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D. Kenny, A. Jain, P. Davis, M. Thoresen. Department of Clinical Science, South Bristol (Child Health)

Seizures may occur secondary to neurotoxicity associated with hyperammonaemic encephalopathy and studies suggest that seizures further damage a compromised brain. Glutamine has been implicated and hypothermia has been shown to reduce concentrations of glutamine in the post-hypoxic cerebral cortex of neonatal animals. Hypothermia has also been shown to reduce the duration of post-hypoxic seizures in encephalopathic infants.1 We describe an infant who presented aged 50 h with hyperammonaemic encephalopathy that was found to be a result of a urea cycle defect. Cerebral function monitoring (CFM), which is a single channel amplitude integrated EEG, displayed seizure activity unresponsive to the common anticonvulsants. Haemodialysis and alternative pathway metabolites were commenced and the patient was paralysed. Cooling has been shown to hasten the reduction of ammonia,2 hence the infant was simultaneously cooled to a rectal temperature of 34°C while dialysed. The seizure activity subsided despite a rapid reduction to sub therapeutic anticonvulsant drug levels, most likely due to increased drug removal during haemodialysis. After a seizure free period at normothermia and drug levels within the therapeutic range, ammonia levels rose to ~500 and non-convulsive seizures were noted on the CFM trace as well as EEG. Rapid cooling for the 12 h of haemofiltration stopped seizure activity while the ammonia levels changed little this time. As soon as rewarming commenced non-convulsive seizures reappeared on CFM despite therapeutic levels of anticonvulsants. In conclusion, continuous CFM is invaluable in monitoring seizure activity where paralysis may mask clinical seizures and other interventions such as haemodialysis lead to rapid changes in anticonvulsant levels. Mild hypothermia has anticonvulsant effect in itself and may also be neuroprotective in hyperammonaemic encephalopathy.




M. A. Kurian1, T. Randall2, P. Barnfield3, C. Turner4, R. N. Dalton4, L. Fairbanks5, M. P. Champion1. 1Department of Paediatric Metabolic Medicine, 2Department of Nutrition and Dietetics, 3Paediatric Laboratory, 4Wellchild Trust Research Laboratory, 5Purine Research Laboratory, Guys’ Hospital, London

Molybdenum cofactor deficiency (MoCD) is a rare combined deficiency of three enzymes that share the molybdenum cofactor: sulphite oxidase, xanthine oxidase, and aldehyde oxidase. It presents with refractory seizures in the neonatal period. Neurotoxicity is thought to be related to sulphite accumulation from the breakdown of sulphur containing amino acids. Treatment is currently symptomatic only, but cases of isolated sulphite oxidase deficiency have shown clinical and biological improvement when treated with methionine and cystine restriction. We report a case of an antenatally diagnosed infant who received such a trial of prospective dietary therapy from birth.

The female infant was born at term weighing 2.47 kg. The parents were consanguineous and had a previous severely affected child. MoCD was diagnosed antenatally on chorionic villous sampling. Antenatal ultrasound revealed a hypoplastic cerebellum, absent inferior vermis, and a large posterior fossa cyst. Seizures noted within 24 hours of birth responded to phenobarbitone. A methionine and cystine restricted diet was started at birth; 1–1.7 g/k/day natural protein supplemented with Analog X methionine X Cystine. Urinary sulphite disappeared by day 14 on dipstick testing. Methionine was regularly measured on blood spot samples by tandem mass spectrometry (for home monitoring) and cystine was monitored at hospital visits aiming to maintain levels at the bottom of the normal range; median methionine 18 μmol/L, range 5–35 μmol/L and median cystine 1 μmol/L, range 0–7 μmol/L. Adequate growth was maintained (weight>50th centile). Despite consistent sulphite reduction (median plasma sulphocysteine 23 μmol/L, range 9–37 μmol/L), the diet failed to prevent intractable seizures, neurodevelopmental regression, and progressive features on MRI brain scan.

Although of some benefit in isolated sulphite oxidase deficiency, dietary treatment does not appear to prevent clinical deterioration in MoCD, even when commenced from birth.


