Kennedy disease …

Robert W Pratt MD

Peripheral Neuropathies

Updated 12.24.2023
Released 01.15.2005
Expires For CME 12.24.2026

Kennedy disease

Author: Robert W Pratt MD

See Contributor Disclosures

Editor: Louis H Weimer MD

Kennedy disease

In This Article

Quick Link

Introduction

Overview

Kennedy disease is a rare, X-linked inherited, neurodegenerative disorder characterized by a progressive weakness of the proximal limbs and bulbar muscles, muscle atrophy, fasciculations (especially perioral), loss of reflexes, tremor, gynecomastia, and diabetes mellitus. It results from an excessive number of trinucleotide (CAG) repeats in the androgen receptor gene on the X chromosome. Due to its X-linked genetic association, males are predominantly affected. Particular clinical features and genetic testing can help distinguish Kennedy disease from amyotrophic lateral sclerosis. Patients with Kennedy disease generally live a normal lifespan, despite the fact there are no treatments currently available to halt the slow progression of the disorder. In this updated article, the author summarizes the latest research on Kennedy disease, with particular emphasis on insights into its natural history, pathophysiological mechanisms, and potential therapeutic strategies.

Key points

	• Kennedy disease is a rare, X-linked inherited, neurodegenerative disorder characterized by proximal limb and bulbar weakness, muscle atrophy, fasciculations (especially perioral), loss of reflexes, tremor, gynecomastia, and diabetes mellitus.
	• Kennedy disease results from an excessive number of trinucleotide (CAG) repeats in the androgen receptor gene on the X chromosome.
	• Due to its X-linked genetic association, males are predominantly affected.
	• Particular clinical features and genetic testing can help distinguish Kennedy disease from amyotrophic lateral sclerosis.
	• Patients with Kennedy disease often live a normal life span, although no treatments are currently available to halt the slow progression of the disorder.

Historical note and terminology

Although Kennedy disease bears the name of William R Kennedy, the first reports of this disease were likely published by LT Kurland, who described an atypical form of lower motor neuron disease in a Japanese family (46). Following the reports by Kurland, Magee provided additional descriptions of patients with X-linked spinobulbar muscular atrophy in the absence of corticospinal tract involvement (61). In 1968, Kennedy reported his experience with two large families at the Mayo Clinic in Rochester, Minnesota (40). The designation “Kennedy disease” was first introduced into the French literature in 1979 (81). The disease garnered particular interest as the first example of a polyglutamine-repeat disorder, of which there are now several other neurologic examples, including Huntington disease and several of the spinocerebellar ataxias.

Clinical manifestations

Presentation and course

The core clinical features of Kennedy disease are proximal limb and bulbar weakness, muscle atrophy, fasciculations (particularly perioral), gynecomastia, loss of reflexes, tremor, and X-linked recessive inheritance. Additional clinical features may include sensory nerve abnormalities, type 2 diabetes, infertility, and other manifestations of androgen dysfunction. These features are variably expressed in individuals of the same family and similar repeat sizes. Family history may be lacking in as many as 26% to 60% of patients (88).

Kennedy disease begins insidiously and progresses slowly. Patients typically report disease onset in their third to fifth decade of life, although subtle clinical manifestations can be missed until obvious symptoms, like weakness, develop. In a series of 57 Kennedy disease patients, the most common presenting symptoms reported were cramps (32%), followed by tremor and leg weakness (23% each) (79). In a different study of 34 patients with Kennedy disease, initial onset of symptoms was demonstrated to occur in adolescence with the presence of gynecomastia (52%), premature muscle fatigue, and muscle cramps (88). Weakness was not a common initial symptom. A third study of 157 patients noted the most common presenting symptom, hand tremor, had a median age of onset of 35 years (12). Gynecomastia, orofacial fasciculations, cramps, and fatigability were the other most common symptoms. Dysphagia and paresthesias were characteristic during late stages of the disease. The median age at which patients started using a cane for walking was 62. Lifespan in Kennedy disease is generally normal; in a retrospective study, long-term survival for patients with Kennedy disease did not differ significantly from that of age-matched control subjects (08). However, optimal supportive care to prevent complications, such as falls or aspiration pneumonia, is required.

