Kennedy's Disease
The patient's symptomatology started 22 years ago with tightness and cramps in his lower extremities. Subsequently, he developed fasciculations and weakness in proximal as well as distal muscles in both upper and lower extremities. Although he was initially thought to have a primary disease of muscle, this diagnosis was unlikely because of the history of fasciculations and the pattern of muscle weakness; namely, the involvement of both proximal (arising from the chair, lifting weights) and distal muscle groups (tripping on his feet, holding objects tightly).
Most adult onset generalized myopathies result in proximal muscle weakness (i.e., polymyositis, dermatomyositis, limb girdle, late onset Becker's). A minority present with a more prevalent distal involvement (i.e. myotonic dystrophy, inclusion body myositis). Other myopathies affect selected muscle groups (scapuloperoneal, fascioscapulohumeral, or oculopharyngeal musculature).
In our patient, the involvement of proximal and distal muscle groups in both upper and lower extremities does not follow the pattern of any of the above mentioned myopathies. Furthermore, fasciculations are not a significant feature of primary muscle disease.
The presence of weakness in proximal and distal muscle groups as well as fasciculations, suggested the diagnosis of motor neuropathy or lower motor neuron disease. The physical examination confirmed the pattern of muscular weakness suggested by the history and indicated involvement of the bulbar musculature with tongue atrophy and perioral weakness. In addition, reflexes were absent. EMG confirmed the involvement of the lower motor neuron with widespread chronic denervation in the extremities, thoracic paraspinal muscles, and tongue. The normal motor conduction velocities in both arms and legs made motor neuropathy less likely. The muscle biopsy confirmed a long standing denervation-reinnervation process as evidenced by type I and type II fiber grouping, and ruled out the presence of an inflammatory process.
The clinical and EMG findings of lower motor neuron involvement suggested a diagnosis of spinal muscular atrophy. The spinal muscular atrophies of adult onset are a clinically well-defined group due to diverse genetic defects. They are characterized by late onset (third to fifth decade), slowly progressive bulbo-spinal muscle weakness with atrophy, fasciculations, and areflexia. Proximal muscles of the shoulders and pelvic girdles are affected earlier and to a greater extent then distal muscles. Intrinsic hand muscles are affected later in the course of the disease. Bulbar involvement is manifested initially as weakness and fasciculations of the oro-mandibular musculature, and subsequently by atrophy and fibrillations of the tongue. Reflexes are usually absent. The clinical syndrome is transmitted by three distinct modes of inheritance: autosomal-dominant, autosomal-recessive, and X-linked recessive. Patients with these three distinct modes of inheritance present with a similar phenotype.
Recent studies of the autosomal recessive forms of SMA have defined a single locus on chromosome 5q11.2-13.3 in acute infantile, late infantile, juvenile, and adult onset types.[1] The genes for two proteins in this region, Survival Motor Neuron (SMN) and Neuronal Apoptosis Inhibitory Protein (NAIP), have been identified as possibly involved in SMA. Deletions in SMN have been described in greater than 98% of SMA cases.[2] However it is still unclear how alterations in SMN give rise to the clinical syndrome of SMA, and what the role of NAIP is in this disease process.
Patients with the X-linked recessive form (Kennedy's disease) present with bulbar and spinal muscular involvement with absent reflexes, as well as gynecomastia, testicular atrophy and non-insulin dependent diabetes mellitus.
Our patient presented with evidence of both bulbar and spinal muscular atrophy as well as a mild degree of gynecomastia, but no testicular atrophy. The combination of symptoms and signs, including the prominent facial fasciculations, suggested the possible diagnosis of Kennedy's disease. Genetic testing was performed, and PCR analysis revealed 43 CAG repeats which is consistent with the diagnosis of Kennedy's disease.
In 1968, William R. Kennedy and co-workers described a distinctive "slowly progressive spinal and bulbar muscular atrophy of late onset" in 11 affected males from two families.[3] According to his original work, the disease is a separate entity from other lower motor neuron disorders because of "the late age of onset; consistent involvement of bulbar, proximal, and distal muscle groups; sex-linked recessive inheritance; and normal life expectancy". Since the original description, the disease has been reported in several kindred, in particular in the U.K., Harding et al.[4]
The disease is thought to be rare, but the true incidence is not known, and probably underestimated, since many patients are undiagnosed or misdiagnosed. The widespread availability of genetic testing will provide a more accurate estimate in the next several years. Onset of the disease is variable from 15 to 59 years of age, although most commonly these patients seek medical attention between the fourth and fifth decade of life.
