Kennedy Disease 

Updated: Sep 29, 2019
Author: David A Shirilla, DO; Chief Editor: Nicholas Lorenzo, MD, CPE, MHCM, FAAPL 

Overview

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:

  • The disease typically lasts at least 2-3 decades.

  • Life expectancy does not appear to be compromised.

  • 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:

  • The typical age of onset is 40-60 years.

  • The disease may appear as early as the mid-20s.

  • 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.

 

Presentation

History

See the list below:

  • A typical constellation of complaints in Kennedy disease (KD) is an insidious onset of easy fatigability, muscle cramps, and weakness in the limbs.

  • As the disease progresses, disability commensurately increases until the patient is wheelchair bound.

  • Involvement of the bulbar musculature may be expressed as difficulty in chewing, swallowing, and speaking. The last often results in a nasal quality of the person's speech because of palatal weakness.

  • Postural tremor and tremor in the upper extremities usually begins late in the course of the illness.

  • Sensory complaints may be present, but they are rarely isolated findings.

  • Patients may have complaints related to endocrinopathy, particularly diabetes. Because the onset of the disease is relatively late, complaints such as infertility or reduced libido may not be appreciated readily. Battaglia et al reported a case in which endocrinopathy was the presenting manifestation of KD.[49]

Physical

Neurologic findings

Cognition is unimpaired.

Examination of the cranial nerves usually shows evidence of weakness in the facial, palatal, and tongue muscles. (See images below.) The weakness may be so profound that the mouth hangs open and is tremulous. In the index case Kennedy et al reported, the facial weakness became so severe that the patient held his chin up with his hands to chew. Jaw drop may be a prominent feature.[50] Although eye movements are typically spared, there has been one case report of abnormal extra-ocular motility in KD.[12]

The forehead of this patient with Kennedy disease 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.
Photographs show asymmetry at rest due to facial w Photographs show asymmetry at rest due to facial weakness, which is enhanced when the muscles are activated by pursing the lips.

Contraction of perioral musculature may elicit twitching movements of the chin (quivering-chin phenomenon). This also may be seen when the patient is at rest, ie, not activating his facial muscles.

The voice changes and may become nasal. The tongue usually shows scalloping (irregularity of the borders) or a deep furrowing in the midline as the bundles of muscle forming the glossal group become wasted and separate at the midline. Laryngospasm may occur.[51] (See image below.)

Note the scalloping of the borders of the tongue, 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.

Although bulbar involvement usually follows limb involvement, it is occasionally the presenting weakness.

Muscle strength may show a classic pattern of proximal-greater-than-distal impairment, beginning in the legs. However, Ferrante and Wilbourn showed variation in distribution of initial weakness ranging from symmetry to asymmetry, from proximal to distal predominant weakness, and from upper extremity to lower extremity.[52]

In mild to moderately severe cases, prominence of bony landmarks should be sought to confirm wasting. If the patient is ambulatory, proximal weakness may cause a hyperlordotic standing posture and internally rotated arms, ie, simian stance, in which the thumbs point medially or toward the patient rather than straight forward (see image below).

Note wasting in the thighs and shoulders. The arms 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.

Fasciculations, or spontaneous discharges of single motor units, are seen easily in affected musculature. The patient should be evaluated at complete rest in a warm environment. In particular, care should be taken not to mistake postural movements in the tongue for fasciculations.

In weak muscles, minimal isometric activation or contraction of muscle may result in large, coarse, and regular movement of a portion of the muscle that superficially may resemble a fasciculation. This is sometimes (and unfortunately) called contraction fasciculation. In normal muscle, isometric activation or contraction of muscle is not associated with what appears to be a coarse and jerking movement.

In patients with chronic denervation-reinnervation in whom motor units are markedly enlarged (ie, a single motor neuron innervates more than twice the number of muscle fibers), these appear as twitches associated with activation.

Although not to be confused with fasciculations per se, these clinical findings are important, as their presence indicates a chronic neurogenic process until proven otherwise.

