Affected infants are usually normal at birth but develop gastrointestinal problems, cirrhosis of the liver, and cataracts in the weeks after they are given milk. The pathogenesis is thought to be due to the negative impact of galactose-1-phosphate accumulation on other critical enzymes. If not recognized, galactosemia causes severe intellectual disability and is often fatal. Complete removal of milk from the diet, however, can protect against most of the harmful consequences, although, as with PKU, learning disabilities are now recognized to be common, even in well-treated patients. Moreover, despite conscientious treatment, most females with galactosemia have ovarian failure that appears to result from continued galactose toxicity.
Another example is provided by hereditary retinoblastoma (Case 39) due to germline mutations in the retinoblastoma (RB1) gene (see Chapter 15). Patients successfully treated for the eye tumor in the first years of life are unfortunately at increased risk for development of other independent malignant neoplasms, particularly osteosarcoma, after the first decade of life. Ironically, therefore, treatment that successfully prolongs life provides an opportunity for the manifestation of a previously unrecognized phenotype.
In addition, therapy that is free of side effects in the short term may be associated with serious problems in the long term. For example, clotting factor infusion in hemophilia (Case 21) sometimes results in the formation of antibodies to the infused protein, and blood transfusion in thalassemia (Case 44) invariably produces iron overload, which must then be managed by the administration of iron-chelating agents, such as deferoxamine.
Genetic Heterogeneity and Treatment
The optimal treatment of single-gene defects requires an unusual degree of diagnostic precision; one must often define not only the biochemical abnormality, but also the specific gene that is affected. For example, as we saw in Chapter 12, hyperphenylalaninemia can result from mutations in either the phenylalanine hydroxylase (PAH) gene or in one of the genes that encodes the enzymes required for the synthesis of tetrahydrobiopterin (BH4), the cofactor of the PAH enzyme (see Fig. 12-2). The treatment of these two different causes of hyperphenylalaninemia is entirely different, as shown previously in Table 12-1.
Allelic heterogeneity (see Chapter 7) may also have critical implications for therapy. Some alleles may produce a protein that is decreased in abundance but has some residual function, so that strategies to increase the expression, function, or stability of such a partially functional mutant protein may correct the biochemical defect. This situation is again illustrated by some patients with hyperphenylalaninemia due to mutations in the PAH gene; the mutations in some patients lead to the formation of a mutant PAH enzyme whose activity can be increased by the administration of high doses of the BH4 cofactor (see Chapter 12). Of course, if a patient carries two alleles with no residual function, nothing will be gained by increasing the abundance of the mutant protein. One of the most striking examples of the importance of knowing the specific mutant allele in a patient with a genetic disease is exemplified by cystic fibrosis (CF); the drug ivacaftor (Kalydeco) is presently approved for treating CF patients carrying any one of only nine of the many hundreds of CFTR missense alleles.