Kennedy syndrome spinobulbar muscular atrophy SBMA

A rare inherited neurodegenerative disease, Kennedy syndrome or spinobulbar muscular atrophy (SBMA), is characterized by progressive neuromuscular weakness resulting from a loss of motor neurons in the spinal cord and brain stem. The onset of this disease occurs in the third to fifth decades of life and is often preceded by muscular cramps on exertion, tremor of the hands and elevated muscle creatine kinase (Kennedy etal. 1968). The initial description of Kennedy syndrome also contains one case with gynaecomastia. Subsequent reports confirmed the presence of androgen insensitivity in men with SBMA, showing various degrees of gynaecomas-tia, testicular atrophy, disorders of spermatogenesis, elevated serum gonadotropins and diabetes mellitus (Arbizu et al. 1983; Shimada et al. 1995). An alteration in the AR was regarded as a pathophysiological sign for SBMA and the expansion of a CAG tract encoding a polyglutamine (polyQ) stretch within the N-terminal region of the receptor was subsequently recognized as the cause of the disorder by La Spada etal. (1991) and confirmed by other studies (Belsham etal. 1992; Brooks and Fischbeck 1995). There is an inverse correlation between the polyQ length and the age at onset, or the disease severity adjusted by the age at examination. (Mariotti etal. 2000; Lund etal. 2001). In addition, the likelihood of gynaecomastia increases with triplet length (MacLean etal. 1995). Also cognitive functions, especially spatial cognition, seem to be less effective in Kennedy patients (for review see Zitzmann and Nieschlag 2003).

Since men have only one AR allele, SBMA occurs predominantly in the male gender. Nevertheless, heterozygous female carriers with one normal and one expanded AR allele often present with cramps after muscular exertion and subclinical muscle weakness. In some cases, slight tongue atrophy and sporadic tongue fasciculations can be observed.Mild signs of chronic denervation maybe revealed by neurophysiological studies in 50-60% ofheterozygous females (Guidetti etal. 1996).

Such observations are obviously not dependent on X-chromosome inactivation patterns since random methylation occurs in these patients (Chen etal. 1999).

In patients with complete androgen insensitivity syndrome (CAIS), the chance for neuromuscular deficits or respective degeneration is not increased (Quigley et al. 1995). This suggests that neurological deficits in SBMA are not caused by a lack of androgen influence but rather that neurotoxic effects are associated with the pathologically elongated polyQ, which possibly causes irregular processing of the AR protein and accumulation of end products.

In molecular terms, the basal and ligand-induced transactivation function of the AR is inversely associated with the length of this CAG repeat chain (Beilin et al. 2000). Several investigators have also shown a reduction in transactivation activity with increased number of CAG repeats (Mhatre et al. 1993; Chamberlain et al. 1994). The modulatory effect on androgen-dependent gene transcription seems to be rather linear over a range from 0 to 200 CAG repeats in in vitro studies (Tut etal. 1997).

The NH2-terminal domain of AR is the target of a number of interacting factors involved in the regulation of its transactivation. In a recent study Irvine et al. (2002) could show that although the binding site for the p160 coactivators at the N-terminus of the AR is downstream from the polyQ stretch, increased length of the polyQ up to 42 repeats inhibited both basal and coactivator-mediated AR transactivation activity. A similar result was also obtained with a nuclear G protein ras related protein termed ARA24 (Hsiao etal. 1999). Presumably increased polyQ length causes allosteric changes at the N-terminal domain of the AR that negatively influence interactions with coactivators and thus result in reduced transactivation potency.

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