Genetic outcomes in children with developmental language disorder: a systematic review

Mendelian Genetics: Patterns Of Inheritance And Single-Gene Disorders

Autosomal recessive single-gene diseases occur only in individuals with two mutant alleles of the disease-associated gene. Remember, for any given gene, a person inherits one allele from his or her mother and one allele from his or her father. Therefore, individuals with an autosomal recessive single-gene disease inherit one mutant allele of the disease-associated gene from each of their parents. In pedigrees of families with multiple affected generations, autosomal recessive single-gene diseases often show a clear pattern in which the disease "skips" one or more generations.

Phenylketonuria (PKU) is a prominent example of a single-gene disease with an autosomal recessive inheritance pattern. PKU is associated with mutations in the gene that encodes the enzyme phenylalanine hydroxylase (PAH); when a person has these mutations, he or she cannot properly manufacture PAH, so he or she is subsequently unable to break down the amino acid phenylalanine, which is an essential building block of dietary proteins. As a result, individuals with PKU accumulate high levels of phenylalanine in their urine and blood, and this buildup eventually causes mental retardation and behavioral abnormalities.

The PKU-associated enzyme deficiency was determined biochemically in the 1950s—long before the PAH-encoding gene was mapped to human chromosome 12 and cloned in 1983. Specifically, Dr. Willard Centerwall, whose child was mentally handicapped, developed the first diagnostic test for PKU in 1957. Called the "wet diaper" test, Centerwall's test involved adding a drop of ferric chloride to a wet diaper; if the diaper turned green, the infant was diagnosed with PKU. The wet diaper test was used to reliably test infants at eight weeks after birth; by this time, however, infants who were affected by PKU had already often suffered irreversible brain damage.

Thus, in 1960, Dr. Robert Guthrie, whose niece suffered from PKU and whose son was also mentally handicapped, established a more sensitive method for detecting elevated phenylalanine levels in blood, which permitted a diagnosis of PKU within three days after birth. Guthrie's test used bacteria that were unable to make their own phenylalanine as messengers to report high blood levels of phenylalanine in an infant's blood sample obtained via heel prick. With Guthrie's method, the phenylalanine-deficient bacteria were grown in media together with a paper disk spotted with a drop of the infant's blood. If the phenylalanine levels in the blood were high, the bacteria would grow robustly, and a diagnosis of PKU could be made. Through the ability to discover that their child had PKU at such an early age, parents became able to respond immediately by feeding their child a modified diet low in proteins and phenylalanine, thereby allowing more normal cognitive development. Guthrie's test continues to be used today, and the practice of obtaining an infant's blood sample via heel prick is now used in numerous additional diagnostic tests.

Several other human diseases, including cystic fibrosis, sickle-cell anemia, and oculocutaneous albinism, also exhibit an autosomal recessive inheritance pattern. Cystic fibrosis is associated with recessive mutations in the CFTR gene, whereas sickle-cell anemia is associated with recessive mutations in the beta hemoglobin (HBB) gene. Interestingly, although individuals homozygous for the mutant HBB gene suffer from sickle-cell anemia, heterozygous carriers are resistant to malaria. This fact explains the higher frequency of sickle-cell anemia in today's African Americans, who are descendants of a group that had an advantage against endemic malaria if they carried HBB mutations. Finally, oculocutaneous albinism is associated with autosomal recessive mutations in the OCA2 gene. This gene is involved in biosynthesis of the pigment melanin, which gives color to a person's hair, skin, and eyes.

Sex-linked Diseases: The Case Of Duchenne Muscular Dystrophy (DMD)

Prenatal diagnostic testing and embryo sexing for sex-linked recessive disease mutations bring up more than ethical issues, however. They also raise some interesting questions about how we as a society can affect the genetic structure of the human population at large, as Hastings (2001) emphasized in his study. Normally, a balance exists between mutation and selection. Deleterious mutations, such as sex-linked disease genes, disappear over time because affected individuals often die before they reach reproductive age or are unable to reproduce. In effect, these mutations are ousted from the gene pool by natural selection. Hastings argues that prenatal testing upsets this balance.

In the past, before prenatal testing or embryo sexing was an option, with no way to know whether a fetus had or might be carrying a deleterious sex-linked mutation, parents were not able to make these reproductive decisions. All fetuses affected with disease genes were born. Then, in the case of DMD, for example, if the affected child was a boy, he would mostly likely either die before reproducing or be incapable of reproducing, thereby removing that individual affected gene from the population. For this reason, diseases such as DMD have continued to occur at relatively low frequencies in the human population.

Hastings took a mathematical modeling approach to show how modern reproductive technologies have the opposite effect: They often result in an increased frequency of sex-linked, disease-causing mutations in a population. This is because, as Hastings argues in his paper, if a woman decides to terminate her pregnancy and then in the future tries to give birth to an unaffected child, a one-in-three chance exists that the next child will be a female carrier (meaning a daughter with one disease allele). So, instead of natural selection removing a mutation from the population, the population would actually gain a mutation. Over time, with many parents making this decision, the number of X-linked, disease-associated recessive mutations in the population would actually increase. In fact, Hastings calculated that the frequency of these mutations could increase as much as 33% or more, and in as quickly as two to five generations. Although easing their own family burden, parents could simultaneously contribute to an increased frequency of deleterious X-linked mutations in the population at large. It is debatable, however, whether this creates a problem for society, because even though the frequency of the lethal mutations would increase, the number of babies born with DMD would decrease.

In fact, based on the results of his mathematical simulations, Hastings argues that the only circumstance under which the number of babies born with lethal recessive X-linked mutations would actually increase, along with the frequency of the mutation itself, is when parents decide not to terminate a pregnancy, whether they have undergone prenatal testing or not, and instead practice another form of family planning. Specifically, parents who decide to let all pregnancies come to term and then, in the event of a baby being born with a fatal sex-linked disease, later "compensate" by having another child, contribute in the same way to the increasing population frequency of the disease allele; remember, there is a one-in-three chance that the next child will be a female carrier. By not terminating the pregnancy, the parents contribute to the number of babies being born with the disease.

Hastings's modeling results have yet to be verified with real data, so questions remain about whether recessive X-linked disease mutations are indeed increasing in frequency in populations in which these three reproductive technologies or behaviors (prenatal genetic testing, embryo sexing, or family planning) are being used on a widespread basis. Even then, questions would remain about whether the observed numbers were a direct or an indirect result of the widespread use of diagnostic tests; in other words, whether the diagnostic testing actually affects population structure, as Hastings predicts, or simply makes it easier to detect mutations that were previously undetectable (Casci, 2001).

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