Fifth Workshop on Primary Hyperoxaluria 12/13 March 1999, Kappel/Zurich (Organized by Ernst Leumann, Zurich)

Nephrol Dial Transplant (1999) 14: 2784–2789 Nephrology Dialysis Transplantation Abstracts Fifth Workshop on Primary Hyperoxaluria 12/13 March 1999, Kappel/Zurich (Organized by Ernst Leumann, Zurich) 1. Molecular basis of PH1: implications for gene therapy Christopher J. Danpure; UCL, London, UK PH1 (AGT deficiency) is the best characterised of an indeterminate number of CaOx stone diseases with genetic origins. Over 20 mutations have been identified in the gene encoding AGT (AGXT ), the most common of which (Gly170Arg) accounts for about 30% of mutant AGXT alleles in European and N. American patients. This mutation, which is always associated with a very common Pro11Leu polymorphism, is especially interesting because it leads to an unparalleled protein trafficking defect in which AGT is mistargeted from the peroxisomes to mitochondria. Detailed structural and functional analyses of the consequences of Gly170Arg+Pro11Leu have yielded insights not only into the molecular basis of the most frequent single cause of PH1, but also into some of the fundamental differences in the way proteins are targeted to and imported into peroxisomes and mitochondria. Luckily, PH1 can be cured by enzyme replacement therapy (i.e. liver transplantation), but this treatment is far from ideal. Although gene therapy has the potential to overcome most of the problems associated with liver transplantation, it is likely to give rise to a whole new set of problems, some associated with vector technology in general and some specifically associated with PH1. A proper analysis of the metabolic and enzymic peculiarities of PH1 and how they might influence gene therapy protocols is mandatory before such procedures can be implemented with any confidence. 2. Epidemiology of primary hyperoxaluria in children in the West Midlands, UK Sally A. Hulton, A. P. Sutardjo; Department of Nephrology, Birmingham Children’s Hospital, Birmingham, UK Primary hyperoxaluria type 1 (PH1) and type 2 (PH2) are rare autosomal recessive diseases. No epidemiological data are available regarding these disorders in the United Kingdom and we attempted to provide descriptive information regarding PH in children in the West Midlands region. Of 22 children suspected of having PH, who attended our hospital between 1985 and 1998, 17 met the criteria for diagnosis. Eleven were classified as PH1 and six as PH2 by appropriate enzyme assays. A family history was present in 36% of cases, most of whom were Asians with a high degree of consanguinity. The predominant presenting feature in PH1 was haematuria in 70% of cases, with calculi in 50%, whereas 67% of PH2 patients presented with calculi. First symptoms in both types were recorded before the age of 5 years in 76% of children. 37% showed a complete and 37% a partial response to pyridoxine. Four PH1 infants presented in chronic renal failure, three of whom commenced dialysis before 1 year of age and all subsequently died. One child remains well following combined liver-kidney transplantation. The estimated prevalence of PH was 10.5 per million inhabitants and estimated incidence rate was 1.07±0.94 per million inhabitants. The incidence and prevalence rates in the region are higher than comparative studies from France and Switzerland and can be ascribed to the high rate of consanguinity as well as awareness of PH, which leads to an earlier diagnosis and improved management. 3. Type 1 primary hyperoxaluria: Tunisian experience of 31 paediatric cases A. Kamoun, R. Lakhoua; Departments of Pediatrics, Hôpital Charles Nicolle, Tunis, Tunisia We report on 31 children (16 boys) presenting with type 1 primary hyperoxaluria (PH1). The mean age at diagnosis was 6.1 years (range 3 months–14.8 years) and the average followup period was 25 months. The mean delay between first symptom and diagnosis was 1.3 years. The diagnosis of PH1 was carried out by determination of oxaluria in 16 cases, by renal histology in 11 cases, and by physical analysis of urolithiasis in nine cases. In the nine cases where urinary glycolate was assayed, the level was found to be high. At the time of diagnosis, renal function was normal in 10 children, moderately altered in one and severely so in 20. During follow-up renal function remained stable in 10, greatly improved in two, and deteriorated in five. Function in the 14 patients already in end-stage renal failure at diagnosis did not improve. Urinary stones were present in 23 patients among 24 aged more than 2 years and in one among seven infants. A response to pyridoxine therapy was noted in two patients. Extracorporeal shock-wave lithotripsy, performed in seven patients, was efficient in only three. In nine patients, oxalate bone disease correlated with both renal function and dialysis duration, whereas retinal involvement observed in seven patients did not. 4. Worldwide view of infantile primary hyperoxaluria type 1 (PH1) P. Cochat, J. Exanthus, O. Basmaison; Department of Pediatrics, Hôpital Edouard Herriot and Université Claude Bernard, Lyon, France PH1 is a rare inborn error of metabolism (15120,000 live births in France) due to deficient liver peroxisome enzyme alanine: glyoxylate aminotransferase (AGT ). Due to recessive inheritance, its frequency is increased in countries with a high rate of consanguinity, e.g. 13% of ESRF children in Tunisia vs 0.3% in Europe. We collected information from 78 children <1 year of age: 44% were Muslims, 33% were managed in developing © 1999 European Renal Association–European Dialysis and Transplant Association Abstracts countries; consanguinity was present in 76% of Muslims. Diagnosis was primarily based on clinical presentation, family history, plain X-ray, ultrasonography, and urinary oxalate. Urinary glycolate, AGT activity measurement, and DNA analysis were limited to developed countries. In most developing countries, prenatal diagnosis used to be rejected, as parents are reluctant to both chorionic villus biopsy and pregnancy termination. Therapeutic withdrawal (40% of ESRF patients) was the final option in 71% of children from developing countries vs 17% in developed countries. Twothirds underwent transplantation ( Tx): Pre-emptive liver and combined liver-kidney Tx were mainly performed in developed countries, whereas isolated kidney Tx was proposed to most patients in developing countries, despite poor results. The management of infantile oxalosis is therefore a major example of the ethical, epidemiological, technical, and financial dilemmas raised by recessive diseases with early, lifethreatening onset. Oxalosis can therefore be regarded as one of the rare condition where therapeutic withdrawal may be an acceptable option according to local resources. 5. Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group Yaacov Frishberg, Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel Primary hyperoxaluria type 1 (PH1) has a wide (...truncated)