A. C. Ramsbottom, M. J. Sharrard, J. Bonham, C. Rittey, J. Watkinson, J. C. Allen. Sheffield Children’s Hospital

A 10 week old baby boy was referred with increasingly jerky episodes. He was found to have infantile spasms with microcephaly, visual impairment, and severe developmental delay. His fits were refractory to standard treatment. An EEG was abnormal suggesting a multi-focal seizure disorder or migrational defect. CT head scan showed a small malformed cerebellum, mainly deficient posteriorly, with small mid brain and brainstem and a cortical migration problem. Initial biochemical investigations, urea and serum electrolytes, liver function tests, blood gas analysis, ammonia, and lactate were all normal.

CSF and plasma serine and glycine levels were found to be low. Initial CSF glycine was <5 (0–10 μmol/l), CSF serine 18 (35–80 μmol/l), and plasma glycine 121 (140–420 μmol/l). There was normal tubular resorption of serine and glycine. An error of serine metabolism such as 3-phosphglycerate dehydrogenase deficiency was presumed and skin biopsy was taken for fibroblast culture and enzyme measurement. Serine and glycine supplements were given in doses of serine, 600 mg/kg/day, and glycine, 150 mg/kg/day, with normalisation of plasma and CSF levels, but without clinical improvement. Intractable seizures continued to be a problem with frequent admissions to intensive care. There was no developmental progress. He died after withdrawal of ITU care at 7 months of age.

Subsequently received fibroblast enzyme results showed activity of 3-phosphoglycerate dehydrogenase, transferase, and 3-phosphoserine phosphotase was normal. This disorder of serine and glycine deficiency is not one of the previously described inborn errors of metabolism associated with microcephaly, seizures and developmental delay. This patient’s parents have now had another baby, a girl. She had similarly low levels of plasma and CSF serine and glycine measured postnatally. On supplements these levels have been normalised. It remains to be seen whether or not her developmental progress will be affected.


A. MacDonald, A. Daly, A. Chakrapani, G. Rylance, D. Asplin, S. K. Hall, I. W. Booth. The Children’s Hospital, Birmingham

Introduction: The optimal dosage of protein substitute (PS) has not been determined in PKU and there is much international disagreement.

Aim: To determine if a lower dose of PS could achieve the same or better level of blood phenylalanine (phe) control when compared to the dosage recommended by the UK MRC (1993).

Methods: In a 7 week randomised, crossover study two dosages of PS (protocol A: 2g/kg/day of protein equivalent; protocol B: 1.2 g/kg/day protein equivalent) were compared in 25 children with well controlled PKU aged 2–10 years (median 6 years). Each dose of PS was taken for 14 days, with a 14 day washout period in between. Twice daily finger pricks (fasting pre-breakfast and in the evening at standard times) for plasma phe were taken on day 8–14 of each protocol. Patients took their usual type of PS, which was taken in 3–4 dosages at standard timings throughout the day. The median control dose of PS was 2.2g/kg/day (range 1.5g/kg/day to 3.1g/kg/day).

Results: When compared with control values, on the low dose of protein substitute median plasma phe increased at pre-breakfast by 301 μmol/l (CI 215 to 386) and in the evening by 337 μmol/l (CI −248 to 431). Similarly, on the high dose of PS median plasma phe decreased at pre-breakfast by 4.5 μmol/l (CI 34 to 23) and in the evening by 6 μmol/l (CI - 46 to 31). However, there was wide variability seen between individual subjects that may be explained by severity of PKU and a reduction in energy intake.

Conclusions: A higher dosage of PS contributes to lower blood phe concentrations and better control in PKU but there is large individual variability. Higher dosages of protein substitute of 2g/kg/day should be recommended for children between 1–10 years in PKU.


