Clinical biochemical genetics

Acylcarnitine analysis for the diagnosis of organic acidemias and particularly of FAO disorders plays an increasingly prominent role in all venues of clinical biochemical genetics prenatal diagnosis, newborn screening, evaluation of symptomatic patients, and postmortem screening. Almost exclusively performed by tandem... 

Rinaldo P, Hahn S, Matern D (2004) Clinical biochemical genetics in the twenty-first century. Acta Paediatr 93 22-26... 

Binkley K, Davis AR Clinical, biochemical, and genetic characterization of a novel estrogen-depen-dent inherited form of angioedema. J Allergy Clin Immunol 2000 106 546-550. 

A comprehensive, up-to-date review A Biochemical, Genetic and Physio-pathological Study of Haptoglobin has recently been presented by Jayle and Moretti (J12). Since the present article is concerned mainly with problems of current interest in clinical work and research, the older literature will be dealt with only in brief outline. 

Many of the larger biochemical genetics laboratories are in academic medical centres and make a significant contribution to research. They have collectively been responsible for much of the progress made in recent years. However, there is always a tension between research, where data need to be accumulated into publishable packets and a degree of secrecy prevails, and clinical care, where results need to reported immediately, perhaps to distant clinicians with their own publication needs. 

The workload is increasing in both volume and scope in all branches of laboratory medicine. In mainstream clinical chemistry, the past 25 years have seen astonishing developments in assay technology and instrumentation assays that were performed manually with a few dozen assays a day can now be accomplished automatically by the thousands. In biochemical genetics (molecular genetics aside), automation has had a less dramatic impact. 

Some important assays commonly used in biochemical genetics laboratories do not provide quantitative data (e.g. MPS-EP, qualitative urinary organic acid analysis, AA-TLC). In addition, all successful investigations depend heavily upon selection of the correct analytes to measure and the appropriate interpretation of the quantitative or qualitative results in their clinical context. These challenges suggest a requirement for external quality assessment or proficiency testing schemes that can inform participants about their performance in these areas when compared with other centres. 

Post-analytically, schemes are beginning to emerge specifically to compare practice and performance between laboratories pertaining to the interpretation of test results. For instance, in the UK, NEQAS in conjunction with the National Biochemical Genetic network, MetBio.Net, are offering a scheme that provides the opportunity, when given relevant clinical details, to interpret quantitative amino acid results. This proficiency scheme can compare interpretive skills without the need to circulate scarce clinical samples. 

Acylcarnitine profiles are dependent on the clinical status of the patient at the time of sample collection [56, 57]. It is therefore important to provide the biochemical genetics laboratory with information regarding the clinical context during which the sample was collected. The laboratory must be conscientious of the fact that carnitine deficiency states can be associated with acylcarnitine profiles that lack any acylcarnitine species that are elevated above the reference range. Therefore, it is essential that the complete profiles are reviewed and even borderline elevated acylcarnitines should prompt further follow up in the presence of abnormally low free acetylcar-nitine (Fig. 3.2.2). If clinically indicated, a repeat sample should be collected at least 24 h after L-carnitine supplementation. 

Gravel, R.A., Kaback, M.M., Proia, R., Sandhoff, K., Suzuki, K., Suzuki, K. (2001) The GM2 gangliosidoses. In The Metabolic and Molecular Bases of Inherited Disease, 8th edn (Scriver, C.R., Sly, W.S., Childs, B., Beaudet, A.L., Valle, D., Kinzler, K.W., Vogelstein, B., eds), pp. 3827-3876, McGraw-Hill, Inc., New York. This article is one of many in a four-volume set that contains definitive descriptions of the clinical, biochemical, and genetic aspects of hundreds of human metabolic diseases—an authoritative source and fascinating reading. 

Mitochondrial Disorders of the Nervous System Clinical, Biochemical, and Molecular Genetic Features... 

Schaefer EJ. Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. Arteriosclerosis 1984 4 303-22. 

Case reports of conditions, which today would be denoted as muscular dystrophies, have appeared for over a hundred years, but only comparatively recently has a satisfactory classification of the different varieties been achieved, based on both clinical and genetic criteria. The basic classification of Walton and Nattrass (W6) with some subsequent modifications is widely accepted. However, occasional cases occur that do not fit exactly into the existing scheme, therefore minor modifications may still be required [see Walton and Gardner-Medwin (W5) ]. It hardly requires emphasizing that in biochemical investigations on muscular dystrophy the clinical type of the case under study should be known and specified in the reported findings, since there may be important biochemical differences between the varieties. Unfortunately, this has not been the case in a few reports in the literature. 

Section on Biochemical Genetics, Clinical Neurogenetics Branch, National Institutes of Mental Health, Bethesda, MD 20892... 

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