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Many enzymes have been found in the AF. Some have specific activities greater than those found in maternal serum, such as diamine oxidase^115–117 and phosphohexose isomerase,^{116, 117} whereas others have greater activity in maternal serum, such as histaminase¹¹⁸ and creatine phosphokinase.¹¹⁹ The activity of some enzymes in fetal serum exceeds that found in AF (e.g. glucose‐6‐phosphate dehydrogenase, malate dehydrogenase, glutamic‐oxaloacetic transaminase, glutamic‐pyruvate transaminase, and leucine aminopeptidase).^{120, 121} Some enzymes were proposed as maturity indices: α‐galactosidase,¹²² pyruvate kinase,¹²³ alkaline phosphatase, γ‐glutamyl transferase,¹²⁴ and prolidase.¹²⁵

The lysosomal enzymes in AF exhibit different activities as pregnancy progresses, as well as at the same stage in different pregnancies.¹²⁶ Fetal skin becomes impermeable to water¹²⁷ at about 20 weeks of gestation, when a number of enzymes change in their level of activity, and fetal urine begins to contribute significantly to the AF.¹²⁸ At some stages of pregnancy, α‐glucosidase has a specific activity in AF exceeding that found in either maternal or fetal serum. This implies a source of these enzymes other than maternal–fetal serum. The disappearance of α‐glucosidase during the second trimester¹²⁹ may indicate that the fetal liver has assumed a major role in glucose homeostasis. It is now known that this enzyme is of fetal intestinal origin.^{130, 131}

The importance of the developmental biology of enzymes in AF is exemplified by observations made on lysosomal α‐glucosidase, which is deficient in type II glycogenosis (Pompe disease) (see Chapter 21); the initial report indicated that there was no activity of this enzyme in AF from a fetus with Pompe disease.¹³² Subsequent studies in another pregnancy, however, showed α‐glucosidase activity in AF, whereas cultured AF cells showed no enzyme activity.¹³³ It turns out that the α‐glucosidase in AF is caused by a maltase of fetal intestinal origin,¹³⁰ distinct from the enzyme deficient in Pompe disease.¹²⁹

Lysosomal enzyme activities vary in relation to gestational age.^{134, 135} There is not total concurrence on the observations made about AF lysosomal enzyme activities. For example, the mean activities of β‐galactosidase and N‐acetyl‐β‐D‐glucosaminidase reported by one group¹³⁶ differed by a factor of two from the mean activities observed by another group.¹²⁸ Technical aspects of the assays (especially the substrates used) and handling or storage of samples likely explain these reported differences.

Hexosaminidase seems to have the highest specific activity of the lysosomal enzymes in AF.¹²⁸ Except for α‐glucosidase, α‐arabinosidase, and β‐glucosidase, lysosomal enzymes generally rise to their highest specific activities at term.¹³⁴ The specific activities of α‐glucosidase and heat‐labile alkaline phosphatase reach a peak of specific activity between 13 and 18 weeks of gestation. Prenatal diagnosis of metachromatic leukodystrophy requires assay of arylsulfatase A enzyme activity in cultured AF or chorionic villus cells, or DNA analysis if the mutation is known.¹³⁷ Higher than normal activities of several lysosomal hydrolases were reported in the AF of a fetus affected with I‐cell disease (mucolipidosis II).^{138, 139} All enzyme diagnostic tests based on cell‐free AF should be used with caution.

In some specific inborn errors of metabolism, such as Tay–Sachs disease, the characteristic enzymatic deficiency (hexosaminidase A) may manifest in the AF.^{140, 141} Desnick et al.¹⁴² found one fetus affected with Sandhoff disease (total hexosaminidase deficiency) with almost complete deficiency of this enzyme in the AF. This finding was confirmed in another Sandhoff‐affected fetus.¹⁴³ Potier et al.¹⁴³ found that the AF samples with high total hexosaminidase activity also contained a high percentage of maternal serum hexosaminidase (form P). The varying rates of enzyme inactivation in AF and the possibilities of maternal or fetal serum contamination or maternal tissue admixture of different isozymes, in addition to points already made, confirm that enzyme assays performed directly on cell‐free AF are unreliable. Thus, direct study of enzyme activity in chorionic villi or cultivated AF cells is preferable.¹⁴⁴