Problem Angela P

At the age of 28 weeks Angela was admitted to the accident and emergency department of her local hospital in a coma, having suffered a convulsion after feeding. She had a mild infection and slight fever at the time. Since birth she had been a sickly child, and had frequently vomited and become drowsy after feeding. She was bottle fed, and at one time cows' milk allergy was suspected, although the problems persisted when she was fed on a soya-milk substitute.

On admission she was mildly hypoglycaemic, ketotic and her plasma pH was 7.29. Analysis of a blood sample showed normal levels of insulin but considerable hyperammonemia (plasma ammonium ion concentration 500 ^mol/L; reference range 40—80 ^mol/L). She responded well to intravenous glucose infusion and enteral administration of lactulose, regaining consciousness, although she showed poor muscle tone.

A liver biopsy sample was taken, and the activity of the enzymes of urea synthesis (see Figure 9.11) were determined and compared with activities in post-mortem liver samples from six infants of the same age. The results are shown in Table 9.20. She remained well on a high-carbohydrate, low-protein diet for several days, although the poor muscle tone and muscle weakness persisted. A second liver biopsy sample was taken after 4 days and the activity of the enzymes determined again.

Table 9.20 Activity of enzymes of the urea synthesis cycle in liver biopsy samples from Angela P on admission and after 4 days on a high-carbohydrate, low-protein diet, compared with activities in postmortem samples from six infants of the same age

Amount of product formed (^mol /min per mg protein)

Angela P

On admission After 4 days

Control

Carbamyl phosphate synthetase 0.337

1.45

1.30

± 0.40

Ornithine carbamyltransferase

29.0

28.6

18.1

± 4.9

Argininosuccinate synthetase

0.852

0.75

0.49

± 0.09

Argininosuccinase

1.19

0.95

0.64

± 0.15

Arginase

183

175

152:

± 56

Table 9.2 1 Metabolism of {ViC}propionate

Angela

Mother

Father

Control

Per cent recovered in 13CO2

1.01

32.6

33.5

65 ± 5

over 3 hours

dpm fixed per mg fibroblast

5.0

230

265

561 ± 45

protein over 30 minutes

Table 9.22 Liver and muscle carnitine

Amount (^mol/g

Liver

Muscle

wet weight tissue)

Angela P

Control

Angela P

Control

Total carnitine

0.23

0.83 ± 0.26

1.56

2.29 ± 0.75

Free carnitine

0.05

0.41 ± 0.17

0.29

1.62 ± 0.67

Short-chain acylcarnitine

0.16

0.37 ± 0.20

1.16

0.58 ± 0.32

Long-chain acylcarnitine

0.01

0.05 ± 0.02

0.11

0.09 ± 0.03

Her very low-protein diet was continued, but in order to ensure an adequate supply of essential amino acids for growth she was fed a mixture of the ketoacids of threonine, methionine, leucine, isoleucine and valine. After each feed she again became abnormally drowsy and markedly ketotic, with significant acidosis. Her plasma ammonium ion concentration was within the normal range, and a glucose tolerance test was normal, with a normal increase in insulin secretion after glucose load.

High-pressure liquid chromatography of her plasma revealed an abnormally high concentration of propionic acid (24 |mol/L; reference range 0.7—3.0 |mol/L). Urine analysis showed considerable excretion of methylcitrate (1.1 |mol per milligram of creatinine), which is not normally detectable. She was also excreting a significant amount of short-chain acyl-carnitine (mainly propionyl carnitine) — 28.6 |lmol/24 h, compared with a reference range of 5.7 ± 3.5 |mol/24 h.

The metabolism of a test dose of [13C]propionate given by intravenous infusion was determined in Angela, her parents and a group of control subjects; skin fibroblasts were cultured and the activity of propionyl CoA carboxylase was determined by incubation with propionate and NaH14CO3, followed by acidification and measurement of the radioactivity in products. The results are shown in Table 9.21.

The results of measuring carnitine in the first liver biopsy sample and in a muscle biopsy sample gave the results shown in Table 9.22.

What conclusions can you draw from these results? Can you explain the biochemical basis of Angela's condition?

CHAPTER

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