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In 1991 the first reports appeared of dynamic mutations resulting from the unstable expansion of trinucleotide repeats.⁷⁷² Thus far, at least 40 proven disorders with these unstable repeats have been described (see Chapter 14).⁷⁷³ All disorders described thus far are autosomal dominant or X‐linked, except for Friedreich ataxia and progressive myoclonic epilepsy with myoclonic tremor,^774–776 which are autosomal recessive and also unique in having intronic involvement.⁷⁷⁷ Typically for these disorders (except for Friedreich ataxia), the carrier will have one normal allele and a second expanded allele. The repeat expansion disorders, although diverse, share many basic features. They arise from normally existing polymorphic repeats, are unstable, changing size on transmission, with longer repeats associated with severe and earlier onset disease, and highly variable phenotypes.⁷⁷³

These disorders (except for Friedreich ataxia and progressive myoclonic epilepsy type 1)⁷⁷⁴ are also generally characterized by progressively earlier manifestations and/or more severe expression with succeeding generations. This genetic mechanism, called anticipation, is associated with further expansion (rarely contraction) of the specific triplet repeat (Box 1.2). These disorders characteristically have a direct relation between the number of repeats and the severity of disease with an inverse relation between the number of repeats and age of onset. These aspects of anticipation weigh heavily in preconception counseling when it becomes clear that the relatively mild‐to‐moderate status of a mother with myotonic muscular dystrophy type 1, for example, with a 50 percent risk, could have an affected child with severe congenital myotonic muscular dystrophy.⁷⁷⁸ Triplet size in this disorder correlates significantly with muscular disability as well as intellectual and gonadal dysfunction.⁷⁷⁹ These authors also noted that triplet repeat size did not correlate with the appearance of cataract, myotonia, gastrointestinal dysfunction, and cardiac abnormalities. For myotonic dystrophy type 2 there is no correlation between disease severity and tetranucleotide (CCTG) repeat length.⁷⁸⁰ Women with myotonic dystrophy type 2 have an increased risk of ovarian and endometrial cancer.^{781, 782} Somatic mosaicism with different amplification rates in various tissues may be one possible explanation for variable phenotypes. Fortunately, in very few repeat expansion disorders, including Huntington disease, do de novo mutations occur.⁷⁸³ Parent‐of‐origin effects influencing anticipation are also recognized (see fragile X syndrome discussion in Chapter 16). The offspring of fathers with Huntington disease, spinocerebellar ataxias types 2 and 7, for example, may present clinically, and on occasion even before the father has become symptomatic.⁷⁸⁴ For myotonic muscular dystrophy, paternally transmitted small expansions have a higher risk of symptomatic offspring compared with females.⁷⁸⁵ Rarely, two triplet repeat disorders occur concurrently, as reported in a patient with both oculopharyngeal muscular dystrophy and Huntington disease.⁷⁸⁶ Anticipation does occur in Huntington disease, but not in oculopharyngeal muscular dystrophy. It is well documented that the paradoxical effects of repeat interruptions in the ATTCT expansion alleles in spinocerebellar ataxia type 10 result in a contraction in intergenerational repeat size.⁷⁸⁷ De novo repeat interruptions may also be associated with less somatic instability and few or no symptoms and signs in myotonic muscular dystrophy type 1.^{788, 789} Spinocerebellar ataxia type 2 has also been associated with Parkinsonism and an increased risk for amyotrophic lateral sclerosis (ALS).⁷⁹⁰ Almost all of the 59 autosomal recessive spinocerebellar ataxias⁷⁹¹ are not characterized by repeat expansions. Marked heterogeneity in the clinical features are common.