Motor symptoms are a prominent feature of Kennedy disease. The symptoms range from nonspecific muscle cramps and early muscle fatigue to obvious muscle atrophy and fasciculations. The majority of patients develop proximal lower extremity weakness first (44%) followed by a slow proximal-to-distal pattern of progression involving both lower and upper limbs. Motor symptoms can be asymmetric in as many as 21% to 30% of patients (83). In most cases, limb weakness is followed by bulbar involvement, leading to varying degrees of facial and tongue weakness, dysphagia, and dysarthria. Fasciculations are ubiquitous in Kennedy disease and, distinctively, are almost always present in perioral regions of the face (88). Recurrent laryngospasm may be an under-recognized symptom in up to half of patients with Kennedy disease and may distinguish Kennedy disease from other forms of motor neuron disease (87). Initial reports that examined the association between polyglutamine repeat length and onset of weakness were conflicting (33; 04). Subsequent studies, with larger cohorts, have demonstrated an inverse correlation between repeat length and both age at onset and degree of weakness (16; 82; 83). A correlation between CAG repeat size and compound muscle action potential (CMAP) amplitude, but not sensory nerve action potential (SNAP) amplitude, has been described (41). A patient with a very large (72 CAG) repeat expansion has been described with a severe phenotype (60). This inverse link is similar to other triplet repeat diseases, though it is still not known how CAG-repeat length influences the progression and prognosis of CAG-repeat diseases (05). However, repeat length should not be considered prognostic for any individual patient; expression of Kennedy disease is too variable to rely on this relationship in the clinical setting.

The lack of sensory symptoms in early case reports suggested pure motor involvement in Kennedy disease. However, on examination, loss of reflexes is a consistent finding, and sensory nerve conduction studies show decreased or absent sensory responses in most patients (19). The possibility of subclinical involvement of the autonomic nervous system in Kennedy disease is also under investigation (80). A study of monozygotic twins, both with Kennedy disease but with phenotypical differences, found evidence of small fiber neuropathy, confirmed by Sudoscan, in the twin with more sensory features (72).

Tremor was part of the initial description of Kennedy disease and remains a common finding (65% to 80%) among large published cohorts (33; 63). It is best characterized as a postural tremor that worsens with activity, similar to that of essential tremor, and it responds similarly to alcohol or beta-blocker treatment (15). Patients can have tremor as their initial symptom in a minority of cases (6%) (88). Peripheral factors, such as subclinical sensory disturbances or decreases in motor unit numbers, may contribute to tremor genesis in Kennedy disease (28).

Although CAG polymorphism length within the androgen receptor (AR) gene has been associated with an increased risk of heart disease, Kennedy disease is generally regarded to only rarely have cardiac manifestations at later stages of the disease. These may include ST-segment abnormalities, Brugada syndrome, dilated cardiomyopathy, hypertrophic cardiomyopathy, or sudden cardiac death. It is possible that these findings are related to progression of age alone and are unrelated to Kennedy disease itself (22).

Affected individuals may also manifest endocrinopathies. Three patients in Kennedy’s initial report had gynecomastia, and two had diabetes (40). Since then, the prevalence of these two features has been investigated. In a study of the early symptoms of Kennedy disease, gynecomastia was found to be the most common initial symptom or sign (52%) (88), followed by testicular atrophy, decreased libido, and subfertility (32). Adult-onset diabetes is found in approximately 10% of patients (63). In regard to hormonal profile, most affected men demonstrate partial androgen resistance with unusually high testosterone levels (32).

Sleep disturbances, including obstructive sleep apnea, nocturnal hypoventilation, and REM sleep without atonia may be more frequent in patients with Kennedy disease (48).

Although X-linked recessive disorders are often asymptomatic in women, female carriers of the Kennedy disease mutation are occasional exceptions. Lyonization, a general mechanism by which selective deactivation of one of the two X chromosomes in heterozygous women occurs, explains how an X-linked recessive disorder may become expressed in a female carrier. The most common clinical features in women are mild muscle cramps (58%) and fatigue (63). Electrophysiologic studies may demonstrate decreased motor unit number estimation and EMG abnormalities, including high-amplitude or polyphasic potentials in female carriers, along with clinical manifestations of mild muscle weakness in neck flexion and a slow walking speed (94).

Prognosis and complications

Life expectancy does not appear to be affected by Kennedy disease (08). The disease is progressive in a nearly linear fashion over decades in the majority of patients, although occasionally the disease course can be variable. From data collected of 223 Kennedy disease patients, investigators found that patients with longer CAG-repeat size developed onset of disability in activities of daily living (ie, requirement of a handrail, use of a cane, use of a wheelchair) at an earlier age, but the rate of subsequent declines were similar regardless of triplet repeat size (05).

