood urea, which was 184 mg./100 infection. Further investigations showed that she had ml. on admission, rose to 204 mg., plasma CO2 content generalized renal impairment with low urea and fell from 5 * 6 to 3 * 4 mEq/l., and Cl from 91 to 75 mEq/l. creatinine clearances in addition to a low hydrogen ion Although the plasma CO2 content then rose to 14 mEq/l., clearance index. However, the x-ray appearances of the he failed to respond clinically, developed anuria, and his kidneys were still normal. convulsions became difficult to control. He died 2 days Although her renal function was deteriorating at this after admission. stage, she was beginning to thrive, but was still unable to The necropsy was performed by Dr. N. E. France, who sit up and weighed only 7 * 25 kg. (16 lb.) at 1 year. She reported as follows. was considered sufficiently stable to go home and was 'Pneumonia due to monilia infection was found. discharged on a high fluid, restricted protein intake with Both kidneys were small (weight 28 g. and 29 g.), and added sodium citrate and potassium acetate, 60 mEq of had scarred stripped surfaces, the thin cortex showing each daily. Thereafter, she made surprisingly good poorly defined architecture. Microscopically, they progress and at 2 years weighed 13 kg. (29 lb.), and was showed a curious appearance with infantile type walking well; Dr. Agatha Bowley reported that she might glomeruli and diminutive tubules arranged in irregular prove less mentally retarded than appeared from her areas showing mildly increased interstitial tissue and a performance at that time. little lymphocytic infiltration. The tissue between these She was admitted to hospital again during the fourth areas consisted of normal tubules with few glomeruli. year of age with a severe clinical episode. This respon- Occasional tubules were dilated and some contained ded well to symptomatic treatment. Her mother was hyaline casts. The liver showed marked fatty change.' beginning to be able to control episodes of upper Case 2. S.H. was the third infant of healthy respiratory tract infections at home by giving, at their parents, and has one normal female sib. She was onset, ample drinks of sweet clear fluids, and she had admitted to hospital when 3 days old with a gross initial sustained uncomplicated mumps without constitutional weight loss from vomiting, and at 7 days was transferred disturbance. She was inquisitive and sociable and to Queen Elizabeth Hospital for Children with considered to be ahead of her sib at the same age. suspected intestinal obstruction. She was a grossly Dr. Bowley's reassessment during the fifth year of life dehydrated infant with abdominal distension, and at 5 showed her IQ to be 100 (Merrill-Palmer Scale). days of age had been passing 'diarrhoeal' stools. There X-ray appearances of the renal tract were normal and the was an acidosis which was consistent with the symptoms, urea and creatinine clearances were improving. Alkali and the finding of Esch. coli 0.26 in the stool suggested therapy was unaltered throughout this period. copyright. gastro-enteritis as the cause of the illness, which was When 5j years old, she was readmitted in an episode treated accordingly. of severe vomiting requiring intravenous fluid therapy. During the next month she had intermittent vomiting, Vomiting persisted even after the acidosis had been constipation, and variable abdominal distension without controlled. Again it was noted that the urine was acid at x-ray evidence of intestinal obstruction. A metabolic a time when the plasma standard bicarbonate was over disorder was considered as the possible cause of her 20 mEq/l. illness, but because of the relatively mild degree of During the past year she has had a similar episode acidosis, the symptoms were thought to be more probably requiring hospital treatment. It is now well recognized alimentary in origin, possibly a partial or intermittent that when she develops uncontrollable vomiting, it obstruction ofthe bowel. Since she began to gain weight quickly leads to severe acidosis with air hunger and needs http://adc.bmj.com/ well during the third month she was discharged from to be treated immediately by intravenous glucose and hospital. alkali solutions. She still requires alkali therapy which One month later she was readmitted for recurrence of is given in the form ofsodium and potassium bicarbonate, vomiting and constipation. She was noted to be 15 mEq of each, three times daily. In other respects she hypotonic. Pyuria was found but a congenital renal is now a well girl, her height and weight being normal defect was excluded by x-ray examination. After for her age. initial improvement, the vomiting with acidosis recurred. Family History. There was no history of fits, Her clinical progress was slow, despite a good appetite, mental defect, or other relevant disease in the family of on October 1, 2021 by guest. Protected and there was little to account for her failure to thrive.