AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Kennedy disease (KD) is named after the author, William R. Kennedy, MD, who first 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 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. 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. 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.² 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. 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.

In 1986, Fishbeck et al reported the genetic defect to be at the DXYS1 marker on the proximal long arm of the X chromosome.³ This was later characterized as an expanded tandem (cytosine-adenine-guanine [CAG]) repeat in the first exon of the androgen receptor gene.⁴

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. Loss of small motor neurons is not a typical finding in acquired 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.⁴⁷

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.⁴⁶ Similar features have been reproduced in transgenic mice and neuronal cell culture. Walcott and Merry further studied these nuclear inclusions.⁵⁵ 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.⁵ 

Although KD typically affects men, women can be symptomatic.^{6, 7} Greenland et al reported a heterozygous female carrier of KD who had one allele containing an expanded number of CAG repeats (44) 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.⁷

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.⁸ Sinnreich et al found some correlation between the number of repeats and the age of onset, but other yet-to-be determined factors are likely influential.⁹ Other investigators have also reviewed CAG repeats in KD.^{10, 11}

A number of molecular pathophysiologic studies of the androgen receptor have been conducted to clarify its role in the pathogenies of KD.^{12, 13, 14, 15, 16, 17, 18, 19} 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).²⁰ High circulating levels of androgens in men might precipitate the motor neuron degeneration observed in KD.²¹

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 toxic-gain-of-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.

Frequency

United States

The estimated incidence is approximately 1 case in 40,000 men.

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.^{22, 23}

Mortality/Morbidity

• The disease typically lasts at least 2-3 decades.
• Life expectancy does not appear to be compromised.
• On occasion, patients have aspiration pneumonia.

Race

No racial predilection is known.

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 50% 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.
• A study of 8 heterozygous female patients with proven tandem CAG repeats showed that 50% had subclinical phenotypic expression.⁶ 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

• The typical age of onset is 40-60 years.
• The disease may appear as early as the mid-20s.
• Doyu et al²⁴ 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. 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.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

• 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. 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.²⁵

Physical

• Neurologic findings
• • Cognition is unimpaired.
  • Examination of the cranial nerves usually shows evidence of weakness in the facial, palatal, and tongue muscles. 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 (see Media files 1-4). Jaw drop may be a prominent feature.²⁶
  • 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 (see Media file 5). Laryngospasm may occur.²⁷
  • 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.²⁸
  • 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 Media file 1).
  • 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 related to this.
  • 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.²⁹
  • Sensation is often normal to the modalities of vibration perception, position sense, sharp touch, and light touch. When sensation is impaired, distinguishing a pattern that might suggest a diabetic polyneuropathy is important.
• General findings
• • Gynecomastia is probably the most common nonneurologic finding on examination, but it is not a criterion for diagnosis (see Media file 2).
  • 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.³⁰

Causes

• Other diagnostic considerations

  Table 1. Primary Differential Diagnoses

  Disease	Differentiating Characteristics or Tests
  ALS	Upper motor neuron involvement with tendency for distal-greater-than-proximal weakness
  Spinal muscular atrophy	See Table 2
  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
  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

  Table 2. Patterns of Hereditary Spinal Muscular Atrophies that May Resemble KD

  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)31

  *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 associated conditions with KD
• • 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

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Autosomal dominant cerebellar ataxia type I
Bulbar hereditary motor neuropathy affecting the lowest 6 cranial nerves (Fazio-Londe disease)
Cervical spondylosis
Cytoplasmic-body myopathy³²
Hereditary proximal motor neuropathy
Hereditary distal motor neuropathy
Hereditary motor neuronopathy with oculopharyngeal involvement
Hexosaminidase A deficiency
Lead neuropathy
Motor neuron disease with macroglobulinemia
Myasthenia gravis - Adult acquired form
Oculopharyngeal muscular dystrophy
Polymyositis
Sandhoff disease
Scapuloperoneal hereditary motor neuropathy
Syphilis (neurovascular form)

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Depending on level of suspicion, immediate genetic testing for 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 Kennedy disease (KD).
• 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. Sorenson and Klein have also reported elevation in CK and transaminases levels in asymptomatic patients with KD.³³
• 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.³⁴ 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.
• • 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. Other insertional and spontaneous activities, such as complex repetitive discharges, myokymia, and fasciculation potentials, also vary in prominence. When myokymia is present, spontaneous discharges of grouped motor-unit action potentials (MUAPs) may be seen and sometimes 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 criteria³⁵ used to support the diagnosis of ALS. In the limbs, 3 muscles supplied by 3 roots and peripheral nerves should be studied to ascertain the presence of a diffuse chronic neurogenic process. In KD, 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 Media files 6-7).
  • 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.³⁶ 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.