The quivering-chin phenomenon, when seen with facial muscle activation, may be the result of the activation of the few enlarged motor units.

Muscle stretch responses are variable; they range from normal to depressed and are usually absent in the ankles. Generally, no upper motor neuron dysfunction occurs in KD; however, Pachatz et al show evidence for subclinical involvement using transcranial magnetic stimulation,[53] but this finding was not confirmed in a subsequent study.[14]

Sensation is often clinically normal to the modalities of vibration perception, position sense, sharp touch, and light touch, despite the demonstration of abnormalities in morphology and autonomic testing.[11, 54, 55, 56] If sensation is impaired, it is important to distinguish a pattern that might suggest a diabetic polyneuropathy.

General findings

Gynecomastia is probably the most common nonneurologic finding on examination, but it is not a criterion for diagnosis (see image below).

Prominence of breast tissue consistent with gyneco Prominence of breast tissue consistent with gynecomastia in Kennedy disease.

Testicular atrophy, oligospermia and/or azoospermia, and erectile dysfunction may be present and typically occur in advanced cases.

In a clinical study, Sinclair et al found that men with KD may have a reduced risk of androgenetic alopecia compared with a cohort of white males of European descent without KD.[57]

Causes

Table 1. Primary Differential Diagnoses of Kennedy Disease (Open Table in a new window)

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

Table 2. Patterns of Hereditary Spinal Muscular Atrophies that May Resemble Kennedy Disease (Open Table in a new window)

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.

Other conditions associated with KD include the following:

  • Lipid disorders

    • Type II hyperlipoproteinemia

    • Type IV hyperlipoproteinemia

    • Hypobetalipoproteinemia

  • Endocrinopathy

    • Testicular atrophy

    • Oligospermia or azoospermia secondary to testicular atrophy

    • Gynecomastia

    • Diabetes mellitus

    • Elevated serum estradiol and gonadotropin

    • Pituitary microadenoma rare

 

DDx

Diagnostic Considerations

Other problems to be considered include the following:

  • Autosomal dominant cerebellar ataxia type I

  • Bulbar hereditary motor neuropathy affecting the lowest 6 cranial nerves (Fazio-Londe disease)

  • Cervical spondylosis

  • Cytoplasmic-body myopathy[63]

  • Facial onset sensory and motor neuropathy (FOSNM syndrome)[60, 61]

  • Hereditary proximal motor neuropathy

  • Hereditary distal motor neuropathy

  • Hereditary motor neuronopathy with oculopharyngeal involvement

  • Hexosaminidase A deficiency

  • Lead neuropathy[64]

  • Motor neuron disease with macroglobulinemia[59]

  • Myasthenia gravis - Adult acquired form

  • Oculopharyngeal muscular dystrophy

  • Polymyositis

  • Sandhoff disease[65]

  • Scapuloperoneal hereditary motor neuropathy

  • Syphilis (neurovascular form)

Differential Diagnoses

 

Workup

Laboratory Studies

Depending on level of suspicion, immediate genetic testing for Kennedy disease (KD) may be performed to confirm the diagnosis, obviating other tests, such as EMG and enzyme studies for hexosaminidase deficiency. The availability of genetic testing markedly expedites the evaluation for KD.[66]

Problems may arise in resolving apparent positive results obtained before genetic testing is done. For instance, serum creatine kinase (CK) testing is not indicated, yet the CK level may be elevated substantially. One of the author's patients had been treated for inflammatory myopathy for years before the correct diagnosis was made. In another case, the patient was aggressively treated for myasthenia gravis (including thymectomy) before KD was diagnosed.[67] Sorenson and Klein have also reported elevation in CK and transaminases levels in asymptomatic patients with KD.[68]

Appropriate initial testing and monitoring is indicated because of associated conditions such as diabetes mellitus, lipid disorders, and other endocrine disorders.

If genetic findings are negative in an individual who has clinical findings suggestive of KD, other laboratory investigations may be indicated (see Table 1, Table 2).

