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Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase, leading to progressive accumulation of glycosaminoglycans in nearly all cell types, tissues and organs. Clinical manifestations include severe airway obstruction, skeletal deformities, cardiomyopathy and, in most patients, neurological decline. Death usually occurs in the second decade of life, although some patients with less severe disease have survived into their fifth or sixth decade. Until recently, there has been no effective therapy for MPS II, and care has been palliative. Enzyme replacement therapy (ERT) with recombinant human iduronate-2-sulphatase (idursulfase), however, has now been introduced. Weekly intravenous infusions of idursulfase have been shown to improve many of the signs and symptoms and overall wellbeing in patients with MPS II. This paper provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS II and provides recommendations for the use of ERT. The issue of treating very young patients and those with CNS involvement is also discussed. ERT with idursulfase has the potential to benefit many patients with MPS II, especially if started early in the course of the disease.

This study aimed to estimate the number of infants who died of unrecognized congenital adrenal hyperplasia (CAH) in Austria and the Czech Republic within the past 13 years, before the introduction of adequate neonatal screening. The study was based on retrospective analysis of neonatal screening cards of 242 infants who died suddenly between 7 days and 12 months of age and whose cause of death could not be identified. 17-hydroxyprogesterone (17-OHP) was measured by fluoroimmunoassay and positive samples were subsequently genotyped. Three infants out of 242 may have had unrecognized CAH due to CYP21 (steroid 21-hydroxylase) gene defect. Their newborn 17-OHP levels and CYP21 genotypes were 706 nmol/l and del/conv//del/conv, 53 nmol/l and I2//I2, and 811 nmol/l and I2//Gln318stop, respectively. CAH due to CYP21 defect can lead to sudden unexpected death without prior symptoms typical for the condition. Hence, newborn screening would have prevented these deaths had it been available. In addition, we have shown that the I2 point mutation that is expected to lead to simple virilizing form may lead to a fatal outcome.

There is a paucity of data documenting the metabolic response to catabolic stress in childhood in general and about protein turnover in critically ill children in particular. Despite a high overall morbidity and mortality rate there is little information on which to base decisions to improve the management either by dietary therapy or by use of growth factors. Protein turnover is a key metabolic process that significantly alters during the catabolic state. Protein kinetics are easy to quantify using various stable isotope models, with some having advantages in the critically ill child. The 1-13C leucine technique is the most widely used and best validated model to date, requiring accurate estimation of CO2 production. There is also uncertainty about the bicarbonate kinetics and pool sizes in ventilated children whose respiratory function is severely impaired. The value of the 15N glycine (end product) technique is more limited because the time to achieve isotopic equilibrium is lengthy and considerable concerns about the validity of the model exist. The ring-D5 phenylalanine technique has the advantage of not requiring the measurement of CO2 production or 13C enrichment, but the model has not yet been validated in critically ill children. Despite it is of obvious value to measure protein turnover, few studies in critically ill children have been done.

Late-onset acid maltase deficiency or glycogen storage disease type II (GSD II) is a rare disorder of intralysosomal glycogen metabolism, resulting in progressive myopathy that is secondary to increased muscle protein breakdown. Stable isotope studies in the postabsorptive state have confirmed that mean protein breakdown in GSD II is increased by 31% compared to control subjects. 6.86 versus 4.69 g/kg per day, that mean protein balance is reduced is GSD II -1.32 versus -1.06 g/kg per day. Indirect calorimetry has demonstrated an increase in mean resting energy expenditure in GSD II, 41.8 versus 31.2 kcal/kg per day. Compliance following the introduction of a high-protein diet is often poor due to the large quantities of protein necessary and to the high caloric intake with the consequent weight gain. Only 25% of all reported subjects with GSD II showed an improvement of muscle or respiratory function after a high-protein diet. Careful evaluation of the underlying pathophysiological changes in GSD II is necessary to develop more logical and therefore more beneficial forms of dietary treatment.

Stable isotope studies have considerable potential to help understand the biochemistry and pathophysiology of inborn errors of metabolism but this has not yet been fully realised. It is to be hoped that this symposium will prove to be a valuable stimulus to this field of research.

The assessment of energy expenditure is valuable for the management of children with various conditions such as obesity and failure to thrive. Total daily energy expenditure (TDEE) includes resting energy expenditure (REE), energy expenditure during physical activity, dietary thermogenesis and growth. TDEE can be assessed by using the double-labelled water technique, but it has complex pitfalls and potential sources of errors and is impractical for everyday use. As REE is a substantial part of TDEE (65%-70%) and computerised indirect calorimeters have become recently available, this non-invasive, relatively cheap and easy to use technique is valuable for the assessment of short-term changes in energy metabolism. This can be used to assess REE of children with inborn errors of metabolism, whilst well and during episodes of metabolic decompensation and therefore to accurately determine energy intake.

Aspects of glucose metabolism have been investigated quantitatively employing stable isotopes for 20 year. Use of non-recycling [6,6-2H2] or [U-13C] glucose labels provides a value for total hepatic glucose production (glycogenolysis plus gluconeogenesis). Quantitation of gluconeogenesis with isotopic tracers has itself recently been revisited employing protocols and analytical options that purport to overcome the isotope exchanges (dilution) experienced at the level of oxaloacetate when the rate of incorporation of label into glucose from infused alanine, lactate or pyruvate is monitored. Labelled glucose has been employed to investigate metabolic disturbances of glycogen storage disease type I (GSD-I) and type III (GSD-III). Endogenous glucose production and glucose recycling have been studied in both these storage diseases employing a primed-continuous infusion of D-[U-13C] glucose and quantitation of isotope enrichments and isotopomer distribution observed in plasma glucose either by mass spectrometry or nuclear magnetic resonance spectroscopy. General aspects of glucose metabolism as investigated with stable isotopes are presented.