Efforts have been made to establish a reliable biomarker that can be used to monitor progression of disease in patients with Kennedy disease. Investigators found that urinary levels of the oxidative stress marker 8-hydroxydeoxyguanosine (8-OHdG) correlated with severity of motor dysfunction in patients with genetically confirmed Kennedy disease (62). Patients with Kennedy disease have insulin resistance, and the degree of this resistance has been shown to correlate with disease severity. The possible mechanism may relate to expression (or reduction thereof) of insulin receptors in skeletal muscle (66). In a clinical study, the 6-minute walking test was found to be a reliable, objectively measurable parameter for tracking motor impairment in patients with Kennedy disease (90).

Patients with Kennedy disease are at risk for aspiration pneumonia, although the incidence of this complication is unknown. Bulbar involvement can contribute to mortality in rare advanced cases. Falls can place the patient at risk for fractures, head injury, or other musculoskeletal injuries. However, most patients with Kennedy disease develop only mild neurologic impairment, maintain good ambulatory function years after diagnosis, and do not become subject to debilitating dysphagia or respiratory dysfunction (08).

Clinical vignette

A 73-year-old man presented with a 2-year history of “tiredness” in the calves and tingling paresthesia in the fingertips. Over the last few years, he had noted that his shoulder muscles would fatigue quickly when he was clipping the hedges in his garden. On specific questioning, he reported that he had felt since his youth that he was weaker than others his age.

The patient was otherwise healthy and took no medications. As a young man, he had been investigated for infertility and was found to have “low sperm count.” His father died of prostate cancer at the age of 89, and his mother died of “malnutrition” at age 69. One older brother, who died at the age of 78, had been followed for years for undiagnosed “motor neuron disease.” A younger brother, aged 71, was recently evaluated by a neurologist after he began to experience difficulty manipulating the gearshift of his car. The patient also had two healthy sisters.

Neurologic examination revealed fasciculations in the face, particularly around the mouth. He was unable to whistle. His tongue was mildly atrophied. Neck strength was slightly diminished. He had atrophy of the shoulder girdle and interosseous muscles, and 4/5 weakness of the proximal muscles in the upper and lower extremities. Reflexes were attenuated. Sensory examination was normal. The remainder of his physical examination was notable for gynecomastia but otherwise was normal.

Characteristic clinical signs in Kennedy disease

This patient has the typical perioral fasciculations and asymmetrical weakness of perioral musculature seen in Kennedy disease. Note also fasciculations and proximal muscle atrophy in the upper limbs, as well as gynecomastia. (Con...

Blood tests showed a serum creatine kinase level of 880 IU/L but otherwise were normal. Nerve conduction studies revealed decreased CMAP and SNAP amplitudes with normal conduction velocities. On needle examination of several proximal and distal muscles, there were motor unit potentials of increased amplitude and duration, without abnormal spontaneous activity. A blood sample sent for genetic testing demonstrated the presence of 43 CAG repeats within the androgen receptor gene (normal: 11 to 36), confirming the diagnosis of Kennedy disease.

Biological basis

Etiology and pathogenesis

Kennedy disease is caused by a trinucleotide CAG repeat expansion in the gene encoding the androgen receptor. The androgen receptor gene is located on the X chromosome (Xq11-12) (50). This excessive number of trinucleotide CAG repeats occurs at the 5’ end of the first exon, near the transcriptional activation region. This portion of the gene is responsible for encoding a series of glutamine residues. The normal range for the number of trinucleotide repeats is 11 to 36; patients affected with Kennedy disease typically have 38 to 62 repeats (OMIM entry 313200). Paternal transmission of the mutation is typically associated with larger expansions in CAG repeat number (82).

The androgen receptor protein is a member of the steroid and thyroid hormone receptor family. It acts as a ligand-dependent transcriptional factor. The androgen receptor protein has three major domains: (1) an N-terminal transactivating domain; (2) a DNA-binding domain; and (3) a ligand-binding domain. Androgen receptor is expressed not only in sexual organs but also in nonreproductive organs including the kidney, skeletal muscle, adrenal gland, skin, and nervous system.

Androgen receptor protein structure

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 (56; 23; 07). 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 (02; 69).

