Costs and outcomes over 36 years of patients with phenylketonuria who do and do not remain on a phenylalanine-restricted diet.

BACKGROUND: To quantify the costs and consequences of managing phenylketonuria (PKU) in the UK and to estimate the potential implications to the UK's National Health Service (NHS) of keeping patients on a phenylalanine-restricted diet for life. METHOD: A computer-based model was constructed depicting the management of PKU patients over the first 36 years of their life, derived from patients suffering from this metabolic disorder in The Health Improvement Network database (a nationally representative database of patients registered with general practitioners in the UK). The model was used to estimate the incidence of co-morbidities and the levels of healthcare resource use and corresponding costs over the 36 years. RESULTS: Patients who remained on a phenylalanine-restricted diet accounted for 38% of the cohort. Forty-seven per cent of patients discontinued their phenylalanine-restricted diet between 15 and 25 years of age. Of these, 73% remained off diet and 27% restarted a restricted diet at a mean 30 years of age. Fifteen per cent of the cohort had untreated PKU. Eleven per cent of patients who remained on a phenylalanine-restricted diet for 36 years received the optimum amount of prescribed amino acid supplements. Patients had a mean 12 general practitioner visits per year and one hospital outpatient visit annually, but phenylalanine levels were only measured once every 18 to 24 months. The mean NHS cost (at 2007/08 prices) of managing a PKU sufferer over the first 36 years of their life was estimated to range between £21 000 and £149 000, depending on the amount of prescribed nutrition they received. CONCLUSION: The findings suggest that the majority of patients with PKU were under-treated. The NHS cost of patient management should not be an obstacle to encouraging patients to remain on a restricted diet until further information becomes available about the long-term clinical impact of stopping such a diet. Nevertheless, patients require counselling and managed follow up regardless of the choices they make about their diet.

Dietary modifications in patients receiving miglustat.

Weight loss and gastrointestinal disturbances are often seen during miglustat therapy for lysosomal storage diseases. A retrospective analysis of data from a mixed group of patients treated with miglustat at two UK centres was performed to evaluate the effect of two different dietary interventions on body weight and gastrointestinal tolerability during the initial 6 months of miglustat therapy. Neurological outcomes in these patients are not discussed herein. Data were analysed from a total of 29 patients with varied neurolipidoses (21 children/adolescents; 8 adults). Negative mean changes in body weight were seen in children/adolescents on an unmodified diet (-8.1%), and in adults (-4.1%) and children/adolescents (-5.2%) on a low-lactose diet. Patients on the low-disaccharide diet showed a positive mean change in body weight (+2.0%), although there was high variability in this group. Non-parametric sub-analysis of median body-weight change in children/adolescents also showed high variability both within and between diet groups, with no statistically significant difference between the effects of different diets on body weight (p = 0.062). The low-lactose diet reduced gastrointestinal disturbances; single small doses of loperamide were required in some patients. Patients on the low-disaccharide diet showed the lowest frequency of gastrointestinal effects. In conclusion, simple dietary modifications allowed the maintenance of body-weight gain in line with normal growth potential during miglustat therapy in young patients with lysosomal storage diseases, and reduced gastrointestinal disturbances.

Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease.

It has been shown that treatment with miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) improves key clinical features of type I Gaucher disease after 1 year of treatment. This study reports longer-term efficacy and safety data. Patients who had completed 12 months of treatment with open-label miglustat (100-300 mg three times daily) were enrolled to continue with therapy in an extension study. Data are presented up to month 36. Liver and spleen volumes measured by CT or MRI were scheduled every 6 months. Biochemical and haematological parameters, including chitotriosidase activity (a sensitive marker of Gaucher disease activity) were monitored every 3 months. Safety data were also collected every 3 months. Eighteen of 22 eligible patients at four centres entered the extension phase and 14 of these completed 36 months of treatment with miglustat. After 36 months, there were statistically significant improvements in all major efficacy endpoints. Liver and spleen organ volumes were reduced by 18% and 30%, respectively. In patients whose haemoglobin value had been below 11.5 g/dl at baseline, mean haemoglobin increased progressively from baseline by 0.55 g/dl at month 12 (NS), 1.28 g/dl at month 24 (p =0.007), and 1.30 g/dl at month 36 (p =0.013). The mean platelet count at month 36 increased from baseline by 22 x 10(9)/L. No new cases of peripheral neuropathy occurred since previously reported. Diarrhoea and weight loss, which were frequently reported during the initial 12-month study, decreased in magnitude and prevalence during the second and third years. Patients treated with miglustat for 3 years show significant improvements in organ volumes and haematological parameters. In conclusion, miglustat was increasingly effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years.

Substrate reduction therapy for glycosphingolipid storage disorders.

Substrate reduction therapy is a novel approach to treating glycosphingolipid (GSL) lysosomal storage disorders. These diseases are caused by mutations in the genes coding for enzymes involved in GSL catabolism and are characterised by the accumulation of GSL substrates within the lysosomes of cells. The aim of substrate reduction therapy is to inhibit the rate of synthesis of GSLs to levels where the residual activity of the mutant catabolic enzyme is sufficient to prevent pathological storage. In this review we discuss the development of N-butyldeoxynojirimycin (NB-DNJ), an imino sugar that inhibits the ceramide-specific glucosyltransferase which catalyses the first committed step of GSL synthesis. This agent has been shown to slow accumulation of stored glycolipid in an in vitro model of Gaucher's disease and in knockout mouse models of Tay-Sachs and Sandhoff diseases. Furthermore, administration of NB-DNJ to Sandhoff mice delays the onset of neurological disease and also slows its progression. We discuss safety and efficacy data from the clinical trial of substrate reduction with NB-DNJ which has been undertaken in patients with Type 1 Gaucher's disease. This trial provides a proof-of-principle for the use of this approach in a wide range of GSL lysosomal storage diseases.