Kennedy Disease

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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:

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:

History

See the list below:

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]



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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 th....



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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.

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.)



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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 muscl....

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).



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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 postur....

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).



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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



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See Table

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



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See Table

Other conditions associated with KD include the following:

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]

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).



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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 d....



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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 vertic....

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.

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:

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]

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:

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

Author

David A Shirilla, DO, Neuromuscular Medicine Fellow, University of Kansas Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Paul E Barkhaus, MD, FAAN, FAANEM, Professor of Neurology and Physical Medicine and Rehabilitation, Chief, Neuromuscular and Autonomic Disorders Program, Director, ALS Program, Department of Neurology, Medical College of Wisconsin

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Neil A Busis, MD, Chief of Neurology and Director of Neurodiagnostic Laboratory, UPMC Shadyside; Clinical Professor of Neurology and Director of Community Neurology, Department of Neurology, University of Pittsburgh Physicians

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Academy of Neurology<br/>Serve(d) as a speaker or a member of a speakers bureau for: American Academy of Neurology<br/>Received income in an amount equal to or greater than $250 from: American Academy of Neurology.

Chief Editor

Nicholas Lorenzo, MD, MHA, CPE, Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc; Chief Strategy Officer, Discourse LLC

Disclosure: Nothing to disclose.

Additional Contributors

Rodrigo O Kuljis, MD, Esther Lichtenstein Professor of Psychiatry and Neurology, Director, Division of Cognitive and Behavioral Neurology, Department of Neurology, University of Miami School of Medicine

Disclosure: Nothing to disclose.

Sumit Verma, MD, Assistant Professor of Pediatrics, Assistant Professor of Neurology, Emory University School of Medicine; Pediatric Neurologist, Medical Director, Neuromuscular Program, Director, EMG Laboratory, Director, MDA Clinic Care Center, Children’s Healthcare of Atlanta

Disclosure: Nothing to disclose.

Acknowledgements

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.

References

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  45. 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. 1998 Aug. 98(2):128-33. [View Abstract]
  46. Tanaka F, Doyu M, Ito Y, et al. Founder effect in spinal and bulbar muscular atrophy (SBMA). Hum Mol Genet. 1996 Sep. 5(9):1253-7. [View Abstract]
  47. Dobyns WB, Filauro A, Tomson BA, et al. Inheritence of Most X-linked traits Is Not Dominant or Recessive, Just X-linked. Am J Med Gen. 2004. 129:136-143.
  48. 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. 1993 Jul. 56(7):832-3. [View Abstract]
  49. Battaglia F, Le Galudec V, Cossee M, Tranchant C, Warter JM, Echaniz-Laguna A. Kennedy's Disease Initially Manifesting as an Endocrine Disorder. J Clin Neuromuscul Dis. 2003 Jun. 4(4):165-167. [View Abstract]
  50. Sumner CJ, Fischbeck KH. Jaw drop in Kennedy's disease. Neurology. 2002 Nov 12. 59(9):1471-2. [View Abstract]
  51. Sperfeld AD, Hanemann CO, Ludolph AC, Kassubek J. Laryngospasm: an underdiagnosed symptom of X-linked spinobulbar muscular atrophy. Neurology. 2005 Feb 22. 64(4):753-4. [View Abstract]
  52. Ferrante MA, Wilbourn AJ. The characteristic electrodiagnostic features of Kennedy's disease. Muscle Nerve. 1997 Mar. 20(3):323-9. [View Abstract]
  53. 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. 2007 Feb. 118(2):262-8. [View Abstract]
  54. Antonini G, Gragnani F, Romaniello A, Pennisi EM, Morino S, Ceschin V. Sensory involvement in spinal-bulbar muscular atrophy (Kennedy's disease). Muscle Nerve. 2000 Feb. 23(2):252-8. [View Abstract]
  55. 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. 1996 May. 243(5):388-92. [View Abstract]
  56. Manganelli F, Iodice V, Provitera V, Pisciotta C, Nolano M, Perretti A. Small-fiber involvement in spinobulbar muscular atrophy (Kennedy's disease). Muscle Nerve. 2007 Dec. 36(6):816-20. [View Abstract]
  57. 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. 2007 Aug. 157(2):290-4. [View Abstract]
  58. 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. 1994 Jul. 124 Suppl:96-107. [View Abstract]
  59. Bauer M, Bergstrom R, Ritter B, et al. Macroglobulinemia Waldenstrom and motor neuron syndrome. Acta neurol Scand. 1977. 55:245-250.
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  61. Vucic S, Tian D, Chong PS, Cudkowicz ME, Hedley-Whyte ET, Cros D. Facial onset sensory and motor neuronopathy (FOSMN syndrome): a novel syndrome in neurology. Brain. 2006 Dec. 129:3384-90. [View Abstract]
  62. 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.
  63. Krishnan AV, Pamphlett R, Burke D, et al. Cytoplasmic body myopathy masquerading as motor neuron disease. Muscle Nerve. 2004 Nov. 30(5):667-72. [View Abstract]
  64. Albers JW, Bromberg MB. X-linked bulbospinomuscular atrophy (Kennedy's disease) masquerading as lead neuropathy. Muscle Nerve. 1994 Apr. 17(4):419-23. [View Abstract]
  65. Thomas PK, Young E, King RH. Sandhoff disease mimicking adult-onset bulbospinal neuronopathy. J Neurol Neurosurg Psychiatry. 1989 Sep. 52(9):1103-6. [View Abstract]
  66. Wang Z, Thibodeau SN. A polymerase chain reaction-based test for spinal and bulbar muscular atrophy. Mayo Clin Proc. 1996 Apr. 71(4):397-8. [View Abstract]
  67. 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. 1982 Feb. 39(2):112-6. [View Abstract]
  68. Sorenson EJ, Klein CJ. Elevated creatine kinase and transaminases in asymptomatic SBMA. Amyotroph Lateral Scler. 2007 Feb. 8(1):62-4. [View Abstract]
  69. 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. 2004 Jul 15. 222(1-2):93-7. [View Abstract]
  70. Olney RK, Aminoff MJ, So YT. Clinical and electrodiagnostic features of X-linked recessive bulbospinal neuronopathy. Neurology. 1991 Jun. 41(6):823-8. [View Abstract]
  71. Meriggioli MN, Rowin J. Fatigue and abnormal neuromuscular transmission in Kennedy's disease. Muscle Nerve. 2003 Feb. 27(2):249-51. [View Abstract]
  72. Warnecke T, Oelenberg S, Teismann I, Suntrup S, Hamacher C, Young P. Dysphagia in X-linked bulbospinal muscular atrophy (Kennedy disease). Neuromuscul Disord. 2009 Oct. 19(10):704-8. [View Abstract]
  73. Mano T, Katsuno M, Banno H, Suzuki K, Suga N, Hashizume A, et al. Tongue pressure as a novel biomarker of spinal and bulbar muscular atrophy. Neurology. 2014 Jan 21. 82 (3):255-62. [View Abstract]
  74. Sorarù G, D'Ascenzo C, Polo A, Palmieri A, Baggio L, Vergani L, et al. Spinal and bulbar muscular atrophy: skeletal muscle pathology in male patients and heterozygous females. J Neurol Sci. 2008 Jan 15. 264(1-2):100-5. [View Abstract]
  75. Goldenberg JN, Bradley WG. Testosterone therapy and the pathogenesis of Kennedy's disease (X-linked bulbospinal muscular atrophy). J Neurol Sci. 1996 Feb. 135(2):158-61. [View Abstract]
  76. Banno H, Katsuno M, Suzuki K, Takeuchi Y, Kawashima M, Suga N, et al. Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. Ann Neurol. 2009 Feb. 65(2):140-50. [View Abstract]
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  79. Fernández-Rhodes LE, Kokkinis AD, White MJ, Watts CA, Auh S, Jeffries NO. Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial. Lancet Neurol. 2011 Feb. 10(2):140-7. [View Abstract]
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  87. Sumner C, Fishbeck KH. Kennedy's disease. Shaw PJ, Strong MJ, eds. Motor Neuron Disorders. Philadelphia, PA: Butterworth-Heineman; 2003. 425-34.