Further insights into the pathophysiology of the mutated androgen receptor protein have been made possible with transgenic animal experiments. Several experiments indicate that the neurotoxic mechanisms underlying Kennedy disease depend on the presence of circulating androgen. In one study, male transgenic mice containing a mutated human androgen receptor with an expanded polyglutamine tract developed a profound motor neuron disease phenotype that reversed with castration. Female mice were only mildly affected by the mutation but deteriorated significantly with administration of testosterone (37). In human subjects, one case report describes the motor deterioration of a patient with known Kennedy disease after initiation of testosterone treatment for prevention of osteoporosis. The patient returned rapidly to his baseline motor status after discontinuing hormonal therapy (44).

Nuclear localization of the mutant protein seems to be necessary for development of neuronal cell dysfunction and degeneration in many of the polyglutamine diseases. Takeyama and colleagues demonstrated that in Kennedy disease translocation of the mutated androgen receptor into the nucleus yielded a neurotoxic effect, whereas trapping of the mutated androgen receptor in the cytoplasm attenuated neuronal cell death (91). Katsuno and colleagues showed that testosterone facilitated the nuclear translocation of the mutated androgen receptor by accelerating its dissociation from heat shock proteins (36; 39). Leuprorelin, an androgen receptor antagonist, inhibited nuclear accumulation of mutant androgen receptors and prevented motor dysfunction in male transgenic mice. Thus, it would appear that testosterone is necessary for the development of neurotoxic effects in Kennedy disease through translocation of the mutated androgen receptor into the nucleus, where it may form toxic aggregates or alter transcriptional activity.

Pathological study of motor fibers shows neuron loss at multiple segments throughout the cord and lower brainstem. All sizes of motor neurons (large, medium, and small) are affected, unlike amyotrophic lateral sclerosis, in which small motor neurons are relatively preserved (92). Larger dorsal root ganglion cells are shrunken and contain mutant androgen receptor mRNA, confirming the involvement of sensory neurons in Kennedy disease (55). The ocular motor nuclei are relatively spared pathologically (as opposed to severe neuronal depletion in other brainstem motor nuclei), in keeping with their typically normal clinical function, consistent with rodent brainstem histology, which shows relatively few androgen-concentrating cells in the ocular motor nuclei (vs. facial and hypoglossal nuclei). However, asymptomatic slowing of horizontal and vertical saccades was documented in a patient with Kennedy disease, consistent with involvement of ocular motor neurons, and possibly internuclear neurons (93).

The presence of nuclear inclusion bodies is a pathological hallmark of the polyglutamine diseases. The nuclear inclusions in Kennedy disease contain the mutated truncated androgen receptor and are most frequently found within motor neurons in the brainstem and spinal cord (53). These nuclear inclusions can also be found in skin, testes, and many other organs (54). Although the majority of inclusions are localized in the cell nuclei, widespread inclusions are also seen in the cytoplasm of certain cells, such as islet cells of the pancreas, and likely contribute to the pathophysiology of Kennedy disease (01).

Poort and colleagues investigated the morphology of neuromuscular junctions in two mouse models of Kennedy disease (75). Counter to their expectations, no evidence of denervation in either model was found, but junctions in both models showed pathological fragmentation and an abnormal synaptophysin distribution consistent with functionally weak synapses. The ultrastructure of these neuromuscular junctions revealed additional pathology, including deficits in docked vesicles presynaptically, wider synaptic clefts, and simpler secondary folds postsynaptically. They concluded that these observed pathologies of neuromuscular junctions in Kennedy disease model mice are likely the morphological correlates of defects in synaptic function, which may underlie motor impairments associated with Kennedy disease.

Surprisingly, in a study of transgenic mice, overexpression of wild type androgen receptor solely in skeletal muscles, and not in motor neurons, resulted in a Kennedy disease phenotype (65). Cortes and colleagues developed a mouse model of Kennedy disease and demonstrated that the muscle expression alone of mutant androgen receptor accounted for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy (13). In a clinical trial, six of eight patients with Kennedy disease showed myogenic changes in their muscle biopsy, and all patients were found to have higher plasma CK levels than expected in degenerative diseases. Both neurogenic and myopathic changes were also observed in female carriers by biopsy (84), though only neurogenic changes were observed by needle EMG and myopathic changes were absent in another study (94). These findings challenge the notion that the symptoms of Kennedy disease are caused exclusively by expression of polyglutamine-expanded androgen receptor in motor and sensory neurons and indicate a key role for muscle fiber pathology to clinical expression of disease (78).

Expansion of the polyglutamine (polyQ) tract of the androgen receptor ultimately leads to Kennedy disease. One study demonstrated that a Leu-rich region preceding this polyQ tract influences its conformation (17). This finding suggests that the residues flanking these repetitive sequences may represent viable therapeutic targets.

