Problem Lucinda K

Lucinda is the second child of unrelated parents. She was born at term after an uneventful pregnancy, weighing 3.4 kg, and was breast fed, with gradual introduction of solids from 3 months of age. Her mother reported that, although Lucinda liked cheese, meat and fish, she frequently became irritable and grizzly after meals, and became lethargic, drowsy and 'floppy' after eating relatively large amounts of protein-rich foods. Her urine had a curious odour, described by her mother as being 'cat-like', on such occasions.

At 9 months of age she was admitted to the Accident and Emergency Department of UCL Hospital in a coma and suffering convulsions. She had been unwell for the previous 3 days, with a slight fever, and for the previous 12 hours had been refusing all food and drink. At this time she weighed 8.8 kg, and her body length was 70.5 cm.

Emergency blood tests revealed moderate acidosis (pH 7.25) and severe hypoglycaemia (glucose < 1 mmol/L); a dipstick test for plasma ketone bodies was negative. A blood sample was taken for full clinical chemistry tests and she was given intravenous glucose. Within a short time she recovered consciousness. The results of the blood tests are shown in Table 10.2.

Lucinda remained in hospital for several weeks while further tests were performed. She was generally well through this time, but became drowsy and severely hypoglycaemic, and hyperventilated, if she was deprived of food for more than about 8—9 hours. Her muscle tone was poor and she was very weak, with considerably less strength (e.g. in pushing her arms or legs against the paediatrician's hand) than would be expected for a girl of her age.

Table 10.2 Clinical chemistry results for a plasma sample from Lucmda K on admission and reference range for 24 hours fasting

Lucinda K

Reference range

Glucose (mmol/L)

0.22

4-5

PH

7.25

7.35-7.45

Bicarbonate (mmol/L)

11

21-29

Ammonium (^.mol/L)

120

< 50

Ketone bodies (mmol/L)

Undetectable

2.5-3.5

Non-esterified fatty acids (mmol/L)

2

1.0-1.2

Insulin (mU/L)

5

5-35

Glucagon (ng/mL)

140

130-160

On one occasion her blood glucose was monitored at 30 minute intervals over 3 hours from waking, without being fed; it fell from 3.4 mmol/L on waking to 1.3 mmol/L 3 hours later. She was deprived of breakfast again the next day, and again blood glucose was measured at 30 minute intervals for 3 hours, during which time she received an intravenous infusion of P-hydroxybutyrate (50 ^mol/min/kg body weight). During the infusion of P-hydroxybutyrate her plasma glucose remained between 3.3 and 3.5 mmol/L.

At no time were ketone bodies detected in her urine, and there was no evidence of any abnormal excretion of amino acids. However, a number of abnormal organic acids were detected in her urine, including relatively large amounts of 3-hydroxy-3-methylglutaric and 3-hydroxy-3-methylglutaconic acids. The excretion of these two acids increased considerably under two conditions:

  • When she was fed a relatively high-protein meal (when she became grizzly, lethargic and irritable). A blood sample taken after such a meal showed significant hyperammonaemia (130 ^mol/L) but normal glucose (5.5 mmol/L).
  • When she was fasted for more than the normal overnight fast, with or without the infusion of P-hydroxybutyrate.

One obvious metabolic precursor of 3-hydroxy-3-methylglutaric acid is 3-hydroxy-3-methylglutaryl CoA (HMG CoA), which is normally cleaved to yield acetoacetate and acetyl CoA by the enzyme hydroxymethyglutaryl CoA lyase (see Figure 5.25). Therefore, the activity of this enzyme was determined in leucocytes from blood samples from Lucinda and her parents. The results are shown in Table 10.3.

Analysis of Lucinda's urine also revealed considerable excretion of carnitine, as shown in Table 10.4.

What is the likely biochemical basis of Lucinda's problem? To what extent can you account for her various metabolic problems from the information you are given?

Table 10.3 Leucocyte HMG CoA lyase activity (nmol product formed per min per g protein)

Lucinda K

1.7

Mother

10.2

Father

11.4

Control subjects

19.7 ± 2.0

Table 10.4 Urinary excretion of carnitine (nmol per mg creatinine)

Lucinda K

Reference range

Total carnitine

680

125 ± 75

Free carnitine

31

51 ± 40

Acyl carnitine

649

74 ± 40

What dietary manipulation(s) would be likely to maintain her in good health and prevent further emergency hospital admissions?

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