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 weakness, which is enhanced when the muscles are activated by pursing the lips.

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.

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.

Prominence of breast tissue consistent with gynecomastia in Kennedy disease.

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 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.

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.

Prominence of breast tissue consistent with gynecomastia in 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 weakness, which is enhanced when the muscles are activated by pursing the lips.

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.

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 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.

Disease



 



Differentiating Characteristics or Tests



 



ALSUpper motor neuron involvement with tendency for distal-greater-than-proximal weakness[58]
Spinal muscular atrophySee Table 2 below
Fascioscapulohumeral muscular dystrophyAutosomal dominant pattern with myopathic findings on muscle biopsy and EMG, positive genetic marker
Myasthenia gravis - Adult acquired formExtraocular muscle frequently involved, EMG consistent with neuromuscular transmission disorder, acetylcholine receptor antibodies frequently positive
Oculopharyngeal muscular dystrophyAutosomal 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 deficiencyRectal biopsy, enzyme assay
Sandhoff diseaseRectal biopsy, enzyme assay
Syphilis (neurovascular form)Positive serology
Lead neuropathyIndex of suspicion based on potential exposure; anemia; elevated serum, blood, and urine lead levels
Motor neuron disease with macroglobulinemiaMonoclonal gammopathy[59]
Autosomal dominant cerebellar ataxia type IAmyotrophy 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
PolymyositisElevated serum creatine kinase, EMG and muscle-biopsy results consistent with inflammatory myopathy
Cervical spondylosisRostral 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 neuropathyVariable transmission: dominant, recessive, X-linked; pattern of weakness as described; bulbar muscles spared
Fascioscapulohumeral hereditary motor neuropathyAutosomal dominant, pattern of weakness as described
Hereditary motor neuronopathy with oculopharyngeal involvementDescribed in Japanese individuals; autosomal recessive or dominant; ophthalmoplegia, dysarthria, and dysphagia
Hereditary proximal motor neuropathyVariable dominant or recessive inheritance; onset usually in first 2 decades; bulbar muscles spared
Hereditary distal motor neuropathyUsually 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.