Clinical Features of Spinal and Bulbar Muscular Atrophy

Lindsay E. Rhodes; Brandi K. Freeman; Sungyoung Auh; Angela D. Kokkinis; Alison La Pean; Cheunju Chen; Tanya J. Lehky; Joseph A. Shrader; Ellen W. Levy; Michael Harris-Love; Nicholas A. Di Prospero; Kenneth H. Fischbeck

Disclosures

Brain. 2009;132(12):3242-3251. 

In This Article

Abstract and Introduction

Abstract

Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models.

Introduction

Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is an X-linked, adult onset motor neuron disease characterized by slowly progressive weakness of the bulbar and extremity muscles. SBMA patients may become wheelchair dependent 20–30 years after onset (Tsukagoshi et al., 1965; Kennedy et al., 1968). Involvement of bulbar muscles may lead to dysarthria and dysphagia (Ferrante et al., 1997). Fasciculations often occur, particularly around the mouth and in the tongue (Ferrante et al., 1997). Affected individuals frequently have muscle cramps and tremor. Other common neurological features include decreased or absent deep tendon reflexes (Antonini et al., 2000) and sensory loss (Ferrante et al., 1997; Antonini et al., 2000). SBMA patients also often have signs of androgen insensitivity, such as gynecomastia and reduced fertility (Dejager et al., 2002).

SBMA is a member of the family of CAG-polyglutamine expansion diseases that includes Huntington's disease and seven spinocerebellar ataxias (Lieberman et al., 2000). Previous studies of SBMA and the other polyglutamine diseases have shown that the length of the CAG expansion correlates inversely with age of disease onset, i.e. the longer the expansion the earlier the onset (La Spada et al., 1992). In SBMA, CAG repeat length has also been reported to correlate with motor and sensory nerve conduction abnormalities (Suzuki et al., 2008).

The SBMA repeat expansion is in the first exon of the androgen receptor gene (La Spada et al., 1991). The androgen receptor is a nuclear receptor that normally regulates gene expression after ligand binding. The primary androgen receptor ligands are testosterone and dihydrotestosterone. Studies in animal models and patients indicate that these ligands are important for the development of the disease. This evidence includes the following observations: (i) male transgenic mice expressing the mutant androgen receptor have a neuromuscular deficit resembling SBMA and females are much less affected; (ii) when the male mice are castrated (Chevalier-Larsen et al., 2004) or treated with the anti-androgen leuprorelin (Katsuno et al., 2002, 2003), the phenotype is improved, and when female transgenic mice are given testosterone, the SBMA phenotype becomes fully manifested; (iii) in humans, heterozygous female carriers of the disease gene are generally asymptomatic, and even homozygous females in one reported family had only mild symptoms (Sobue et al., 1993; Schmidt et al., 2002). Together, this evidence supports the hypothesis that SBMA disease manifestations are primarily due to a ligand-dependent toxic gain of function in the mutant androgen receptor.

While the clinical features of SBMA are fairly well known, little natural history data are available to inform the selection of sample size, outcome measures, and biomarkers for SBMA intervention trials (Katsuno et al., 2006). Additional retrospective data would help to define the natural history of SBMA and guide the design of future clinical trials. Here we present an analysis of retrospective and cross-sectional data collected from 57 patients with SBMA.

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