S. Mohamed, K. Reddy, S. Yap, C. O’Neill, P. D. Mayne, E. P. Treacy. The National Centre for Inherited Metabolic Disorders and The National Newborn Screening Laboratory, Children’s University Hospital, Temple Street, Dublin 1, Ireland

Introduction: Galactosaemia results from complete or near deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT). Ireland has had newborn screening for galactosaemia since 1972, detecting cases of classical galactosaemia and some cases with residual enzymatic activity, (D/G) or rarely D/D phenotype. Controversy remains as to the necessity for long term treatment for D/G cases.

Objectives: To determine the long term outcome of D/G cases detected by newborn screening and family screening and review the effect of diet.

Methods: A retrospective study was performed on cases ascertained by the Irish newborn screening programme (years 1989–2003) and cases ascertained by family screening of classical galactosaemia cases at our centre. Initial and follow up blood levels of Gal-1-P, and urinary galactitol were measured. RBC GALT activity and mutation analysis were performed at presentation. Dietary information was collated. Clinical assessment included growth, neurodevelopmental, speech outcome, and eye examination.

Results: Of 752 000 newborn screened samples, 2 D/G cases were ascertained, a further 15 cases were ascertained by family studies, age at follow up between 1 and 20 years, (mean 10). Mean Gal-1-P levels at detection were 230 μmol/Lpc (range 0–1196) (n 0–30), galactitol 81 mmol/mol Creat (0–800). At follow up, mean Gal-1-P levels were 4 μmol/Lpc (0–8), and mean galactitol levels were 5 mmol/mol Creat, (0–10). Mean enzyme activity at detection was 6.3 μmolsubc/H/gHb, (3.4–10.0), (n 18–24). Of 12/17 cases tested, the genotype was Q188R/N314D. Dietary intervention varied from strict restriction from birth to follow up in five cases, partial restriction in eight cases and no dietary intervention in four cases. Neurodevelopment and eye examinations were normal in all patients, other than one case with mild speech delay.

Conclusion: We did not identify any significant complications in our study cohort, including cases on or off diet. These data question the necessity of long term dietary intervention. Further research would help to answer this question.


S. Mohamed, P. Mulhair, C. O’Neill, E. Naughten, S. Yap, E. P. Treacy, P. D. Mayne. The National Centre for Inherited Metabolic Disorders and The National Newborn Screening Laboratory, Children’s University Hospital, Temple Street, Dublin 1, Ireland

Introduction: Galactosaemia is an inborn error of metabolism affecting the enzyme galactose-1-phosphate uridyl transferase (Gal-1-PUT). It may present during the first week of life with liver dysfunction and bleeding tendency. A national newborn screening programme for galactosaemia was introduced in Ireland in 1972 to screen all infants between 72 and 120 h after birth using a bacterial inhibition assay. In 1996, a formal day one high risk screen for galactosaemia was introduced using a fluoremetric assay for Gal-1-PUT (Beutler) for sibs of known cases and infants born to traveller parents in whom the incidence in Ireland is 1 in 450. Travellers are a distinct Irish socioeconomic group with a high incidence of consanguinity. All at risk infants were put on a galactose free feed until the results of the Beutler test were available. The objectives of this study were to review the outcome of the newborn screening for galactosaemia in Ireland between 1989 and 2003 and to assess the effectiveness of the high risk screening strategy.

Methods: This study is a retrospective review of the database of the newborn screening programme in Ireland.

Results: Fifty two infants were diagnosed with classical galactosaemia, giving an overall incidence of 1 in 14 400 live births during this time period. Since 1996, 30 infants have been diagnosed, 18 by the high risk screen and 12 by the routine assay. To our knowledge, no baby was undetected during this period. Between 1989 and 1996, 22 infants were diagnosed with galactosaemia, of whom 17 were born to traveller families, or with positive family history, but only 11 were detected using the high risk screen as a formal high risk approach was not widespread. The remaining were diagnosed on routine screen between day 5 and 10.

Conclusion: The introduction of the high risk strategy has improved the efficiency of the newborn screening for galactosaemia. In other countries where there is no screening programme, infants at high risk of galactosaemia should be identified during antenatal visit and a high risk screening implemented at birth to facilitate early diagnosis and prevention of a significant morbidity and mortality.

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