In contrast to cytogenetic conditions, which involve large packages of genes, molecular diseases are usually mono-genic (involve only one gene) and are often due to a single point mutation in DNA, such as that in hemoglobin described by Pauling. Among some better known examples of genetic disease due to molecular changes in DNA are sickle cell disease, Tay-Sachs disease, and achondroplasia (see Table 1 of the entry Genetic Disease II).
Subsequent to the discovery of vitamins by Funk in 1911—as the result of dietary deficiencies described in animal models—the etiology of several human "nutritional diseases," such as scurvy, was better understood. Some humans, however, fail to respond to vitamin therapy, and have been found to possess errors in the biochemical pathways that involve vitamin metabolism. These deficiencies tend to be rare, and are due usually to a point mutation in the DNA that codes for the proteins in the pathways involved. Examples of such molecular genetic diseases include maple syrup urine disease and familial hypophosphatemia (see Table 1 of the entry Genetic Disease II).
Mutations to DNA: "Point" Mutations. These are changes in single base pairs within a linear DNA sequence. Point mutations are rare, unpredictable, and permanent changes that result in a small, localized alteration to the chemical structure of DNA. Mutation is one of the mechanisms or forces of evolution, and the ultimate source of all new genetic variation in populations. When a point mutation occurs in a coding portion of DNA (as in a gene) it sometimes, but not always, results in a change in a protein with deleterious effects to the phenotype, and the event may affect the fitness of the individual who possesses it.
Not all mutations to DNA are point mutations, however. Many recently described mechanisms, such as those that are the cause of the nucleotide triplet repeat expansion disorders, involve more than single base pairs (see the discussion of anticipation below).
Although unpredictable, mutations to DNA exhibit spatial clustering near causal agencies such as, for example, regional sources of radiation. Interestingly, the probability of experiencing certain mutations is also a function of advancing parental age, usually after about age 50. The incidence of achondroplastic dwarfism, for example, increases with advancing paternal age. Paternal age effects have also been confirmed for Marfan syndrome and for the progerias (see table 1 of the entry Genetic Disease II).
About 6% of all live-born children possess a molecular genetic defect,6 although not all such defects manifest at birth.
Some molecular genetic defects manifest during later stages of life. Examples of late-onset molecular conditions include Marfan syndrome (in the second decade), hereditary hemochromatosis (third decade), Huntington disease (fourth decade), amyotrophic lateral sclerosis (fifth decade), and many forms of cancer (variable onset, e.g., breast cancer, familial adenomatous polyposis, and malignant melanoma).
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