Procedures

• Nerve biopsy is not indicated for the diagnosis of KD. In KD, sural-nerve biopsy shows loss of large-diameter myelinated axons.
• Muscle biopsy is not necessary in KD, particularly if the EMG shows evidence of a chronic neurogenic process, which may increase the suspicion for KD.
• In some cases, muscle biopsy may have been performed before KD was considered.
• In the author's series, marked predominance of type I muscle fibers with variable and diffuse atrophy was present in 2 patients in whom biopsy material was available.
• Predominance of type II muscle fibers has been described in other cases.
• When such predominance is present, fiber-type grouping is not easily appreciated.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

• No proven, effective treatment of KD is available.
• • In a limited study of 2 patients, empiric therapy with high-dose testosterone failed to show consistent benefit.³⁷
  • Nevertheless, some rationale supports the use of testosterone in KD.²¹
  • One potential consideration in a treatment trial is the duration, given the chronicity of this disease.
• 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.
• • Despite what appears to be 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.
  • The results of such assessment allows for thoughtful, proactive management to minimize the patient's risk for falls, to optimize his or her 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. Okamoto et al (2004) advocate the use of spinal epidural anesthesia in appropriate settings, such as internal urethrotomy.³⁸

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 his or her 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 his or her condition.

FOLLOW-UP

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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

Patient Education

• 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

MISCELLANEOUS

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• In the author's experience, misdiagnosis or underdiagnosis of KD is common.
• • KD is most frequently misdiagnosed as amyotrophic lateral sclerosis (ALS).
  • If appropriate genetic testing is performed, KD should not be misdiagnosed. However, testing is not routinely performed, it is expensive, and Medicare does not pay for such testing. Therefore, KD tests may not be the first-line diagnostic tool in many cases, particularly sporadic ones.
• The physician must have a high index of suspicion in any male patient with a chronic neurogenic process in the appropriate distribution in association with positive family history or endocrinopathy.
• Male patients with previous diagnosis of diseases such as ALS or sporadic spinal muscular atrophy and/or motor neuron disease, and whose findings do not conform to the expected clinical findings or clinical course of those diseases should be reassessed for KD.

ACKNOWLEDGMENTS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

The author acknowledges support in part from the Department of Veterans Affairs.

Disclaimer: This article does not necessarily reflect the views of the Department of Veterans Affairs or the United States Government.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  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 (copyright Paul E. Barkhaus, MD, 2000, with permission).
	View Full Size Image
Media type:  Photo

Media file 2:  Prominence of breast tissue consistent with gynecomastia in Kennedy disease (copyright Paul E. Barkhaus, MD, 2000, with permission).
	View Full Size Image
Media type:  Photo

Media file 3:  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 (copyright Paul E. Barkhaus, MD, 2000, with permission).
	View Full Size Image
Media type:  Photo

Media file 4:  Photographs show asymmetry at rest due to facial weakness, which is enhanced when the muscles are activated by pursing the lips (copyright Paul E. Barkhaus, MD, 2000, with permission).
	View Full Size Image
Media type:  Photo

Media file 5:  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 (copyright Paul E. Barkhaus, MD, 2000, with permission).
	View Full Size Image
Media type:  Photo

Media file 6:  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) (copyright Paul E. Barkhaus, MD, 2000, with permission).
	View Full Size Image
Media type:  Graph

Media file 7:  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 (copyright Paul E. Barkhaus, MD, 2000, with permission).
	View Full Size Image
Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

1. Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology. Jul 1968;18(7):671-80. [Medline].
2. Harding AE, Thomas PK, Baraitser M, et al. X-linked recessive bulbospinal neuronopathy: a report of ten cases. J Neurol Neurosurg Psychiatry. Nov 1982;45(11):1012-9. [Medline].
3. Fischbeck KH, Ionasescu V, Ritter AW, et al. Localization of the gene for X-linked spinal muscular atrophy. Neurology. Dec 1986;36(12):1595-8. [Medline].
4. La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. Jul 4 1991;352(6330):77-9. [Medline].
5. Echaniz-Laguna A, Rousso E, Anheim M, Cossée M, Tranchant C. A family with early-onset and rapidly progressive X-linked spinal and bulbar muscular atrophy. Neurology. Apr 26 2005;64(8):1458-60. [Medline].
6. Sobue G, Doyu M, Kachi T, et al. Subclinical phenotypic expressions in heterozygous females of X-linked recessive bulbospinal neuronopathy. J Neurol Sci. Jul 1993;117(1-2):74-8. [Medline].
7. Greenland KJ, Beilin J, Castro J, Varghese PN, Zajac JD. Polymorphic CAG repeat length in the androgen receptor gene and association with neurodegeneration in a heterozygous female carrier of Kennedy's disease. J Neurol. Jan 2004;251(1):35-41. [Medline].
8. Amato AA, Prior TW, Barohn RJ, Snyder P, Papp A, Mendell JR. Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology. Apr 1993;43(4):791-4. [Medline].
9. Sinnreich M, Sorenson EJ, Klein CJ. Neurologic course, endocrine dysfunction and triplet repeat size in spinal bulbar muscular atrophy. Can J Neurol Sci. Aug 2004;31(3):378-82. [Medline].
10. Dejager S, Bry-Gauillard H, Bruckert E, Eymard B, Salachas F, LeGuern E. A comprehensive endocrine description of Kennedy's disease revealing androgen insensitivity linked to CAG repeat length. J Clin Endocrinol Metab. Aug 2002;87(8):3893-901. [Medline].
11. Van Golde R, Van Houwelingen K, Kiemeney L, et al. Is increased CAG repeat length in the androgen receptor gene a risk factor for male subfertility?. J Urol. Feb 2002;167(2 Pt 1):621-3. [Medline].
12. Brinkmann AO. Molecular basis of androgen insensitivity. Mol Cell Endocrinol. Jun 20 2001;179(1-2):105-9. [Medline].
13. Lieberman AP, Harmison G, Strand AD, et al. Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor. Hum Mol Genet. Aug 15 2002;11(17):1967-76. [Medline].
14. LaFevre-Bernt MA, Ellerby LM. Kennedy's disease. Phosphorylation of the polyglutamine-expanded form of androgen receptor regulates its cleavage by caspase-3 and enhances cell death. J Biol Chem. Sep 12 2003;278(37):34918-24. [Medline].
15. Lee DK, Chang C. Endocrine mechanisms of disease: Expression and degradation of androgen receptor: mechanism and clinical implication. J Clin Endocrinol Metab. Sep 2003;88(9):4043-54. [Medline].
16. Matsumoto T, Takeyama K, Sato T, Kato S. Androgen receptor functions from reverse genetic models. J Steroid Biochem Mol Biol. Jun 2003;85(2-5):95-9. [Medline].
17. Cullen DA, Killick R, Leigh PN, Gallo JM. The effect of polyglutamine expansion in the human androgen receptor on its ability to suppress beta-catenin-Tcf/Lef dependent transcription. Neurosci Lett. Jan 2 2004;354(1):54-8. [Medline].
18. Kato S, Matsumoto T, Kawano H, et al. Function of androgen receptor in gene regulations. J Steroid Biochem Mol Biol. May 2004;89-90(1-5):627-33. [Medline].
19. Thomas M, Dadgar N, Aphale A, et al. Androgen receptor acetylation site mutations cause trafficking defects, misfolding, and aggregation similar to expanded glutamine tracts. J Biol Chem. Feb 27 2004;279(9):8389-95. [Medline].