There is evidence for mitochondrial dysfunction in Kennedy disease (77). Mitochondrial dysfunction in Kennedy disease is a result of complex interactions of elongated poly-Q AR with mitochondria, mitochondrial proteins, nuclear or mitochondrial DNA, causing oxidative stress, decreased mitochondrial membrane potential, or activation of the mitochondrial caspase pathway. As mitochondrial disease may mimic Kennedy disease, therapeutic approaches may depend on modifications of mitochondrial pathways (21).

Differential diagnosis

The differential diagnosis for Kennedy disease is broad, encompassing a number of other motor neuron diseases, as well as forms of neuropathy and myopathy that are phenotypically similar to Kennedy disease. There is an average delay of 5 years from the onset of weakness to reaching a diagnosis of Kennedy disease (79). However, as long as the possibility of Kennedy disease is considered, the availability of genetic testing now makes confident diagnosis relatively straightforward.

Amyotrophic lateral sclerosis is perhaps the most common misdiagnosis. In one study, 2% of patients initially diagnosed with amyotrophic lateral sclerosis and being followed in amyotrophic lateral sclerosis clinics were found to have a molecular diagnosis of Kennedy disease (70). Another study found that 13% (6 of 47) of patients with Kennedy disease received an initial misdiagnosis of amyotrophic lateral sclerosis, and 32% (15 of 47) overall received an initial misdiagnosis (79). In amyotrophic lateral sclerosis, both upper and lower motor neuron involvement is typically found, whereas in Kennedy disease, only lower motor neuron involvement is clinically seen (96). Unlike in amyotrophic lateral sclerosis, sensory nerve conduction studies are usually abnormal in Kennedy disease, even in the absence of sensory symptoms (27). Progression of disease is faster and life span is shortened in amyotrophic lateral sclerosis compared with Kennedy disease.

Kennedy disease can also be mistaken for other disorders causing lower motor-neuron weakness, particularly those presenting with predominantly proximal weakness. The clinical phenotype of limb-girdle muscular dystrophies or inflammatory, endocrine, or toxic myopathies may resemble Kennedy disease. Patients with fascioscapulohumeral muscular dystrophy have slowly progressive facial and limb weakness, but inheritance is autosomal dominant, and androgen insensitivity does not occur. Patients with oculopharyngeal muscular dystrophy present with bulbar weakness but can be largely distinguished by the presence of symptomatic ocular findings not seen in Kennedy disease. The common occurrence of elevated serum CK values in patients with Kennedy disease may further prompt an initial misdiagnosis of myopathy.

Patients with chronic inflammatory demyelinating polyradiculoneuropathy can exhibit symmetrical proximal muscle weakness, hyporeflexia, facial weakness, and bulbar dysfunction in advanced cases. Nerve conduction studies with features of demyelination and cytoalbuminologic dissociation on lumbar puncture are the hallmarks of this disorder, distinguishing it from Kennedy disease. Forms of spinal muscular atrophy, such as type I and II, will have a much younger onset of disease, without features of androgen insensitivity.

Disorders of the neuromuscular junction can sometimes present similarly to Kennedy disease. In Lambert Eaton myasthenic syndrome, patients develop slowly progressive proximal muscle weakness with diminished deep tendon reflexes. The presence of associated autonomic disturbances, as well as characteristic electrophysiological abnormalities, can help distinguish this entity from Kennedy disease. Occasionally, patients with myasthenia gravis can resemble those with Kennedy disease and present with proximal muscle weakness and bulbar-predominant features in the absence of symptomatic ocular impairment. Furthermore, decremental responses of compound muscle action potentials to slow (3 Hz) repetitive nerve stimulation have been found in some patients with Kennedy disease (34).

Other disorders that could be mistaken for Kennedy disease include scapuloperoneal neuropathies or neuronopathies, cervical spondylosis, and hereditary motor neuropathies. The latter group of disorders includes a distal form of neuropathy, characterized by spinal and bulbar muscular atrophy and vocal cord paralysis that results from mutations in the dynactin gene (74). Very late-onset Sandhoff disease has been mistaken for Kennedy disease (10), and Kennedy disease has been misdiagnosed as POEMS syndrome (98).

