Background
Kennedy disease (KD) is named after William R. Kennedy, MD, who described this entity in an abstract in 1966. The full report followed in 1968. [1] The history of this entity is summarized briefly here by way of a personal memoir from Dr Kennedy to the author.
Three months after completing his residency in neurology at the Mayo Clinic in 1964, Dr Kennedy examined a 57-year-old man of French and Native American ancestry from Minnesota who had been having problems with weakness for over 20 years. At that time, Dr. Kennedy had just taken a faculty position at the University of Minnesota where he has remained for his professional career. Other affected family members were identified, and an extensive pedigree developed. Dr Kennedy recalled, "This was an exciting patient! As a resident I had reviewed the entire Mayo Clinic film collection of patients, and every muscle and nerve biopsy taken before 1964, but I had not encountered this disease. I thought I knew how to document this patient. But I had never performed a muscle biopsy, had never photographed a patient, and had never used a motion picture camera."
Two months later, a similar patient, a 68-year-old man from Iowa, was referred for evaluation. Again, the patient's family history was positive, and Dr Kennedy noted that this patient's clinical picture closely resembled that of the previous patient. Evaluation of both families included his loading an electromyograph (EMG) into a car and driving to Iowa. (The present author had a similar experience when evaluating another affected family with Dr Kennedy in northern Minnesota in 1979. Performing clinical evaluations and EMG in the field is challenging work.)
Dr Paul Delwaide, a Belgian neurologist, first used the appellation Kennedy disease in a 1979 paper. [2] In the author's discussions over the years with Dr Kennedy, he tended to downplay the use of eponyms for diseases. When the author recently asked him again about "his disease," he admitted that now, as he grows older, "It feels kind of good."
In 1982, Harding et al reclassified the disease as X-linked bulbospinal neuronopathy to reflect the sensory conduction abnormalities noted in several of their cases. [3] Although the concept of the disease has been broadened, it remains an X-linked disorder with the hallmark of progressive weakness of the limb and bulbar musculature and is more commonly known as spinal and bulbar muscular atrophy (SBMA) . Additional neurologic features include sensory abnormalities, tremor of the upper extremities, and a quivering chin. A number of patients also have various endocrinologic abnormalities, such as diabetes, testicular atrophy, gynecomastia, oligospermia, and erectile dysfunction. [4]
In 1986, Fischbeck et al reported the genetic defect to be at the DXYS1 marker on the proximal long arm of the X chromosome. [5] This was later characterized as an expanded tandem (cytosine-adenine-guanine [CAG]) repeat in the first exon of the androgen receptor gene. [6, 7, 8]
Pathophysiology
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.
Epidemiology
Frequency
United States
The estimated incidence is approximately 1 case in 40,000 men. There is a general impression that Kennedy disease may be under diagnosed, owing in part to misdiagnosis and to the mild symptoms exhibited by some patients. [43, 44]
International
The incidence is unknown, but frequencies similar to those in the United States are anticipated in areas reporting the disease, including Europe, Japan, Australia, and Brazil. Some regions, such as western Finland and Japan, may have a high prevalence. [45, 46]
Mortality/Morbidity
See the list below:
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The disease typically lasts at least 2-3 decades.
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Life expectancy does not appear to be compromised.
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On occasion, patients have aspiration pneumonia.
Sex
KD is a disease of the X chromosome; therefore, only males express the full phenotype. Affected men cannot pass the genetic trait on to their sons, but their daughters have a 100% risk of being carriers. Carrier females have a 50% risk of having sons with the disease gene and a 50% risk of having daughters who are carriers [47] .
A study of 8 heterozygous female patients with proven tandem CAG repeats showed that 50% had subclinical phenotypic expression. [26] Their clinical findings were normal, except for muscle cramps and finger tremors. Laboratory investigations showed abnormalities ranging from chronic reinnervation changes on EMG to abnormal findings on muscle biopsy. Such women are considered manifesting carriers.
Age
See the list below:
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The typical age of onset is 40-60 years.
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The disease may appear as early as the mid-20s.
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Doyu et al reported an 84-year-old man without a family history who had difficulty climbing stairs and muscle cramps in his calves for 10 years. Clinical, endocrinologic, and electrophysiologic results suggested KD. Genetic polymerase chain reaction (PCR) testing for KD revealed CAG repeats but in the low range of abnormality. Expression of the disease in this man was mild. [48] This case emphasizes the importance of testing individuals, even those without a family history, for possible spontaneous mutations when the results of careful clinical evaluation and laboratory testing are compatible with KD.
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Note wasting in the thighs and shoulders. The arms hang down and are rotated internally so that the thumbs point toward the patient (ie, simian posture) rather than forward, as in a healthy individual. This observation strongly suggests weakness in shoulder girdle muscles.
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Prominence of breast tissue consistent with gynecomastia in Kennedy disease.
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The forehead of this patient with Kennedy disease is smooth, in fact, too smooth for a man this age. The smoothness is particularly noticeable when the patient tries to perform upgaze, when wrinkling of the forehead due to contraction of the frontalis is expected.