Most authors agree that the clinical features include muscle weakness, atrophy, and fasciculations. The proximal muscle groups are affected at an earlier stage, subsequently followed by atrophy and weakness of the intrinsic muscles of the hands and peroneal muscles. Weakness and fasciculations of the oro-mandibular musculature, as well as perioral fasciculations, are present early and are subsequently followed by facial weakness, atrophy, and fibrillations of the tongue. Some authors also describe a nasal component to the speech, most likely due to facial weakness. Deep tendon reflexes are usually absent. Sensation may be abnormal. Gynecomastia is present in many of the cases, but can be quite variable, as are testicular atrophy and reduced fertility. EMG and muscle biopsy typically show chronic neurogenic atrophy with reinnervation. Post mortem examination of the spinal cord reveals marked loss and/or atrophy of anterior horn cells.
In 1991, La Spada et al. [5] mapped the genetic mutation that causes Kennedy's disease to the first exon of the androgen receptor (AR) gene on the proximal long arm of the X chromosome. PCR analysis revealed amplification of CAG triplet nucleotide repeats. DNA sequence analysis showed that the average CAG repeats was 21 ± 2 in 75 normal controls versus a range of 40 to 52 in the 24 patients with Kennedy's disease. There was no overlap between the two groups. The enlarged band segregated with disease in 15 Kennedy's disease families, with no recombination in 61 meioses. The maximum odds ratio (lod score) of this mutation being the cause of the disease was determined to be 13.2 at 0 centimorgans, which is highly significant. Since the original report, the mutation has been confirmed by many groups.[6,7] The CAG repeats encode for glutamine residues in the amino-terminal domain of the AR receptor. It has been reported that the size of the amplified CAG repeats correlates with age of onset.[8,9] The larger the number of CAG repeats, the earlier the age of onset. This phenomenon is present in other neurological disorders with trinucleotide repeats. Expansion of trinucleotide repeats has been found to be present in several inherited neurological disorders. The trinucleotide repeats that have been discovered are:
While GAA repeats are not transcribed into mRNA, CAG repeats in the coding region are transcribed and translated into a peptide of polyglutamine. The size of the polyGlu tract is determined by the number of repeats. The polyGlu can bind to DNA, mRNA, and cellular proteins. Therefore, it has been hypothesized that the binding of polyGlu tract with nucleic acids or proteins could derange cellular functions ultimately inducing cell death. For example, in HD the polyGlu tract binds to a protein called Huntingtin Associated Protein (HAP1), which is highly expressed in brain. HAP1 may be associated with microtubule-mediated transport.[10] The authors speculate that the binding of polyGlu with HAP1 could result in a toxic gain of function leading to apoptosis.[10] More recently, Burke et al. reported that the polyGlu tract could also bind to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in brains of HD and DERPLA patients.[11] GAPDH, besides being a fundamental step in the glycolytic pathway, can bind to uracyl DNA glycosylase and tubulin.
The mutation present in Kennedy's disease involves the AR gene. The AR is a member of a superfamily of DNA binding proteins that includes steroid, Vitamin D, and retinoic acid receptors. The AR is a nuclear transcription factor that mediates the steroid dependent activation of several genes necessary for the biologic action of steroids. It has been shown that CAG encodes for the glutamine residues of the NH2 terminal domain of the AR protein.[6] The NH2 terminal is the same site where another protein, the receptor accessory factor (RAF), binds to enhance the binding of the AR to the DNA.[12] Therefore, it has been hypothesized that the polyGlu tract interferes with the complex AR, RAF, and DNA impairing the efficiency of the hormonal mediated AR action.
The possibility that an alteration of the AR gene could be associated with motor neuron disease has led many investigators to study the potential relationship of androgens with motor neuron injury. However, the exact mechanism of disease is unknown. Many reports have described mutations of the AR gene.[14] Such mutations cause a variety of defects of virilization, but none result in motor neuron disease. Moreover, the deletion of the entire AR gene (present in some of the patients affected by androgen insensitivity syndrome), results in severe virilization abnormalities, but does not give rise to motor neuron disease.[15] In defects of virilization, the decreased binding properties of AR do not always correlate with the severity of the disease.[14] However, in Kennedy's disease, the decreased binding affinity of the AR not only correlates with the mild degree of gynecomastia and testicular atrophy, but also with the size of the CAG repeats.[13]
The low binding affinity of the AR in Kennedy's disease does not correlate with the degree of weakness.[13] Thus, it seems that there are two independent components in Kennedy's disease: gynecomastia and testicular atrophy, which are mild and androgen dependent; and lower motor neuron disease, which is the main feature of the disease and is androgen independent. The major question still exists as to how the CAG repeats in the AR gene lead to motor neuron injury.
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