Diagnostic workup

In electrophysiological studies by Ferrante and Wilbourn of Kennedy disease patients, compound muscle action potential amplitudes were reduced in 37% to 46% of cases (19). Needle examination showed long-duration, large-amplitude motor unit potentials indicative of chronic denervation and reinnervation in all symptomatic patients. Sensory nerve action potentials were diminished or absent in 82% to 95% of patients. In some cases, decremental responses to repetitive nerve stimulation, as are commonly found in disorders of the neuromuscular junction, have been reported (43). Motor nerve conduction block has also been detected in patients with Kennedy syndrome and has been linked to patient reports of chronic fatigue (67).

Elevations of serum creatine kinase (often 500 to 1500 IU) can be found in patients with symptomatic Kennedy disease and may even precede the onset of symptoms by 10 years or more (85; 09). Serum testosterone levels are usually normal or elevated (02). When the diagnosis is in question, an elevated serum myoglobin may help differentiating Kennedy disease from amyotrophic lateral sclerosis (26).

Although CAG polymorphism length within the androgen receptor (AR) gene has been associated with an increased risk of heart disease, it is unclear whether patients with Kennedy disease should undergo regular screening cardiac investigations (22). A more recent publication recommends cardiac screening with ECG, testosterone levels, and potentially cardiovascular magnetic resonance imaging to assess cardiac risk factors. Patients with spinal and bulbar muscular atrophy may show abnormal ECGs (Brugada pattern, early repolarization, or fragmented QRS) and structural abnormalities (left ventricular hypertrophy, low end-diastolic ventricular volumes, diffuse myocardial fibrosis), which may explain an increased risk of sudden death (89).

A 2016 study compared magnetic resonance imaging alterations of the cortex and white matter in patients with Kennedy disease compared to patients with amyotrophic lateral sclerosis (ALS) (20). Patients with Kennedy disease showed degeneration of the pontine crossing fibers, right frontotemporal and fronto-occipital tracts, and right cingulum. Also noted was subtle cortical thinning of the inferior frontal gyrus bilaterally, left premotor regions, middle temporal gyrus, and right precuneus. Compared to Kennedy disease patients, patients with ALS showed greater involvement of the corticospinal tracts, corpus callosum, external capsule bilaterally, and left superior longitudinal fasciculus.

Sensory impairment secondary to dorsal root ganglion neuronopathy is a common, though typically subclinical, finding in Kennedy disease. Cross-sectional area, as measured by ultrasound, of nerves of patients with spinal and bulbar muscular atrophy were significantly smaller than those of patients with axonal neuropathy or controls (71).

Proton magnetic resonance spectroscopy demonstrated a significant reduction in the ratio of N-acetyl-aspartate (NAA) to phosphocreatine (Cr) in the motor cortex of patients with Kennedy disease compared to normal controls, indicating involvement of the motor cortices in patients with Kennedy disease (51).

Ten patients with genetically confirmed Kennedy disease demonstrated glucose hypometabolism in the frontal areas of the cerebrum by (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET). This disturbance of cerebral glucose metabolism in patients with Kennedy disease is evidence against Kennedy disease being a pure lower motor and sensory neuron syndrome. Mutations in the androgen receptor gene likely have a more widespread effect in the cerebrum than previously recognized (47).

Magnetic resonance imaging of the cervical and thoracic spinal cord in 19 patients with Kennedy disease revealed spinal cord atrophy when compared to the spinal cords of control subjects and patients with other disorders involving lower motor neurons (86). A whole-body muscle MRI study of 81 patients with Kennedy disease demonstrated that the posterior calf was the first muscle to show fat infiltration in this population, and thigh muscle involvement most significantly correlated with a patient’s 6-minute walk test distance (42).

Bright tongue sign (tongue hyperintensity seen on brain sagittal T1-weighted MRI), most commonly seen in bulbar amyotrophic lateral sclerosis, may also be present in Kennedy disease (57). In a study to determine the prevalence and features of fatty liver disease in Kennedy disease patients, nonalcoholic liver disease was diagnosed by laboratory analysis and liver imaging in nearly all patients (24).

It has been suggested that a finding of gynecomastia by computed tomography of the chest may facilitate diagnosis of Kennedy disease (45).

For definitive diagnosis, DNA analysis of a blood sample to detect a CAG triplet repeat expansion in the androgen receptor gene is available. This test also reliably distinguishes Kennedy disease from other motor neuron disorders, including amyotrophic lateral sclerosis (70). The normal repeat number varies from 11 to 36 CAG trinucleotide repeats; in Kennedy disease patients, the repeat varies from 38 to 62 CAGs. Presymptomatic testing for at-risk male relatives or carrier testing for female relatives of an affected family member is possible.

