Kennedy's Disease (kennedy + disease)

Distribution by Scientific Domains

Selected Abstracts

Diagnosis of motor neuropathy

J. -M.
Motor neuropathy is a clinical entity which leads to consideration of a wide spectrum of peripheral nerve disorders. Firstly, it may be distinguished from other causes of peripheral motor involvement such as muscle diseases and disorders of the neuromuscular junction. Secondly, it may be discussed in two different forms: acute and chronic. Acute chronic neuropathies are mainly observed in Guillain-Barré syndrome, in which electrophysiological studies allow us to recognize the classical demyelinating form and the axonal form. The other causes of acute motor neuropathy are mainly poliomyelitis and porphyrias. Chronic motor neuropathies are mainly observed in motor neuron diseases, mainly amyotrophic lateral sclerosis, but also Kennedy's disease and other lower motor neuron diseases which may be inherited or acquired. The other causes are multifocal motor neuropathy and the predominantly motor forms of chronic inflammatory demyelinating polyneuropathy. The characterization of these different types of chronic neuropathy is of major importance because of the therapeutic consequences which may lead to the proposal of specific treatments. [source]

Kennedy's disease: pathogenesis and clinical approaches

K. J. Greenland
Abstract Kennedy's disease, also known as spinal and bulbar muscular atrophy, is a progressive degenerative con­dition affecting lower motor neurons. It is one of nine neurodegenerative disorders caused by a polyglutamine repeat expansion. Affecting only men, Kennedy's disease is the only one of these conditions that follows an X-linked mode of inheritance. The causative protein in Kennedy's disease, with a polyglutamine expansion residing in the first N-terminal domain, is the androgen receptor. Research in this field has made significant advances in recent years, and with the increased understanding of pathogenic mechanisms, feasible approaches to treatments are being investigated. In Kennedy's disease research, the most significant issue to emerge recently is the role of androgens in exacerbating the disease process. On the basis of animal experiments, a viable hypothesis is that higher circulating levels of androgens in men could trigger the degeneration of motor neurons causing this disease, and that lower levels in heterozygous and homozygous women are protective. This is a major issue, as treatment of individuals affected by Kennedy's disease with testosterone has been con­sidered a reasonable therapy by some neurologists. The rationale behind this approach relates to the fact that Kennedy's disease is accompanied by mild androgen insensitivity. It was therefore believed that treatment with high doses of testosterone might compensate for this loss of androgen action, with the added benefit of preventing muscle wasting. The current review provides an overview of recent advances in the field of Kennedy's disease research, including approaches to treatment. (Intern Med J 2004; 34: 279,286) [source]

Cortical versus spinal dysfunction in amyotrophic lateral sclerosis

MUSCLE AND NERVE, Issue 5 2006
Shahram Attarian MD
Abstract Little is known about the possible link between cortical and spinal motor neuron dysfunction in amyotrophic lateral sclerosis (ALS). We correlated the characteristics of the responses to transcranial magnetic stimulation (TMS) with the electromechanical properties and firing pattern of single motor units (MUs) tested in nine ALS patients, three patients with Kennedy's disease, and 15 healthy subjects. In Kennedy's disease, 19 of 22 MUs were markedly enlarged with good electromechanical coupling and discharged with great variability. Their excitatory responses increased with MU size. In ALS, 17 of 34 MUs with excitatory responses behaved as in Kennedy's disease. By contrast, 28 MUs with nonsignificant responses showed poor electromechanical coupling and high firing rates, whereas 28 MUs with inhibitory responses showed moderate functional alterations. This result indicates that in ALS as in Kennedy's disease, sprouting of corticospinal axons may occur on surviving motoneurons. A clear relationship exists between the responsiveness of MUs to TMS and their functional state. Muscle Nerve, 2006 [source]

Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy

H. Adachi
Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is a motor neurone disease characterized by muscle atrophy, weakness, contraction fasciculations and bulbar involvement. SBMA mainly affects males, while females are usually asymptomatic. SBMA is caused by expansion of a polyglutamine (polyQ)-encoding CAG trinucleotide repeat in the androgen receptor (AR) gene. AR belongs to the heat shock protein 90 (Hsp90) client protein family. The histopathologic hallmarks of SBMA are diffuse nuclear accumulation and nuclear inclusions of the mutant AR with expanded polyQ in residual motor neurones in the brainstem and spinal cord as well as in some other visceral organs. There is increasing evidence that the ligand of AR and molecular chaperones play a crucial role in the pathogenesis of SBMA. The success of androgen deprivation therapy in SBMA mouse models has been translated into clinical trials. In addition, elucidation of its pathophysiology using animal models has led to the development of disease-modifying drugs, that is, Hsp90 inhibitor and Hsp inducer, which inhibit the pathogenic process of neuronal degeneration. SBMA is a slowly progressive disease by nature. The degree of nuclear accumulation of mutant AR in scrotal skin epithelial cells was correlated with that in spinal motor neurones in autopsy specimens; therefore, the results of scrotal skin biopsy may be used to assess the efficacy of therapeutic trials. Clinical and pathological parameters that reflect the pathogenic process of SBMA should be extensively investigated. [source]

Protein aggregation in motor neurone disorders

J. D. Wood
Toxicity associated with abnormal protein folding and protein aggregation are major hypotheses for neurodegeneration. This article comparatively reviews the experimental and human tissue-based evidence for the involvement of such mechanisms in neuronal death associated with the motor system disorders of X-linked spinobulbar muscular atrophy (SBMA; Kennedy's disease) and amyotrophic lateral sclerosis (ALS), especially disease related to mutations in the superoxide dismutase (SOD1) gene. Evidence from transgenic mouse, Drosophila and cell culture models of SBMA, in common with other trinucleotide repeat expansion disorders, show protein aggregation of the mutated androgen receptor, and intraneuronal accumulation of aggregated protein, to be obligate mechanisms. Strong experimental data link these phenomena with downstream biochemical events involving gene transcription pathways (CREB-binding protein) and interactions with protein chaperone systems. Manipulations of these pathways are already established in experimental systems of trinucleotide repeat disorders as potential beneficial targets for therapeutic activity. In contrast, the evidence for the role of protein aggregation in models of SOD1-linked familial ALS is less clear-cut. Several classes of intraneuronal inclusion body have been described, some of which are invariably present. However, the lack of understanding of the biochemical basis of the most frequent inclusion in sporadic ALS, the ubiquitinated inclusion, has hampered research. The toxicity associated with expression of mutant SOD1 has been intensively studied however. Abnormal protein aggregation and folding is the only one of the four major hypotheses for the mechanism of neuronal degeneration in this disorder currently under investigation (the others comprise oxidative stress, axonal transport and cytoskeletal dysfunctions, and glutamatergic excitotoxicity). Whilst hyaline inclusions, which are strongly immunoreactive to SOD1, are linked to degeneration in SOD1 mutant mouse models, the evidence from human tissue is less consistent and convincing. A role for mutant SOD1 aggregation in the mitochondrial dysfunction associated with ALS, and in potentially toxic interactions with heat shock proteins, both leading to apoptosis, are supported by some experimental data. Direct in vitro data on mutant SOD1 show evidence for spontaneous oligomerization, but the role of such oligomers remains to be elucidated, and therapeutic strategies are less well developed for this familial variant of ALS. [source]