Imaging Studies

Patients with KD tend to be middle aged or elderly, and they may have common neurologic conditions, such as spondylosis.

If cervical spondylosis is a consideration, or if marked asymmetry in muscle weakness is noted on follow-up of a patient with KD, imaging of the cervical spine is indicated.

MRI of the brain is indicated if clinical symptoms or endocrinologic testing suggest microadenoma.

Hamano et al reported MRI studies of the leg muscle in patients with KD and amyotrophic lateral sclerosis.[69] In contrast to patients with amyotrophic lateral sclerosis who showed atrophy, patients with KD showed associated high-signal intensity with atrophy consistent with fatty degeneration. This was seen in both proximal as well as distal muscles.

Other Tests

Other tests may not be needed if the results of genetic testing are positive.

Other tests may include electrodiagnostic studies.[70, 55]

  • Somatosensory evoked potentials: The potentials may be abnormal, reflecting dysfunction in the pathways of the posterior column.

  • Nerve conductions: Compound muscle action potentials have normal or reduced amplitude. Sensory conductions show normal, reduced, or absent sensory-nerve action potentials.

Needle-electrode examination may be needed. A full discussion of electrodiagnostic approaches to motor neuropathy is beyond the scope of this article. In a slowly progressive disease such as KD, fibrillation potentials may be relatively infrequent and small in amplitude. Other insertional and spontaneous activities, such as complex repetitive discharges, myokymia, and fasciculation potentials, also vary in prominence. When clinical myokymia is present, spontaneous discharges of grouped motor-unit action potentials (MUAPs) may be recorded. When present in the mentalis muscle they may correspond to the clinical observation of the quivering chin when the patient is at rest.

Needle-electrode examination should reveal a diffuse, chronic neurogenic process based on changes in the MUAPs, such as complexity, increased amplitude and duration, and reduced recruitment rate. Muscles are affected unequally (side-to-side asymmetry, proximal vs distal muscle).

The study should be planned to demonstrate multisegmental involvement of muscles (myotomes) in at least 3 of 4 regions (ie, bulbar, cervical, thoracic, or lumbar), similar to the El Escorial criteria[58] used to support the diagnosis of ALS. In the limbs, 2 muscles supplied by 2 different roots and peripheral nerves should be studied to ascertain the presence of a diffuse chronic neurogenic process. In KD examination of the bulbar region should be emphasized.

Increase in MUAP complexity (eg, increase in phases, turns, or the presence of late components or satellites) is a nonspecific finding and may be seen as an early abnormal finding in neurogenic or myopathic processes.

If the process is established and weakness is present, a reduced number of moderately to markedly enlarged MUAPs may be observed. This finding is expected in a slowly progressive, chronic neurogenic process in which one third to half the motor neurons in a given muscle may be lost before clinical weakness manifests (see images below).

Motor-unit action potentials recorded from the bic 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).
Recording of motor-unit action potentials from the 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.

Meriggioli and Rowin reported a case of KD with increased jitter on single-fiber EMG in a patient with KD who had fatigue with normal muscle strength on clinical evaluation.[71] Routine needle-electrode examination showed evidence of chronic motor axonopathy or neuronopathy. The authors postulated that abnormal neuromuscular transmission was the underlying mechanism of the patient's fatigue.

Fiber-optic endoscopic evaluation or swallow study is recommended for dysphagia as 80% of KD patients have swallowing dysfunction[72]

Tongue pressure is decreased in KD. It has shown to be an early and reliable biomarker of swallowing dysfunction in KD, much before subjective dysphagia symptoms.[73]

Procedures

Given the availability of genetic testing, muscle and nerve biopsy are not indicated for diagnostic work-up in KD.

Histologic Findings

In some instances, nerve and muscle biopsy may have been performed in cases of KD when the diagnosis was not suspect.

  • Sural-nerve biopsy may show loss of large-diameter myelinated axons.[11]

  • In the author's series, muscle biopsy showing marked predominance of type I muscle fibers with variable and diffuse atrophy was present in 2 patients in whom biopsy material was available.[67]

  • Predominance of type II muscle fibers has been described in other cases.