20. Ellerby LM, Hackam AS, Propp SS, Ellerby HM, Rabizadeh S, Cashman NR. Kennedy's disease: caspase cleavage of the androgen receptor is a crucial event in cytotoxicity. J Neurochem. Jan 1999;72(1):185-95. [Medline].
21. Greenland KJ, Zajac JD. Kennedy's disease: pathogenesis and clinical approaches. Intern Med J. May 2004;34(5):279-86. [Medline].
22. Udd B, Juvonen V, Hakamies L, Nieminen A, Wallgren-Pettersson C, Cederquist K. High prevalence of Kennedy's disease in Western Finland -- is the syndrome underdiagnosed?. Acta Neurol Scand. Aug 1998;98(2):128-33. [Medline].
23. Tanaka F, Doyu M, Ito Y, et al. Founder effect in spinal and bulbar muscular atrophy (SBMA). Hum Mol Genet. Sep 1996;5(9):1253-7. [Medline].
24. Doyu M, Sobue G, Mitsuma T, et al. Very late onset X-linked recessive bulbospinal neuronopathy: mild clinical features and a mild increase in the size of tandem CAG repeat in androgen receptor gene. J Neurol Neurosurg Psychiatry. Jul 1993;56(7):832-3. [Medline].
25. Battaglia F, Le Galudec V, Cossee M, et al. Kennedy's disease initially manifesting as an endocrine disorder. J Clin Neuromuscul Dis. Jun 2003;4(4):165-7. [Full Text].
26. Sumner CJ, Fischbeck KH. Jaw drop in Kennedy's disease. Neurology. Nov 12 2002;59(9):1471-2. [Medline].
27. Sperfeld AD, Hanemann CO, Ludolph AC, Kassubek J. Laryngospasm: an underdiagnosed symptom of X-linked spinobulbar muscular atrophy. Neurology. Feb 22 2005;64(4):753-4. [Medline].
28. Ferrante MA, Wilbourn AJ. The characteristic electrodiagnostic features of Kennedy's disease. Muscle Nerve. Mar 1997;20(3):323-9. [Medline].
29. Pachatz C, Terracciano C, Desiato MT, Orlacchio A, Mori F, Rocchi C. Upper motor neuron involvement in X-linked recessive bulbospinal muscular atrophy. Clin Neurophysiol. Feb 2007;118(2):262-8. [Medline].
30. Sinclair R, Greenland KJ, Egmond S, Hoedemaker C, Chapman A, Zajac JD. Men with Kennedy disease have a reduced risk of androgenetic alopecia. Br J Dermatol. Aug 2007;157(2):290-4. [Medline].
31. Trentin A, Scola R, Teive H, et al. Kennedy's disease phenotype with positive genetic study for Kugelberg-Welander's disease: case report. Muscle Nerve. 2003;(Suppl 12):S55.
32. Krishnan AV, Pamphlett R, Burke D, et al. Cytoplasmic body myopathy masquerading as motor neuron disease. Muscle Nerve. Nov 2004;30(5):667-72. [Medline].
33. Sorenson EJ, Klein CJ. Elevated creatine kinase and transaminases in asymptomatic SBMA. Amyotroph Lateral Scler. Feb 2007;8(1):62-4. [Medline].
34. Hamano T, Mutoh T, Hirayama M, Kawamura Y, Nagata M, Fujiyama J. Muscle MRI findings of X-linked spinal and bulbar muscular atrophy. J Neurol Sci. Jul 15 2004;222(1-2):93-7. [Medline].
35. Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial "Clinical limits of amyotrophic lateral sclerosis" workshop contributors. J Neurol Sci. Jul 1994;124 Suppl:96-107. [Medline].
36. Meriggioli MN, Rowin J. Fatigue and abnormal neuromuscular transmission in Kennedy's disease. Muscle Nerve. Feb 2003;27(2):249-51. [Medline].
37. Goldenberg JN, Bradley WG. Testosterone therapy and the pathogenesis of Kennedy's disease (X-linked bulbospinal muscular atrophy). J Neurol Sci. Feb 1996;135(2):158-61. [Medline].
38. Okamoto E, Nitahara K, Yasumoto M, Higa K. Use of epidural anaesthesia for surgery in a patient with Kennedy's disease. Br J Anaesth. Mar 2004;92(3):432-3. [Medline].
