Trinucleotide Repeat Disorders

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Trinucleotide repeat expansions, initially described in 1991 (1), are responsible for a number of neurological diseases, including Fragile X syndrome (FRAXA), myotonic dystrophy (DM), spinal and bulbar muscular atrophy (SBMA), Huntington's disease (1HD), Friedreich ataxia (FRDA), spinocerebellar ataxias (types SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, and SCA12), and dentatorubral-pallidoluysian atrophy (DRPLA) (2-5). A number of other rare forms of SCA continue to be identified in families, but commercial testing for these is currently unavailable. Most recently, SCA10 and myotonic dystrophy type 2 (DM II) have been found to result from an expansion of intronic pentanucleotide (ATTCT) and tetranucleotide (CCTG) repeats, respectively (6,7). It is also worth noting that the clinical manifestation of a neurological disorder could vary with type of mutation (i.e., a trinucleotide repeat expansion vs a point mutation). This is exemplified in the case of SCA6, where point mutations in CACNL1A4 gene have resulted in familial hemiplegic migraine and episodic ataxia in contrast to the triplet repeat expansions of the same gene, which produce the spinocerebellar phenotype (8,9). Because a detailed discussion of all the complexities of genetic basis of nucleotide repeat disorders is beyond the scope of our discussion, this chapter will focus mainly on the trinucleotide repeat disorders tested routinely in a clinical laboratory. Clinical and molecular features of some of the trinucleotide repeat disorders are described in the following section and are summarized in Table 1.

2.1. FRAGILE X SYNDROME Fragile X syndrome is the most frequent form of inherited mental retardation, with an incidence of about 1 in 4000 males and 1 in 6000 females. It is associated with a fragile site on Xq27.3. Fragile X syndrome exhibits X-linked dominant inheritance with reduced penetrances of 80% in males and 30% in females. Dysmorphic features associated with Fragile X syndrome include large ears, a long and narrow face, and moderately increased head circumference.

Macro-orchidism is a common finding in postpubescent affected males. Other common features include hyperactivity, attention deficit disorder, and autism.

2.2. MYOTONIC DYSTROPHY TYPE I Myotonic dystrophy type I (DM I) is the most common form of autosomal dominant adult muscular dystrophy, with a prevalence of 1 in 8000. DM is characterized by progressive muscle weakness, myotonia, cataracts, cardiac arrhythmia, and insulin-dependent diabetes. Phenotypic expression of myotonic dystrophy is variable both within and between families. Individuals who have the congenital form of myotonic dystrophy display myopathic facial appearance, respiratory distress, hypotonia, feeding difficulties, delayed motor development, and mental retardation. Increased pregnancy complications and polyhydramnios as a result of decreased fetal swallowing secondary to fetal muscle weakness are also frequently noted in cases of congenital

Table 1

Genetic and Molecular Characteristics of Trinucleotide Repeat Diseases

Disorders

Table 1

Genetic and Molecular Characteristics of Trinucleotide Repeat Diseases

Disorders

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