Forty‐two infants (20 males, 22 females) with classical phenylketonuria (PKU) entered a prospective, double‐blind, randomized study to investigate the effects on biochemical and physiological outcomes of a phenylalanine‐free infant formula containing a fat blend supplemented with the long‐chain polyunsaturated fatty acids (LC‐PUFA), docosahexaenoic acid (DHA, C22:6n‐3), and arachidonic acid (AA, C20:4n‐6). Between entry and 20 weeks (entry and 1y) of age, median DHA levels in erythrocyte membrane phospholipids decreased by 15% (22%) in the LC‐PUFA supplemented group (n=21) and by 61% (64%) in the control group (p<0.001; n=18). A dietary supply of LC‐PUFA in infants with PKU prevents the decline in DHA levels associated with a diet supplying minimal sources of LC‐PUFA. DHA status in turn, independent of diet, may influence the maturation of the visual system in infants with PKU.

Severe mental handicap in phenylketonuria (PKU) can be prevented if dietary treatment is implemented at birth. Controversy remains about the optimum age for terminating treatment. A group of adolescents and young adults with PKU from the West of Scotland Register was identified which had received early treatment, been well-controlled on diet, ceased treatment at 10 years old and subsequently were hyperphenylalaninaemic for 3 years or more. They were given a battery of neuropsychological tests and their results were compared with those of on-diet subjects with PKU and normal controls. The findings generally supported the view that dietary cessation at age 10 is sufficient to prevent a substantial reduction of cognitive and motor ability, and that the central nervous system is probably mature enough to withstand the toxic effects of high blood phenylalanine by then. However, there were minor indications, in keeping with Welsh et al.'s hypothesis [M.C. Welsh, B.F. Pennington, S. Ozonoff, B. Rouse & E.R.B. McCabe (1990) Neuropsychology of early-treated phenylketonuria: specific executive function deficits.

SUMMARY A severely affected haemophilic boy became tetraparetic as a result of a spontaneously occurring intraspinal haematoma. Myelography defined the extent of the lesion and showed it to be extradural in site. Infusion of large doses of factor VIII concentrate led to dramatic improvement and avoided the need to operate.Intraspinal bleeding in haemophilia is extremely rare and recovery is even rarer. To date 14 cases have been recorded, and 11 of these have died. We report here a severely affected haemophilic patient who developed acute tetraparesis from spontaneous intraspinal bleeding; prompt treatment with large doses of factor VIII (antihaemophilic factor) contributed to a remarkable clinical recovery, accompanied by radiological resolution of the haematoma. Case reportThe patient was a 20 year old, severely affected haemophilic male with a baseline factor VIII level of less than 1%. He was previously described when he sustained a ruptured left ureter in the Ibrox football disaster of 1970of (Forbes et al., 1971. Four days before his referral he had again been a spectator on the terraces at a football match during which he 'strained' his neck but had no direct trauma. After this he had experienced mild neck and shoulder pain which had been treated as a suspected muscular bleed with a single infusion of factor VIII concentrate (about 750 units), a dose which was sufficient to raise his plasma level to about 20% of normal. This level would normally be considered adequate for such a trivial bleed. At that time no neurological signs were apparent. However, next day he was ad-

Blood phenylalanine concentrations were experimentally increased for 3 months by means of a phenylalanine‐complemented amino acid supplement in a group of 16 children aged 10‐16 years with classical phenylketonuria who had been treated early and who had remained on the restricted diet. Average concentrations achieved during challenge were between 1000 and 1300 µmol/L. Psychological outcome was measured by a neuropsychological battery consisting of tests of verbal and spatial memory, attention and fine motor coordination. A triple‐blind, repeated measures, randomized, crossover design was adopted to control for practice and expectancy effects. Subjects were assessed at baseline and at the end of the first and second phenylalanine manipulation periods. Significant interactions (ANOVA) emerged as predicted for phenylalanine concentrations, but similar crossover effects were not found for any of the neuropsychological tests. The results suggested that medium‐term hyperphenylalaninaemia in treated PKU is not harmful to psychological functioning in older children and adolescents who have been continuously treated up to and beyond age 10 years, though the susceptibility of executive functions needs to be further researched. The findings add some weight to the idea that by late childhood the vulnerability of the nervous system to the neurotoxic influence of phenylalanine may be much reduced.

