Anticipation describes the clinical phenomenon in which a genetic condition seems to worsen over successive generations. For example, a child with myotonic dystro phy may have severe hypotonia and failure to thrive, yet the affected grandparent has only early balding and pre-senile cataracts. Anticipation has mostly been described in autosomal dominant neurological disorders, such as Huntington disease, the spinocerebellar ataxias, and myotonic dystrophy (La Spada et al., 1994). In these conditions, nucleotide runs of three are excessively repeated in the DNA. Thus, they are called trinucleotide or triplet repeat disorders. Spinobulbar muscular atrophy and fragile X syndrome are X-linked neurological trinucleotide repeat disorders.
Most genes are transmitted unaltered through each generation of a family. In triplet repeat disorders, the triplet repeat is unstable once it reaches a critical size threshold, and the size can increase in successive generations. These unstable mutations are called dynamic mutations (Sutherland and Richards, 1994). It is normal to have fewer than a certain number of these trinucleotide repeats. The instability of the trinucleotide repeats tends to be related to their size (with longer repeats being more unstable and more likely to increase in size). Although contractions in size can occur, this is rare, and the contractions are usually small (less than five repeats) (La Spada et al., 1994). Some repeats are transmitted unchanged with neither expansion nor contraction.
A premutation describes an intermediate size range between trinucleotide repeat sizes in the normal (stable) range, and larger repeats in the range associated with disease. Individuals who carry a premutation often have no symptoms of disease, mild symptoms, or a later age of presentation of symptoms than individuals with larger expansions. Premutations are unstable and may expand into the full mutation range during meiosis.
For some trinucleotide repeat diseases, the stability of the mutation is influenced by the sex of the parent transmitting the mutation. Congenital myotonic dystrophy seems to be inherited exclusively from the mother, whereas childhood-onset Huntington disease seems to be inherited exclusively from the father. In fragile X syndrome, normal premutation carrier males cannot transmit a full mutation to their daughters, though all their daughters inherit the premutation. However, when the unstable fragile X mutation is transmitted by females, it usually increases in size (Nance, 1997a).
A large number of trinucleotide repeats is often associated with a more severe presentation of the disease (La Spada et al., 1994; Nance, 1997a). For example, in myotonic dystrophy, it is normal to have 30 or fewer CTG repeats. In the premuta-tion range between 30 and 50 repeats, the individual is unlikely to develop symptoms of myotonic dystrophy. However, an expansion can occur in the egg or sperm of an unaffected premutation carrier; thus the person's offspring are at risk to be affected. An individual with a thousand or more CTG repeats usually displays the severe congenital form of myotonic dystrophy (Harper, 1997).
Huntington disease (HD) is an example of an autosomal dominant trinucleotide repeat disorder showing variable expressivity, age-related penetrance, anticipation, and parental bias in the stability of the trinucleotide repeat. Huntington disease is a progressive neurological condition characterized by uncontrolled movements (chorea) and problems with thinking, coordination and judgment. The penetrance is believed to be 90% by the age of 90, with an average age of symptom onset of 39 years (Nance, 1997a). The gene alteration in HD is a CAG repeat on the tip of the short arm of chromosome 4. An affected individual has 40 or more CAG repeats; an unaffected individual has 35 or fewer repeats. The area between 36 and 39 CAG repeats is considered an area of reduced penetrance (although the empirical pene-trance risk is unknown) (ACMG/ASHG, 1998). Persons with repeat sizes in this range may or may not develop symptoms later in life. In the premutation range between 27 and 35 repeats, the individual will not be affected but an expansion can occur in the sperm (Brinkman, 1997; ACMG/ASHG, 1998). Juvenile Huntington disease is associated with CAG expansions over 80 repeats. These large expansions seem to be inherited exclusively from an affected father (Nance, 1997b).
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