Heterozygous carriers detection

Galactose tolerance tests have also been used in attempts to detect heterozygous carriers for galactosemia (D5, H6) this is dealt with in Section 5.3.1. Some heterozygotes are made ill by the galactose load (D3, H3, H16). Galactose tolerance tests have now been replaced, for this purpose, by the more specific and sensitive method of assay of enzyme activity. 

Heterozygous carriers of functionally relevant mutations usually present with HDL cholesterol levels that are frequently below the fifth percentile. As would be expected, apoA-I levels are also frequently below the fifth percentile (i.e., < 1.05 g/1 and < 1.1 g/1 in Caucasian men and women, respectively). In most cases, heterozygous carriers of apoA-I variants do not present with specific clinical symptoms. An important exception are some structural apoA-I variants with amino acid substitutions in the amino terminus, which have been detected in patients with familial amyloidosis of the liver, the intestine, the kidney, the heart, peripheral nerves, and in the skin. In addition, some apoA-I variants like apoA-I L178P or L159P have been associated with increased risk of premature coronary heart disease or enhanced progression of carotid intima media thickness, whereas others did not show this association, or were even claimed to have reduced cardiovascular risk and advocated as possible agents for the treatment or prevention of atherosclerosis (notably apoA-I R173CMiiano) [22,43,53]. 

Shintaku H, Niederwieser A, leimbacher W, Curtius HC (1988) Tetrahydrobiopterin deficiency assay for 6-pyruvoyl-tetrahydropterin synthase activity in erythrocytes, and detection of patients and heterozygous carriers. Eur J Pediatr 147 15-19... 

Genetic screening had reached a new stage in late 1960 when public health officials initiated voluntary screening of adults to detect heterozygous carriers of specific recessive traits, such as Tay-Sachs, another degenerative disease. Subsequently, several states passed laws to establish mandatory programs to screen for carriers of sickle-cell anemia. 

Table 12.6 Detection of heterozygous carriers of lipid storage diseases (taken from Brady, 1972, with permission)...

With a view to the biochemical detection of homo- and hetero-zygous carriers and Gm, gangliosidosis, serum j8-r>-2-acetamido-2-deoxyhexosidase activities have been investigated in patients with Tay-Sachs and Sandhoff diseases and in normals. Two related methods for the differential determination of the A and B enzymes were possible, but more conclusive results for heterozygous carriers were attained by the heat inactivation method. 

Fluororaetric determination of the a-D-galactosidase activity in tears has been used to detect hemizygotes with Fabry s disease and heterozygous carriers. Two components of the enzyme were distinguished by their thermal stabilities and behaviours on ion-exchange chromatography. 

Once the diagnosis of Wilson s disease has been confirmed beyond doubt, all other family members have to be examined as well. During this process, occasional cases of a presymptomatic course of disease are detected. A reduction of ceruloplasmin in serum may even be present in carriers of heterozygous features. Genetic analysis can provide a diagnosis in some 95% of cases, even prenatally. 

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