This chapter presents practical guidelines for the laboratory testing of inborn errors of metabolism. The purpose is to provide a convenient guide to a laboratory diagnostic approach for the clinician who has restricted diagnosis to one or two categories of disease based upon clinical signs, symptoms and results of routine laboratory tests (ie, electrolytes, plasma NH3, urine ketones, etc.). Each disease-specific chapter in this text also covers laboratory diagnosis; however this coverage is specific to each individual disorder and is convenient only when such a specific diagnosis is being pursued. Although some tests are readily available in major hospital laboratories or commercial reference laboratories, others are offered by only a small number of laboratories worldwide (and sometimes only in a single laboratory). It should also be pointed out that very few community hospital laboratories are likely to offer on-site testing beyond simple screening procedures, necessitating sample referrals to outside laboratories and mandating clinically-significant delay in obtaining results. A number of useful internet resources exist for identifying laboratories performing such esoteric testing, including GeneTests (http://www.genetests.org), the Genetic Testing Registry (http://www.ncbi.nlm.nih.gov/gtr/), the Society of Inherited Metabolic Disorders (http://www.simd.org/Links/index.asp), and the Metabolic Center at the University of Heidelberg (www.stoffwechsel.uni-hd.de). A general overview of testing strategies for the evaluation of specific metabolic disorders is shown in Table 50-1. Providers are urged to contact the testing laboratory prior to specimen collection for specific instructions and information about newly available tests. The interpretation of tests performed to investigate inborn errors of metabolism often requires information about the patient’s clinical status, diet history, and medications. Laboratorians and providers should work together to ensure the best possible results for their patients.
TABLE 50-1Testing Strategies for the Evaluation of Metabolic Disorders ||Download (.pdf) TABLE 50-1 Testing Strategies for the Evaluation of Metabolic Disorders
|Disease ||Screening and Diagnostic Tests ||Additional Confirmatory Studies |
|Amino Acid Disorders |
|Phenylketonuria ||AA (P), pterins (U, DBS), DHPR activity (RBC) ||DNA sequencing (PAH) |
|Tyrosinemia (types I, II and III) ||AA (P, U), OA (U), succinylacetone (U), AFP (S) ||Targeted mutation analysis or sequencing (FAH) (tyrosinemia type I) |
|Maple syrup urine disease ||AA (P), OA (U) ||BCKAD enzyme assay (cultured cells), DNA sequencing (BCKDHA, BCKDHB, DBT), targeted mutation analysis (BCKDHA, BCKDHB) for Menonites and Jewish |
|Glycine encephalopathy ||AA (P, CSF), CSF/Plasma glycine ratio, OA (U) ||GCS enzyme assay (liver), GCS subunit gene sequencing (GLDC, AMT, and GCSH) |
|Urea cycle defects ||AA (P, U), OA (U), orotic acid (U) ||Enzyme assays (liver, F or RBC), mutation analysis |
|Homocystinuria due to CBS deficiency ||AA (P), total homocysteine (P) ||CBS enzyme assay (F) and/or mutation analysis |
|Organic Acid Disorders |
|Methylmalonic acidemia ||OA (U), AA (P), ACP (P), carnitine (P), MMA (S), total homocysteine (P) |
Complementation studies (F)
DNA sequencing (MUT, MMAA, ...