What is the pathophysiology of Kennedy disease (KD)?

Updated: Sep 30, 2019
  • Author: Paul E Barkhaus, MD, FAAN, FAANEM; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

KD is an inherited disorder characterized by degeneration of both motor and sensory neurons. It involves loss of lower motor neurons supplying the limb and bulbar musculature. Extraocular muscles are spared, possibly because of reduced numbers of androgen receptors in these muscles.

Autopsy studies showed loss of large, medium, and small motor neurons. [9, 10] Loss of small motor neurons is not a typical finding in sporadic or non-hereditary amyotrophic lateral sclerosis (ALS). Subsequent investigators emphasized the loss of larger dorsal root ganglion cells, thereby establishing a sensory neuron component. Li et al suggested a pattern of central-peripheral distal axonopathy. [11] Autonomic testing in 2 patients with KD demonstrated abnormality in small nerve fibers. In a recent study by Rocchi et al, impaired cardiovascular response to physiological stimuli was recorded in patients with KD. Failure of autonomic nervous system accompanied low plasma levels of norepinephrine. [12, 13] In contrast to prior studies suggesting upper motor neuron involvement in KD based on transcranial magnetic stimulation studies, one study found differences in cortical excitability between KD and ALS. [14]

Li et al demonstrated nuclear inclusions in the spinal motor neurons of patients with KD that stained positively for androgen receptor protein when immunohistochemical methods are used. [15] Similar features have been reproduced in transgenic mice and neuronal cell culture. Walcott and Merry further studied these nuclear inclusions. [16] Although the inclusions are a neuropathologic finding in KD, their role in the disease remains unresolved.

As mentioned before, the genetic basis of the disease involves an expanded repeat of the CAG trinucleotide in the proximal portion of the q arm of the X chromosome. It is thought to encode a polyglutamine tract on the androgen receptor protein. Patients with KD have about 40-62 repeats, compared with 10-36 repeats in healthy individuals. This expanded repeat is unstable in that its length may change from generation to generation. Reports indicate that repeat lengths, which are minimally expanded, are associated with atypical presentations. Echaniz-Laguna et al reported a family with early-onset and rapidly progressive KD that showed 50-54 CAG repeats. [17]

The polyglutamine repeat expansion in the androgen receptor is responsible for the clinical manifestations of Kennedy disease. Precisely how this mutation produces motor dysfunction and androgen insensitivity remains uncertain. Both loss and gain of function of the mutated androgen receptor have been implicated as underlying mechanisms of Kennedy disease. [18, 19, 20] To account for this purported dual effect of the Kennedy disease mutation, some authors attribute the endocrine symptoms of the disorder to loss of function and the neurologic symptoms predominantly to gain of function of the androgen receptor. [21, 22]

In a review of the mechanisms mediating spinal and bulbar muscular atrophy (SBMA), Beitel et al suggested loss or gain of function of the polyglutamine expanded androgen receptor, leading to disturbance of the cellular homeostasis, which then leads to neuronal and muscular dysfunction. Important among the mechanisms were alteration in androgen receptor structure, altered protein interactions, aggregation, formation of soluble oligomers, change in posttranslation modifications, transcriptional dysregulation, altered RNA splicing, ubiquitin proteasome system impairments, induction of autophagy, loss of neurotrophic support, myogenic contributions, nongenomic androgen receptor signaling, mitochondrial dysfunction, and impaired axonal transport. [23]  More recent studies show abnormal autophagy in SBMA. Histone deacetylase 6 (HDAC6) has been found to play an important role in proten degradation via autophage in an SBMA fly model and HDAC6 has also been found to be decreased in SBMA-induced pluripotent cells. [24, 25]

Although KD typically affects men, women can be symptomatic. [26, 27] Greenland et al reported a heterozygous female carrier of KD who had one allele containing an expanded number of CAG repeats (10) with the normal allele showing 28 repeats (upper normal range). They felt that this particular combination of allele repeats may have led to this patient's clinical expression of the disease. [27]

Authors have suggested that anticipation occurs in KD. That is, the length of the expanded repeat and the age of onset appear to be inversely related: a longer repeat seems to indicate a younger age of onset. However, subsequent observations have not supported this suggestion. Amato et al found no correlation between the severity of disease and the length of CAG repeat. [28] Sinnreich et al [29] and Doyu et al [30] found some correlation between the number of repeats and the age of onset, but other yet-to-be determined factors are likely influential. Other investigators have also reviewed CAG repeats in KD. [31, 32]

A number of molecular pathophysiologic studies of the androgen receptor have been conducted to clarify its role in the pathogenesis of KD. [33, 18, 34, 35, 36, 37, 38, 39] Androgen-receptor protein is produced in the cytoplasm and modified and bound to other molecules. When a ligand such as testosterone is present, it may be transported to the nucleus, where it may undergo further change and function.

Ellerby et al demonstrated that caspases, or "cysteine protease cell-death executioners", may act on the gene product (ie, androgen-receptor protein) resulting from the trinucleotide-repeat expansions, which act as substrates. Caspase cleavage affects proteins with the abnormal expanded polyglutamine tracts, resulting in cell death. Ellerby et al concluded that caspase cleavage is an important step in cytotoxicity (ie, neuronal cell death). [40] High circulating levels of androgens in men might precipitate the motor neuron degeneration observed in KD. [41] Ranganathan et al have shown that the mutant protein may affect mitochondrial function. [42]

In summary, the locus of the mutation is at the Xq11-q12 band of the long arm of the X chromosome, and the gene product is an androgen-receptor protein with a polyglutamine tail at the N -terminal end. The exact mechanism by which the neuronal degeneration occurs remains unknown, but the abnormal protein presumably alters the function of the androgen receptor.

An alternate mechanism of how the expanded repeat causes KD may be a gain of toxic function effect by mutant gene products. The motor neuron loss imputed to the abnormal (or mutant) androgen receptor is not a simple, passive loss of function. Instead, it is a transformed protein that is actively adverse (or toxic) to cell function. This mechanism is analogous to genetic defects in other, but dissimilar, neurologic disorders, including Huntington disease and some spinocerebellar ataxias (SCAs, types 1, 2, 3, 6, and 7), which also are associated with tandem repeats.


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