A clinical biochemist's view of the investigation of suspected inherited metabolic disease

Abstract

The necessity for a multi-disciplinary approach to the study of genetic disease is discussed. The progress of laboratory investigation programmes made it not feasible and inefficient to run a full metabolic investigation programme in every new patient suspected of inherited metabolic disease. An application form for metabolic investigation is described, which can be used to collect clinical information relevant to metabolic disease. On the basis of the patient's clinical information, selection criteria are given to decide which laboratory investigation programme has to be performed in the individual patient. A full metabolic laboratory investigation programme is described and illustrated with some examples of abnormal metabolite patterns. Diagnostic results over a 2-year period are presented.

Study of Inherited Metabolic Disorders in Singapore – 13 Years Experience

“…4,43 In a 2-year study conducted by the Metabolic Laboratory of the Institute of Clinical Genetics in Rotterdam serving a population of 3 million people in the south-western part of The Netherlands, the observation was: organic aciduria (19.8%), amino acidaemias/acidurias including some urea cycle defects (64.0%), carbohydrate, lysosomal storage and peroxisomal disorders (16.2%). 44 Based on the results of our 13-year study, the positive detection rate in high-risk patients was 3.5%. The apparent difference between this detection rate and the 5.2% observed for the 5-year MOH study period was due to the inclusion of a heterogenous group of carbohydrate and miscellaneous disorders in the calculation of detection rate for the earlier study.…”

“…However secondary increase is also observed in some newborns and is associated with liver cirrhosis, hyperlysinaemia and hypersarcosinaemia. 44…”

Differential diagnosis of (inherited) amino acid metabolism or transport disorders

“…Citrulline is mildly and orotic acid slightly increased. If the fetus is affected, argininosuccinic acid is already increased in the amniotic fluid [13]. During the chromatographic run the cyclic metabolites are spontaneously formed,.which explains the baseline shift behind the argininosuccinic acid peak.…”

Quantitative Methods for Amino Acid Analysis in Biological Fluids

“…Urinary tyrosine may be increased in premature or small babies on a high protein intake. 11,12,128,145,155 …”

“…Diet influences excretion of some amino acids. ll , 12,15,128,146,158 These causes of secondary amino acid abnormalities, and artefacts from poor samples, must be considered, before making a diagnosis of an inherited defect. Amino acid disturbances often accompany inherited disorders of other metabolites, for example, increased alanine in congenital lactic acidaemia, glutamine in urea cycle defects, glycine in organic acidaemias.…”