Management

Management of Kennedy disease is mainly supportive. No effective disease-modifying therapy is currently available to slow or cure the disease (76). The natural history of Kennedy disease, including its slow progression and tendency to plateau, renders its clinical status difficult to evaluate in therapeutic trials. Furthermore, the low incidence of the disease renders recruitment for clinical trials demanding (97). Because of the slow progression of Kennedy disease, it has been proposed that future clinical trials assess patients with a unique scale developed specifically for patients with Kennedy disease (the KD 1234 scale), rather than the previously used ALSFRS scale (58).

The major focus of experimental studies of treatment for Kennedy disease has been on the interaction of the androgen receptor with its ligand, testosterone. Elimination of testosterone in animal models through castration appears to be protective and potentially restores some lost motor function (37; 11). This finding led to interest in the use of antiandrogenic therapies for treating humans with Kennedy disease. However, two randomized, placebo-controlled trials did not demonstrate a significant effect of dutasteride (a 5alpha-reductase inhibitor) or leuprorelin (a gonadotropin-releasing hormone agonist) on the progression of muscle weakness or swallowing dysfunction in patients with Kennedy disease treated for 24 to 48 months (38; 18). Interestingly, a 2016 case study described a 40-year-old male-to-female transgender Kennedy disease patient who developed full disease manifestations despite undetectable levels of androgens. It was postulated that spironolactone, the anti-androgen the patient used for 15 years, promoted nuclear localization and toxicity of the mutant protein, potentially explaining the disease manifestations in the patient (49).

Nevertheless, interest in androgen-modulating therapy as a treatment for Kennedy disease continues (32), and a study using long-term treatment (8 years) with leuprorelin appeared to delay functional decline and reduce incidence of pneumonia and death (29). A 1-year observational study similarly showed improved pharyngeal function in patients treated with leuprorelin (35). The thiazole class of antibiotics were identified as neuron-selective androgen receptor (AR) signaling inhibitors, sparing androgen receptor signaling in muscles, and thus, they hold potential in the prevention or treatment of Kennedy disease symptoms (68).

The androgen receptor protein has three major domains: (1) an N-terminal trans-activating domain, (2) a DNA-binding domain, and (3) a ligand-binding domain. The N-terminal domain contains the polyglutamine tract. Expansion of the polyglutamine (polyQ) tract of the androgen receptor ultimately leads to Kennedy disease. A study demonstrated that a Leu-rich region preceding this polyQ tract influences its conformation. This finding suggests that the residues flanking these repetitive sequences may represent viable therapeutic targets (17).

Treatment of SBMA knock-in mice with clenbuterol, a beta-agonist, decreased the accumulation of polyglutamine-expanded androgen receptor, improved muscle pathology, ameliorated motor function, and extended survival, suggesting a novel therapeutic strategy for Kennedy disease (64).

The activation function-2 (AF2) domain of the androgen receptor may be a potential drug target for selective modulation of toxic androgen receptor activity. 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB) has shown promise in a mouse model of spinal bulbar muscular atrophy in this regard, demonstrating a dose-dependent rescue from loss of body weight, rotarod activity, and grip strength as well as MEPB ameliorated neuronal loss, neurogenic atrophy, and testicular atrophy (06).

Heat-shock protein 70 (Hsp70) serves in cellular protein quality control, facilitating degradation of misfolded proteins. In Kennedy disease, expanded CAG repeat length in the androgen receptor leads to misfolding and aggregation of mutant proteins. Thus, there is interest in the development of small molecules designed to enhance Hsp70 function in order to treat polyglutamine diseases including Kennedy disease (14).

There have been significant advances in nucleic acid therapeutics for hereditary neurologic disorders. Spinal-bulbar muscular atrophy is a trinucleotide repeat expansion disorder and affects both motor neurons and skeletal muscle. Thus, there are many potential targets for nucleic acid-based therapies in spinal-bulbar muscular atrophy (31).

