BIOCHEMICAL GENETICS

Biochemical genetics deals not only with enzymatic defects but also with proteins of all functions, including cytoskeletal and extracellular structure, regulation, and receptors. The principal functions of the biochemical genetics laboratory are to determine the presence or absence of proteins, to assess the qualitative characteristics of proteins, and to verify the effectiveness of proteins in vitro. The key elements from the referring clinician's perspective are: (1) to indicate what the suspected clinical diagnoses are and (2) to make certain that the proper specimen is obtained and transported to the laboratory in a timely manner.
Indications for Biochemical Investigations
Some inborn errors are relatively common in the general population, eg, hemochromatosis, defects of the low-density lipoprotein receptor, and cystic fibrosis (Table 44–3). Others, although rare across the entire population, are common in certain ethnic groups, such as Tay-Sachs disease in Ashkenazic Jews, sickle cell disease in African Americans, and thalassemias in populations from around the Mediterranean basin and Asia. Many of these disorders are autosomal recessive, and the frequency of heterozygotes is many times that of the fully expressed disease. Screening for carrier status can be effective if certain requirements are satisfied (Table 44–4). For example, all of the United States and the District of Columbia require screening of newborns for phenylketonuria and often other metabolic diseases. Such programs are cost-effective even for rare conditions such as phenylketonuria, which occurs in only one of every 11,000 births. Unfortunately, not all disorders that meet the requirements in Table 44–4 are screened for in every state. Furthermore, compliance is highly variable among programs, and follow-up diagnostic tests, management, and counseling are in some cases inadequate. Babies most likely to be missed are those born at home and those discharged before they have digested much milk or formula. In some states, parents can refuse to have their infants studied. Several commercial laboratories have marketed screening for over 35 inborn errors of metabolism to hospitals. This supplemental newborn screening involves tandem mass spectroscopic analysis of the same blood spots used in state-mandated programs.
Use of the biochemical genetics laboratory for other than screening purposes must be justified by the need for data on which to base a diagnosis of specific disorders or classes of related disorders. The possibilities are limited only by the extent of knowledge, the enthusiasm of the primary clinician or consultant, the willingness of the patient or family to pursue the diagnosis and specimens to be taken, and the availability of a laboratory to examine the specimens.
Though many inborn defects are so subtle they escape detection, there are a number of clinical situations in which an inborn error should be part of the differential diagnosis. The urgency with which the investigation is undertaken will vary depending on the severity of the disorder and the availability of treatment. Table 44–5 lists various clinical presentations.
The possibility of acute metabolic disease of the neonate is the most important indication, because prompt diagnosis and treatment may often make the difference between life and death. The clinical features are nonspecific because the newborn has a limited repertoire of responses to severe metabolic insults. The physician must be both inclusive and systematic in evaluating such ill babies.

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Erbe RW et al. Neonatal screening. In: Emery and Rimoin's Principles and Practice of Medical Genetics, 5th ed. Rimoin DL et al (editors). Churchill Livingstone, 2007.

Scriver CR et al. The Metabolic and Molecular Bases of Inherited Disease, 8th ed. McGraw-Hill, 2001.

Seashore MR et al. Newborn screening and the pediatric practitioner. Semin Perinatol. 2005 Jun;29(3):182–8. [PMID: 16114581]