  • In another series, both neurogenic and myopathic changes were reported in muscle biopsies from patients with KD, as well as in female carriers of KD.[74]

  • When such muscle fiber type predominance is present, fiber-type grouping is not easily appreciated.

 

Treatment

Medical Care

No proven, effective treatment of Kennedy disease (KD) is available. However, the androgen-dependent nature of the disease is the rationale for use of anti-androgens, which have been shown to improve some aspects of the disease manifestations in patients.

The following is the summary of the relevant clinical trials performed in this area:

  • In a limited study of 2 patients, empiric therapy with high-dose testosterone failed to show consistent benefit.[75] Nevertheless, some rationale supports the use of testosterone in KD.[41]

  • Leuprorelin acetate is a luteinizing hormone-releasing hormone agonist. A phase 2, randomized, placebo-controlled trial of leuprorelin acetate in 50 patients with spinal and bulbar muscular atrophy for 48 weeks appeared to show some benefit based on cricopharyngeal opening duration (videofluorography) and reduced mutant AR accumulation (scrotal skin biopsy).[76] In an editorial on this trial, Fishbeck and Bryan cautioned on the results with respect to using cricopharyngeal opening duration as a surrogate marker.[77] A 48-week trial may also be too short given the chronicity of the disease.

  • From August 2006-March 2008, the Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was performed as a 48-week, randomized, double-blind trial with 204 patients. The authors concluded that treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, but leuprorelin was well tolerated.[78] While disease duration might influence the efficacy of leuprorelin, more clinical trials with sensitive outcome measures should be done. A 48-week trial may be too short given the chronicity of the disease.

  • In an another randomized, placebo-controlled trial using dutasteride (a 5alpha-reductase inhibitor) to inactivate testosterone no change was seen in the progression of muscle weakness or swallowing dysfunction in patients with Kennedy disease.[79]

  • In a review by Fishbeck, androgen-reducing strategies did not help control symptoms of KD.[80]

Other emerging therapeutic strategies tested in animal models include decreasing expanded polyglutamine androgen receptor expression, increasing degradation of the polyglutamine-expanded protein using heat shock protein 70, leading to misfolding of the mutant protein and elimination via the ubiquitin-proteasome system and autophagy mediated abnormal protein degradation. Improving mitochondrial function and providing trophic support to motor neurons and peripheral tissues using coenzyme Q10, idebenone, and growth factors have also been proposed.[81]

In an open trial using oral beta 2 agonist (clenbuterol), Querin et al found significant improvement in 6-minute walking distance and forced vital capacity at 12 months in 20 patients of KD (Class IV evidence). However, no difference in the Medical Council of Research (MRC) scores was noted preintervention and postintervention. Clenbuterol was well tolerated, except elevation of CK level and hand tremor in 2 subjects. The authors postulated an anaboliceffect of clenbuterol in preventing disease progression and recommended considering a trial with more widely available beta 2 agonist salbutamol in the future.[82]

Overall management of KD is directed at maintaining maximal function in the presence of this slowly progressive disease.

The severity and progression of illness should be monitored. Given the ongoing, slowly progressive weakness, assessing the patient's strength and tolerance to exertion, along with any compromise in activities of daily living or occupation, is important. Such periodic assessments allow for thoughtful, proactive management to minimize the patient's risk for falls, to optimize their mobility, and to provide for appropriate assistive devices as the disability increases.

Certification for disabled parking should be made when appropriate.

Surgical Care

Some patients with marked dysphagia may require a gastrostomy tube. With respect to the other procedures, Okamoto et al (2004) advocate the use of spinal epidural anesthesia in appropriate settings, such as internal urethrotomy.[83]

Consultations

Depending on degree of weakness, input from the physical therapist or physiatrist may be useful in optimizing the patient's abilities. If clinically significant dysphagia occurs, appropriate evaluation of their swallowing (eg, video radiographic swallow study) is indicated. This evaluation may need to be repeated to ascertain the need for and timing of gastrostomy-tube placement.

