Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (1227 page)

   Identification for genetic counseling of specific disease-causing alleles in affected individuals and carriers.

   Available tests can be grouped as

   Targeted mutation analysis

   A panel of six mutations comprising

•   
c.1274_1277dupTATC (+TATC1278), c.1421+1G>C (IVS12+1G
>
C), p.G269S (Gly269Ser), c.1073+1G>A (IVS9+1G>A)

•   
p.R247W (Arg247Trp) and p.R249W (Arg249Trp):
the two pseudodeficiency alleles that do not cause TSD but reduce HEX A enzymatic activity as measured by the synthetic substrate

   More extended panels include ethnic-specific mutations as
c.805+1G>A (IVS7+1G>A), del 7.6kb, p.R170Q (Arg170Gln), p.R170W (Arg170Trp), deltaF304/305 (c.915_917delCTT), c.571-2A>G (IVS5-2A>G)

   HEX A gene sequence analysis: analysis of the entire coding region and exon–intron boundaries useful for identifying rare mutant alleles associated with TSD

   Limitations

   The results of a genetic test may be affected by DNA rearrangements, blood transfusion, bone marrow transplantation, or rare sequence variations.

TESTOSTERONE, TOTAL, FREE, BIOAVAILABLE

   Definition

   Testosterone circulates in the blood of men and women in several forms. In healthy adults, approximately 44% of circulating testosterone is specifically bound to sex hormone–binding globulin (SHBG), 50% is nonspecifically bound to albumin, and 3–5% is bound to cortisol-binding globulin, indicating that only 2–3% is unbound and free. Current methods available to evaluate the androgen status include measurement of total testosterone, free testosterone by direct immunoassays, equilibrium dialysis, HPLC-MS, SHBG, calculated free (non–SHBG- and nonalbumin-bound) testosterone, and bioavailable (non–SHBG-bound) testosterone. In most, but not all clinical conditions, a measurement of total testosterone is adequate for the evaluation of a patient. It is widely believed that SHBG-bound testosterone is not readily available to most tissues, whereas albumin-bound and free testosterones are bioavailable. Because SHBG concentrations can be influenced by many factors (e.g., decreased by obesity, testosterone treatment, and hypoandrogenic female conditions such as polycystic ovary syndrome; increased by aging, pregnancy, and estrogen therapy), there are clinical situations in which measured concentrations of total testosterone may not reflect the bioavailable concentrations or the clinical status of the patient. In these circumstances, a supplemental test assessing bioavailable and free testosterone is helpful in clinical decision making.

   
Normal range:
see Table 16.75.