No abstract

Tyrosinaemia type III is a rare disorder caused by a deficiency of 4-hydroxyphenylpyruvate dioxygenase, the second enzyme in the catabolic pathway of tyrosine. The majority of the nine previously reported patients have presented with neurological symptoms after the neonatal period, while others detected by neonatal screening have been asymptomatic. All have had normal liver and renal function and none has skin or eye abnormalities. A further four patients with tyrosinaemia type III are described. It is not clear whether a strict low tyrosine diet alters the natural history of tyrosinaemia type III, although there remains a suspicion that treatment may be important, at least in infancy.

We report on late-onset ornithine transcarbamylase (OTC) deficiency in two families with mutations in the same codon, but different base substitutions. Onset of symptoms showed great variation, and five hemizygotes finally died. Clinical diagnosis was late and difficult. In family A, 1 patient also developed the signs of Gilbert's disease. In family B, the index case came to attention as OTC deficiency, after the transplantation of his liver when the recipient died of cerebral edema and hyperammonemia. In family A, the hemizygote males died at the ages of 12 and 18 years; in family B, they died at the ages of 20, 26, and 30 years, respectively. Diagnosis was confirmed by reduced OTC activity in liver specimens. The residual activity in autopsy liver of the index patient in family A was less than the activity in the biopsy of the transplanted liver of the index patient in family B. The molecular investigations showed mutations in exon 2 at codon 40 in the OTC gene in both families. However, different bases were substituted. In family A, the single-base mutation was a cytosine-to-thymine transition (Arg 40 Cys); in family B, it was a guanine-to-adenine transition (Arg 40 His). Published data on in vitro expression studies of the recurrent OTC mutation Arg 40 His have shown little effect on the protein structure of the enzyme. These studies would fit well with our observation of higher OTC activity and later age of onset of symptoms in family B.

The clinical efficacy of intravenous Augmentin (a formulation containing amoxycillin plus clavulanic acid) was investigated in an open study in fifty-eight children with a mean age of 6 years (range 1-15 years). The normal dosage was in the range 100-200 mg/kg/day Augmentin, administered parenterally by short i.v. infusion in 3 or 4 divided doses. Most patients were hospitalised for lower respiratory tract infections. Complete clinical cure or distinct clinical improvement was achieved in all assessable cases. Bacteriological success was obtained in 92% of the assessable cases. In two patients, mild, transient exanthema was noted after i.v. Augmentin was replaced by oral Augmentin. No additional therapeutic measures were required.

A 1-year-old Austrian girl of healthy non-consanguineous parents was admitted ~o hospital because of vomiting and diarrhoea. During infancy vomiting and feeding difficulties were reported repeatedly. Nutrition consisted unusually in a mixture of one-third milk and two-thirds water. Shortly before admission change to whole milk had taken place.The liver was enlarged, consciousness was reduced. There was acidosis (pH 7.32), some ketosis and hypoglycaemia (50 mg/dl). Transaminases were elevated. The organic acids in urine showed, in addition to dicarboxylic aciduria (glutaric acid 0.06, adipic acid 0.60, suberic acid 0.11 and sebacic acid 0.04mmol/mmol creatinine), the typical pattern for 3-hydroxy-3-methylglutaric aciduria (3-hydroxy-3-methylglutaric acid 8.12, 3-methylgtutaconic acid 3.26, 3-methylglutaric acid 0.40 and 3-hydroxyisovaleric acid 2.12 mmol/mmol creatinine) due to 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (McKusick 24645).After protein reduction the abnormal organic acids decreased but did not completely disappear in the following months. While hepatomegaly disappeared 3 weeks after admission, transaminases normalized after the next 2months. The activity of 3-hydroxy-3-methylglutaryl-CoA lyase (Sovik et al., 1984) was reduced to 0.07nmolmin -1 (mg protein) -~ in the patient's fibroblasts, only 1.5% of mean controk An oral glucose tolerance test showed the following glucose values: 0min, 77; 30rain, 113.9; 60min, 91.6; 120min, 74.8 and 180min, 96mg/dl, and the following insulin values: 0min, 13.4; 30min, 20.1; 60min, 18.0; 120min, 9.0 and 180min, 13.0~tU/ml. About 3weeks after admission not only a protein-(1.5 g kg -1 day -1) and fat-(1.4 g kg-1 day-i) restricted diet, but also carnitine supplement was introduced. With approximately 100mgkg -t day -1 there was no carnitine deficiency (total carnitine in plasma 77, free carnitine 39~mol/L, creatinine 47~tmol/L; total carnitine in urine 4900~tmol/L, free carnitine 2900/xmol/L, creatinine 6560/zmol/L). The mother changed the regime on her own and discontinued the carnitine supplementation for 2 months.With the exception of severe hypoglycaemic seizures on one morning (blood glucose 18 mg/dl) the 2-year-old child shows a normal development.