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Screening, prevention, treatment and pathogenesis of congenital peroxisomal diseases

Objective

a) to improve prevention by early and complete diagnosis, listing of carriers, genetic counseling, and preimplatation- and prenatal detection; by increasing the awareness of medical practitioners and patients and their families;
b) to promote and evaluate controlled experimental treatments ;
c) to study pathogenesis using tissues and DNA of patients, cell cultures and animals.

Most peroxisomal diseases are characterized by severe and progressive neurological dysfunction. A Network is organized of 23 clinical centres and research laboratories, in order to pool patients over 10 European contries, and to coordinate special investigations of which only one or a few laboratories have expertise. This Concertation aims at :
1. Registry of known and novel cases by screening families and neonates, infants, juveniles, adults presenting typical (age-dependent) symptoms, by assaying blood and urine metabolites according to a standard protocol, and by dissemination of useful information through practitioners and associations of patients (European Leukodystrophy Association, a.o.).
2. Early and complete diagnosis at the clinical, biochemical, microscopical and genomic level, including : a) pediatric, neuropsychological and electrophysiological performance, brain imaging and proton MR spectroscopy; b) peroxisomal metabolites in blood and urine; enzyme activity assays; c) immunolocalization of peroxisomal proteins in patients' tissues and electron microscopy; d) classification by complementation analysis; e) identification of the mutation.
3. Carrier detection and prenatal prevention, including preimplantation diagnosis, using metabolite-, enzymatic-, microscopical- and DNA analysis; by informing practitioners and associations of patients.
4. Clinical trials : a) statistical evaluation of long-term GTO-GTE treatment in Europe and USA (standard protocol); b) supplementation with DHA ethylester, if decreased; c) bone marrow transplantation in selected cases; d) plasmapheresis and low phytanate diet if important accumulation of phytanic acid; e) beta-interferon. Evaluation by objective measurements, a.o. of neurological function; registry of side-effects.
5. Transfection of the missing gene in cultured fibroblasts, oligodendrocytes and hematopoietic stemcells from patients, in preparation for gene replacement therapy.
6. Search for pathogenetic mechanisms : a) follow-up on fetal and autopsy material (a.o. DHA in brain); outcome of clinical trials; b) biological consequence of mutations : expression and life-time of mutated ALD protein; c) immune reactions in X-ALD; d) regulation of peroxisomal genes during development in vivo, in cell culture and in patients' tissues.
7. Development of a European repository of cell cultures and tissues from peroxisomal patients and their relatives for common studies.
8. Training in specialized techniques used for screening and DNA analysis.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Universiteit Gent
Address
4,Godshuizenlaan
9000 Gent
Belgium