Plasma prekallikrein levels, kallikrein activity and antikallikrein levels were investigated in nine premature infants with respiratory distress syndrome (RDS) and six premature infants without. Plasma prekallikrein and kallikrein were determined with a chromogenic substrate measuring amidolytic activity. Antikallikrein was measured with a functional assay. In infants with severe RDS, prekallikrein levels were significantly reduced (median 58% of initial values (p less than 0.01) about 48 hours after onset of symptoms. In infants with moderate RDS prekallikrein level was reduced less, while in babies without RDS there were no significant changes in prekallikrein levels the first 5-7 days of life. Antikallikrein levels did not change significantly in any babies. The results suggest that the kallikrein-kinin system might be involved in RDS. This could explain several features of this syndrome such as hypotension and edema. Furthermore the findings show that homeostatic functions are altered in this disease, and they suggest that other cascade systems as the coagulation, fibrinolytic and complement system may be involved as well. The findings emphasize that trauma might be a significant pathogenetical factor for development of this syndrome and indicate that RDS is not simply a biochemical disease with lack of surfactant as the only pathogenetic factor.

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Four members spanning three generations of one family have phenylketonuria of varying degrees ofseverity. Two first cousins were screened in the neonatal period and have had dietary phenylalanine restriction since diagnosis, the older patient having been classified as having more severe PKU and the younger one as having mild PKU. Their mutual grandfather and his older brother also have a significant hyperphenylalaninaemia and are of normal intelligence despite never having had restricted phenylalanine intake. Mutation analysis of the phenylalanine hydroxylase (PAH) gene has established that there are four different mutations, two in exon 2 (F39L and L48S) and two in exon 3 (RlllX and S67P), which give rise to PKU in this family. In order to establish their relative severity, we screened the PKU populations of western Scotland and the south west of England for these mutations. The exon 3 mutations are rare; however, F39L is relatively common in Scotland and L48S in England. A comparison of diagnostic blood phenylalanine concentrations in subjects carrying L48S/null or F39L/null mutations with those carrying two null mutations suggest that these exon 2 mutations are less deleterious. Thus, in this family, the different biochemical phenotypes can be explained, in part, by different genotypes at the PAH locus but our results show that the relationship between genotype and clinical outcome is more complex and is a function of multiple effects.

thyroid, and increased lipofuscin deposition. Increasing use of minocycline could produce additional examples.Pigmentation of the thyroid need not cause functional upset. However, nuclear pyknosis indicates epithelial damage, and the studies of Benitz et al showed that minocycline has an antithyroid effect. Patients on long-term minocycline should have their thyroid function monitored.1 Benitz, K F, et al, Toxicology and Applied Pharmacology, 1967, 11, 150. 2 Borel, D M, and Reddy, J K, Archives of Pathology, 1973, 96, 269. 3 Ryan, G B, et al, Brain, 1970, 93, 617. 4 Without treatment the mortality from neonatal thyrotoxicosis is 120.' In the case reported here the fetus was recognised as being at risk when the mother was five months pregnant. Carbimazole was given to the mother in an effort to control the fetal thyroid. Case historyA 29-year-old woman had a partial thyroidectomy at the age of 11 for Graves's disease. At 16 she became hypothyroid and was started on thyroxine 0-3 mg daily.When she was 21 she aborted a macerated female fetus at 28 weeks. She had not had any antenatal care. The fetus weighed 1868 g, and at necropsy a goitre and an enlarged left ventricle of the heart were noted. At the age of 23 she gave birth to a 36-week boy weighing 2160 g and 43 cm long. During the first day he developed exophthalmos. The second day his heart rate was 200/min and his spleen became palpable. Treatment was started with carbimazole, Lugol's solution, hydrocortisone, and digoxin but he died four days after birth. His weight at death was 1760 g. Necropsy showed slight jaundice, an enlarged (7-5 g) and slightly nodular thyroid, and increased heart weight (25 g), with dilatation of both ventricles.The patient was first seen at this hospital in July 1973 when she was five months pregnant. She was euthyroid but had bilateral exophthalmos and diplopia. As she was likely to have another affected baby she was given carbimazole 5 mg three times a day and her dose of thyroxine was increased to 0-4 mg daily. On this regimen she felt well during the rest of her pregnancy and remained euthyroid. At 37 weeks she was delivered of a healthy girl. The infant's heart rate was 140/min just before delivery and 130/min immediately afterwards. The Apgar score was 10 at one minute. She weighed 3420 g, was 52-1 cm long, and her head circumference was 34-3 cm. Cord blood hormone levels are shown in the table.The child was placed in the special baby care unit. The day after delivery she developed a tachycardia of 140-150/min, was noted to be feeding voraciously and sweating, and her eyes appeared prominent. Thyroid and spleen were palpable. Treatment with carbimazole 0 75 mg three times daily was initiated and continued in reducing doses for three weeks, by which time her heart rate had fallen to 120/min and her weight had risen to 3810 g. Conversion: SI to traditional units-Thyroxine: 1 nmol/1 0 08 tug/100 ml. Triiodothyronine: 1 nmol/1 z 0-7 ng/ml. was found, but the concentration of LATS protector (27 U/ml) was consistent with tha...