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The signifcance of allelic variation for the phenotypic diversity of phenylketonuria examined by application of a new and fast mutation detection assay and by the development of a European data base

Objective



The primary goal is to study the significance of allelic variation for the various biological phenotypes of phenylketonuria (PKU) in order to improve diagnosis and treatment of the disease in Europe.
The study involves the development of a European data base
correlating mutant alleles with biological phenotypes and includes the application of a new technique for fast, simple, and reliable detection of mutations in all coding regions and flanking intronic sequences of the gene.
The new mutation detection assay has enabled us to detect and identify a molecular lesion in 99% of Danish PKU alleles.
The approaches available so far are based on detection of previously identified mutations and the applicability is generally hampered by a large number of mutations.
Until now, approximately 100 differnt mutations causing PKU have been identified.
The proportion of mutations detected for a population has, however, not exceeded 30-70%.
We have established unified conditions for mutation analysis of the entire coding sequence of the gene, and the resulting assay offers a simple and reliable methodological entity that can be applied to rapid detection of the mutant alleles in any individual, irrespective of the frequency and distribution of mutations in the population.
The results obtained by this European study will establish whether the new assay system is marketable in its present form.
Neonatal screening programmes followed by therapy for PKU introduced within the first weeks of life were implemented in Europe 20 years ago. Within recent years, however, the effectiveness and adequacy of dietary therapy have been questioned by an increasing number of reports demonstrating learning disabilities, neurological abnormalities, psychological problems, and white matter changes detectable by MRI even in early treated patients.
These findings stress the importance of intensified research on the genetic basis for the pathobiological function.
To initiate a better coordination of the Member States research on the genetic basis for PKU, Professor Jean Rey organized a Symposium in Paris in November 1990. The participants agreed to establish a data base in Europe on the various mutant alleles and their relation to different biological phenotypes of PKU (re. copy of enclosed letter of december 1992 from Professor Rey).
A European data base has not yet been established due to lack of financial support and in the meantime a data base on mutant alleles has been established in Montreal.
The establishment of this data base only stresses the need for the development of European data base which strengthen the coordination of the Member States research on allelic variation in PKU, particularly related to the genetic basis for the biological diversity of the disease. With the establishment of a European data base relating allelic genotype to biological phenotype, knowledge about the genotype of the
hyperphenylalaninemic neonate will provide information regarding the severity of the disorder.
This will permit an earlier implementation of dietary therapy better tailored to each individual patient and in tum may provide a more favourable prognosis.
The project benefits PKU patients in Europe and in turn benefits the economic and social implications of the disease.
Finally, the new method for mutation detection surpasses previous methods and all Member Countries will benefit from this method.
It should be added that due to continues budget cutbacks the Kennedy Institute cannot establish a European data base without EC-support.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

John F.Kennedy Institute
Address
7,Gl.landevej
2600 Glostrup
Denmark

Participants (1)

Dr L.Willems-Instituut v.z.w.
Belgium
Address

3590 Diepenbeek