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Photographs show asymmetry at rest due to facial weakness, which is enhanced when the muscles are activated by pursing the lips.
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Note the scalloping of the borders of the tongue, which strongly suggests wasting. In addition, the marked wasting of the large group of glossal muscles on each side has caused them to separate and form a midline furrow.
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Motor-unit action potentials recorded from the biceps brachii in a patient with Kennedy disease. Upper tracing shows 2 action potentials discharging during low-to-moderate effort. In a healthy person, additional discharges are expected. (Calibration is 1 mV per division on the vertical axis and 10 ms per division on the horizontal axis.) Potential on the left is approximately 1.2 mV and 26 ms. It is moderately increased in amplitude, almost twice the upper limit in duration, and shows marked irregularity or serrations (ie, turns) in the main component. Potential to the right is markedly increased in amplitude (approximately 3.3 mV), and its duration is at least 30 ms but cannot be measured on this tracing because it extends off to the right and qualifies as a giant motor-unit action potential. Bottom tracing shows the same 2 potentials at standard setting used to view motor-unit action potentials (0.1 mV per vertical division), which emphasizes their large size and complexity (ie, increased number of changes in polarity of the waveform).
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Recording of motor-unit action potentials from the pectoralis muscle in a patient with Kennedy disease. Calibration is 1 mV per division on the vertical axis and 10 ms per division on the horizontal axis. The patient's level of effort in activation is high. Therefore, the number of motor unit action potentials clearly is reduced, and the individual potentials observed are enlarged, consistent with a chronic neurogenic process.
Tables
Disease
|
Differentiating Characteristics or Tests
|
ALS |
Upper motor neuron involvement with tendency for distal-greater-than-proximal weakness [58] |
Spinal muscular atrophy |
See Table 2 below |
Fascioscapulohumeral muscular dystrophy |
Autosomal dominant pattern with myopathic findings on muscle biopsy and EMG, positive genetic marker |
Myasthenia gravis - Adult acquired form |
Extraocular muscle frequently involved, EMG consistent with neuromuscular transmission disorder, acetylcholine receptor antibodies frequently positive |
Oculopharyngeal muscular dystrophy |
Autosomal dominant pattern, late onset, predominant involvement of bulbar muscle with ptosis and mild ophthalmoparesis, EMG and muscle biopsy results consistent with myopathic process, positive genetic marker |
Hexosaminidase A deficiency |
Rectal biopsy, enzyme assay |
Sandhoff disease |
Rectal biopsy, enzyme assay |
Syphilis (neurovascular form) |
Positive serology |
Lead neuropathy |
Index of suspicion based on potential exposure; anemia; elevated serum, blood, and urine lead levels |
Motor neuron disease with macroglobulinemia |
Monoclonal gammopathy [59] |
Autosomal dominant cerebellar ataxia type I |
Amyotrophy occasionally prominent finding in SCAs, particularly types II and III; other clinical and laboratory findings suggest condition other than a pure motor-neuron process; appropriate tests of genetic markers for SCA |
Polymyositis |
Elevated serum creatine kinase, EMG and muscle-biopsy results consistent with inflammatory myopathy |
Cervical spondylosis |
Rostral cervical segmental myotomes (eg, C5, C6) commonly affected, but pattern on EMG testing is highly localizing; possible pyramidal-tract signs if spondylosis compresses spinal cord at same segmental level; no evidence of lower motor-neuro involvement in legs; imaging (eg, cervical MRI, myelography with low-dose CT) findings correlated with suspected lesion |
Facial onset sensory and motor neuropathy (FOSMN syndrome) [60, 61] |
Slow progressing, trigeminal-onset sensory loss that may spread to upper limbs and torso, associated with lower motor syndrome with prominent bulbar involvement |
Pattern
|
Characteristics*
|
Bulbar hereditary motor neuropathy affecting lowest 6 cranial nerves (Fazio-Londe disease) |
Autosomal recessive, onset in childhood, limbs not affected; when associated with deafness, pattern called Vialleto-van Laere disease, which may be X-linked or autosomal dominant |
Scapuloperoneal hereditary motor neuropathy |
Variable transmission: dominant, recessive, X-linked; pattern of weakness as described; bulbar muscles spared |
Fascioscapulohumeral hereditary motor neuropathy |
Autosomal dominant, pattern of weakness as described |
Hereditary motor neuronopathy with oculopharyngeal involvement |
Described in Japanese individuals; autosomal recessive or dominant; ophthalmoplegia, dysarthria, and dysphagia |
Hereditary proximal motor neuropathy |
Variable dominant or recessive inheritance; onset usually in first 2 decades; bulbar muscles spared |
Hereditary distal motor neuropathy |
Usually recessive inheritance; onset usually in first 2 decades; bulbar muscles spared; autosomal-dominant distal spinal muscular atrophy linked to chromosome 7 (same locus as that of hereditary sensorimotor neuropathy type 2D) [62] |
*In none of these diseases are results of test for the KD marker positive, and associated endocrinopathy or sensory nerve conduction abnormality should be absent. |
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