Diet

No special diet is needed in most cases, unless symptomatic dysphagia occurs.

Activity

The patient's activity level depends on their condition. Aerobic exercise in the form of a formal training program was not found to be of benefit.[84]  A clinical trial using exercise in 50 subjects with KD at the National Institutes of Health for 12 weeks showed no significant difference in muscle function overall, but most low-functioning patients improved.[85]

A trial examining the efficacy of exercise in Kennedy disease found that low-functioning men with KD may respond better to functional exercise rather than stretching. Overall, however, functional exercise had no significant effect on total Adult Myopathy Assessment Tool (AMAT) scores or on mobility, strength, balance, and quality of life.[85]

Findings from a small Japanese study suggested that the head lift exercise may improve swallowing dysfunction, particularly tongue pressure, in patients with Kennedy disease.[86]

 

Follow-up

Complications

A risk for falls is best addressed by assessments by a physical therapist.

If questions or concerns arise regarding the patient's job performance, an evaluation of his or her functional or physical capacity may be appropriate. A physical therapist or staff at a rehabilitation center typically performs this evaluation. Patients are understandably reluctant to surrender their functional independence. However, they must not be a danger to themselves or others while working or performing their activities of daily living.

If the patient's ability to operate a motor vehicle is a concern, this concern should be noted in the chart, and the patient should be advised to seek further evaluation by means of formal assessment at a rehabilitation center or the local Department of Motor Vehicles or its equivalent.

Prognosis

As stated, the life expectancy is not reported to be reduced in Kennedy disease if care has been taken to prevent complications (eg, aspiration, falls).

Patient Education

See the list below:

  • The treating physician must have an ongoing dialogue with the patient to keep him or her informed about the status of the disease.

  • Although patient issues should be addressed as needed, the physician must be proactive and anticipate issues such as potential difficulties with driving and other activities of daily living.

  • The treating physician should maintain a balance between the reality of the patient's disease process and a sense of hope and the patient's ability to cope with the disease.

  • National Organization for Rare Disorders: This association addresses some uncommon or orphan neurologic disorders for which no dedicated organization exists.

  • Kennedy's Disease Association

 

Questions & Answers

Overview

What is Kennedy disease (KD)?

What is the pathophysiology of Kennedy disease (KD)?

What are the mortality and morbidity associated with Kennedy disease (KD)?

Which age groups have the highest prevalence of Kennedy disease (KD)?

What is the US prevalence of Kennedy disease (KD)?

What is the global prevalence of Kennedy disease (KD)?

What are the sexual predilections of Kennedy disease (KD)?

Presentation

Which clinical history findings are characteristic of Kennedy disease (KD)?

Which neurologic findings are characteristic of Kennedy disease (KD)?

Which physical findings are characteristic of Kennedy disease (KD)?

What are the primary differential diagnoses of Kennedy disease (KD)?

Which conditions are associated with Kennedy disease (KD)?

DDX

Which conditions are included in the differential diagnoses of Kennedy disease (KD)?

What are the differential diagnoses for Kennedy Disease?

Workup

What is the role of genetic and lab testing in the workup of Kennedy disease (KD)?

What is the role of imaging studies in the workup of Kennedy disease (KD)?

What is the role of EMG in the workup of Kennedy disease (KD)?

What is the role of biopsy in the workup of Kennedy disease (KD)?

Which histologic findings are characteristic of Kennedy disease (KD)?

Treatment

How is Kennedy disease (KD) treated?

What is the role of surgery in the treatment of Kennedy disease (KD)?

Which specialist consultations are beneficial to patients with Kennedy disease (KD)?

Which dietary modifications are used in the treatment of Kennedy disease (KD)?

Which activity modifications are used in the treatment of Kennedy disease (KD)?

Follow-up

What are the possible complications of Kennedy disease (KD)?

What is the prognosis of Kennedy disease (KD)?

What is included in patient education about Kennedy disease (KD)?