Developments in Biochemical Genetic Testing in Europe: the role of ERNDIM

General introduction

The difficulty and complexity of Biochemical Genetic Testing for inherited metabolic diseases (IMD) has increased in parallel to the explosion of the number of recognised disorders. At the end of the1940s a few amino acid disorders could be detected with simple paper chromatography whereas today hundreds of different disorders can be identified such as amino acid, organic acid, lipid, carbohydrate, mucopolysaccharide, purine and pyrimidine metabolism defects and disorders of post-translational modification such as glycosylation. The scope of Biochemical Genetic Testing has expanded in parallel with technological advances such as quantitative ion-exchange chromatography, gas chromatography coupled with mass spectrometry, high performance liquid chromatography and tandem mass spectrometry alongside classical techniques of macromolecule identification, enzymology and molecular genetic analysis. A small number of these disorders can be detected by newborn screening. Most however need to be searched for by selective screening based on clinical suspicion.

During the last decade tandem mass spectrometry together with automated sample processing and sophisticated data handling has facilitated the detection of many more inherited disorders than previously possible.

Thus some neonatal screening laboratories throughout the world now screen for additional fatty acid oxidation disorders, organic acidurias and amino acidaemias.

Quality control and Biochemical Genetic Testing.

Previously validation of methods used for diagnosis and treatment monitoring in the IMD was mainly achieved by comparison of data between control and patient groups in a single centre and results published after peer review. Now agreed thresholds of metabolite levels after treatment, multi-centre studies, increased mobility of patients between countries and agreed critical cut off values in newborn screening by tandem MS all demand satisfactory quality assurance including external quality control to guarantee comparability of results between different centres. It is necessary to raise the levels of accuracy, precision, reproducibility and harmonisation of Biochemical Genetic Testing to those obtained in other disciplines of laboratory medicine such as clinical chemistry. At the same time it must be emphasised that the complexity of Biochemical Genetic Testing often requires highly specialised techniques and equipment with interpretation of the results by experienced personnel. Also the types of laboratories involved vary from university departments working mainly in research to clinical chemistry laboratories in hospitals.

Improving the standard of Biochemical Genetic Testing in Europe: the ERNDIM Foundation

It is generally accepted that quality control for Biochemical Genetic Testing must be implemented on an international basis due to the small number of participating laboratories in any individual country.

Therefore quality control of Biochemical Genetic Testing has been addressed on a European wide basis by ERNDIM (European Research Network for evaluation and improvement of screening, Diagnosis and treatment of Inherited disorders of Metabolism) since its founding in 1994. Its EQA schemes are operated according to accepted norms on a European wide scale. ERNDIM aims to develop a consensus between European Biochemical Genetics Centres on reliable and standardised procedures for diagnosis, treatment and monitoring of inherited metabolic diseases. It also promotes education through meetings and provision of relevant documentation such as recommended operating procedures and annual reports of EQA schemes on the internet. ERNDIM aims to be financially self sufficient through minimal administration costs and efficient subscription collection.

Today ERNDIM offers 9 different schemes including quantitative organic acids, quantitative amino acids, special assays in plasma and urine, proficiency testing for organic acids, purines & pyrimidines, white cell cystine, acyl carnitines and diagnostic proficiency testing. Schemes are operated according to guidelines summarised by Sciacovelli et al. (2001) and are harmonized with respect to numbers and frequency of samples and direct submission of results and receipt of reports by internet. Schemes are provided by SKML (Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek, Dutch Foundation for Quality Assessment in Clinical Laboratories) or academic centres working closely with a Scientific Advisory Board and administered by the ERNDIM executive committee, which represents the ERNDIM Foundation Board.

Future issues within ERNDIM

There is clear evidence of improvement in performance in Biochemical Genetic Testing since ERNDIM started but much improvement is still necessary. Scoring and assessment of performance needs to be harmonised  in order to define good performance and to link this to c ertificates of participation.

New schemes need to be introduced for new groups of analytes but only on a sound scientific and economic basis. New schemes under consideration include neurotransmitters and other analytes in cerebrospinal fluid and lysosomal enzymes.

In addition the accreditation of the QA schemes themselves as well as participating labs must be achieved.

Formal training for clinical biochemists in Biochemical Genetic Testing, similar to that existing for paediatricians needs to be established.

A new European Directory of Biochemical Genetic Testing laboratories needs to be developed and should include information on EQA participation and accreditation status of participating labs.

Last changed: 2010-03-19