39. Albers JW, Bromberg MB. X-linked bulbospinomuscular atrophy (Kennedy's disease) masquerading as lead neuropathy. Muscle Nerve. Apr 1994;17(4):419-23. [Medline].
40. Antonini G, Gragnani F, Romaniello A, Pennisi EM, Morino S, Ceschin V. Sensory involvement in spinal-bulbar muscular atrophy (Kennedy's disease). Muscle Nerve. Feb 2000;23(2):252-8. [Medline].
41. Arbizu T, Santamaria J, Gomez JM, et al. A family with adult spinal and bulbar muscular atrophy, X-linked inheritance and associated testicular failure. J Neurol Sci. Jun 1983;59(3):371-82. [Medline].
42. Barkhaus PE, Kennedy WR, Stern LZ, Harrington RB. Hereditary proximal spinal and bulbar motor neuron disease of late onset. A report of six cases. Arch Neurol. Feb 1982;39(2):112-6. [Medline].
43. Cooper DN, Krawczak M, Antonarakis SE. The nature and mechanisms of human gene mutation. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. 7^th ed. New York, NY: McGraw-Hill; 1995:281.
44. Doyu M, Sobue G, Mukai E, et al. Severity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG repeat in androgen receptor gene. Ann Neurol. Nov 1992;32(5):707-10. [Medline].
45. La Spada AR. Spinal and bulbar muscular atrophy. Gene Reviews. Gene Tests. Available at http://www.geneclinics.org. Accessed October 19, 2000.
46. Li M, Miwa S, Kobayashi Y, et al. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol. Aug 1998;44(2):249-54. [Medline].
47. Li M, Sobue G, Doyu M, et al. Primary sensory neurons in X-linked recessive bulbospinal neuropathy: histopathology and androgen receptor gene expression. Muscle Nerve. Mar 1995;18(3):301-8. [Medline].
48. Olney RK, Aminoff MJ, So YT. Clinical and electrodiagnostic features of X-linked recessive bulbospinal neuronopathy. Neurology. Jun 1991;41(6):823-8. [Medline].
49. Polo A, Teatini F, D'Anna S, Manganotti P, Salviati A, Dallapiccola B. Sensory involvement in X-linked spino-bulbar muscular atrophy (Kennedy's syndrome): an electrophysiological study. J Neurol. May 1996;243(5):388-92. [Medline].
50. Schoenen J, Delwaide PJ, Legros JJ, Franchimont P. Hereditary motor neuron disease: the proximal, adult, sex-linked form (or Kennedy disease): clinical and neuroendocrinologic observations in French]. J Neurol Sci. May 1979;41(3):343-57. [Medline].
51. Sobue G, Hashizume Y, Mukai E, et al. X-linked recessive bulbospinal neuronopathy. A clinicopathological study. Brain. Feb 1989;112 ( Pt 1):209-32. [Medline].
52. Sumner C, Fishbeck KH. Kennedy's disease. In: Shaw PJ, Strong MJ, eds. Motor Neuron Disorders. Philadelphia, PA: Butterworth-Heineman; 2003:425-34.
53. Terao S, Sobue G, Hashizume Y, et al. Disease-specific patterns of neuronal loss in the spinal ventral horn in amyotrophic lateral sclerosis, multiple system atrophy and X-linked recessive bulbospinal neuronopathy, with special reference to the loss of small neurons in the intermediate zone. J Neurol. Feb 1994;241(4):196-203. [Medline].
54. Thomas PK, Young E, King RH. Sandhoff disease mimicking adult-onset bulbospinal neuronopathy. J Neurol Neurosurg Psychiatry. Sep 1989;52(9):1103-6. [Medline].
55. Walcott JL, Merry DE. Ligand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy. J Biol Chem. Dec 27 2002;277(52):50855-9. [Medline].
56. Wang Z, Thibodeau SN. A polymerase chain reaction-based test for spinal and bulbar muscular atrophy. Mayo Clin Proc. Apr 1996;71(4):397-8. [Medline].

Article Last Updated: Jan 24, 2008