Current treatments focus on alleviating symptoms rather than modifying disease progression. Many symptomatic interventions for Kennedy disease mirror symptomatic treatments for ALS, and like for ALS, referral to a multidisciplinary clinic may improve quality of life and prolong survival. Tremors may be treated with beta-blockers. There are no FDA-approved medications for alleviation of cramps. Off-label medications that are sometimes used include benzodiazepines, anticonvulsants, muscle relaxants, or quinine sulfate. There is a lack of controlled studies regarding efficacy of these treatments, and all have potential side effects, including prolonged QT syndrome for quinine sulfate. Early foot drop can be aided by an orthotic device. Occupational and physical therapy are helpful for addressing mobility concerns and maintaining function for as long as possible, and they help minimize the risk of falls later in the disease course. Bulbar dysfunction can also be problematic. Sialorrhea may be treated with tricyclic antidepressants, scopolamine patch, and sympathomimetics such as pseudoephedrine, botulinum toxin B injection of the salivary glands, or alternatively low-dose radiation therapy to the salivary glands. Later in the disease course, dysphagia may require placement of a percutaneous endoscopic gastrostomy tube for feeding. Aspiration precautions and involvement of speech pathology are also important to reduce the risk of life-threatening pulmonary complications. Frequent, moderate-intensity aerobic conditioning has shown little beneficial effect in patients with Kennedy disease (73).

A regular exercise routine, as long as the patient’s degree of weakness allows, is recommended. The goal should be to maintain range of motion of joints and to promote cardiovascular health. However, recommendations generally also advise the avoidance of severe exercise to the point of muscle exhaustion (to avoid muscle breakdown). Hirunagi and colleagues proposed a potential mechanism of action of the benefits of exercise (30). This study showed that exercise reduced polyQ-expanded androgen receptor proteins in rat muscle cells, leading to improvement in muscle function.

Media

References

01: Adachi H, Katsuno M, Minamiyama M, et al. Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain 2005;128(Pt. 3):659-70. PMID 15659427
02: Adachi H, Waza M, Katsuno M, Tanaka F, Doyu M, Sobue G. Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy. Neuropathol Appl Neurobiol 2007;33(2):135-51. PMID 17359355
03: Alves CN, Braga TK, Somensi DN, et al. X-linked spinal and bulbar muscular atrophy (Kennedy’s disease): the first case described in the Brazilian Amazon. Einstein (Sao Paulo) 2018;16(2):eRC4011. PMID 29898093
04: Amato AA, Prior TW, Barohn RJ, Synder P, Papp A, Mendell JR. Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology 1993;43:791-4. PMID 8469342
05: Atsuta N, Watanabe H, Ito M, et al. Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain 2006;129(Pt 6):1446-55. PMID 16621916
06: Badders NM, Korff A, Miranda HC, et al. Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy. Nat Med 2018;24(4):427-37. PMID 29505030
07: Cary GA, La Spada AR. Androgen receptor function in motor neuron survival and degeneration. Phys Med Rehabil Clin N Am 2008;19(3):479-91. PMID 18625411
08: Chahin N, Klein C, Mandrekar J, Sorenson E. Natural history of spinal-bulbar muscular atrophy. Neurology 2008;70(21):1967-71. PMID 18490617
09: Chahin N, Sorenson EJ. Serum creatinine kinase levels in spinobulbar muscular atrophy and amyotrophic lateral sclerosis. Muscle Nerve 2009;40(1):126-9. PMID 19533663
10: Chardon JW, Bourque PR, Geraghty MT, Boycott KM. Very late-onset Sandhoff disease presenting as Kennedy disease. Muscle Nerve 2015;52(6):1135-6. PMID 26769462
11: Chevalier-Larsen ES, O'Brien CJ, Wang H, et al. Castration restores function and neurofilament alterations of aged symptomatic males in a transgenic mouse model of spinal and bulbar muscular atrophy. J Neurosci 2004;24(20):4778-86. PMID 15152038
12: Cho HJ, Shin JH, Park YE, et al. Characteristics spinal and bulbar muscular atrophy in South Korea: a cross-sectional study of 157 patients. Brain 2023;146(3):1083-92. PMID 35639850
13: Cortes CJ, Ling SC, Guo LT, et al. Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy. Neuron 2014;82(2):295-307. PMID 24742458
14: Davis AK, Pratt WB, Lieberman AP, Osawa Y. Targeting Hsp70 facilitated protein quality control for treatment of polyglutamine diseases. Cell Mol Life Sci 2020;77(6):977-96. PMID 31552448
15: Dias FA, Munhoz RP, Raskin S, Werneck LC, Teive HA. Tremor in X-linked recessive spinal and bulbar muscular atrophy (Kennedy’s disease). Clinics 2011;66(6):955-7. PMID 21808858
16: 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 1992;32:707-10. PMID 1449253
17: Eftekharzadeh B, Piai A, Chiesa G, et al. Sequence context influences the structure and aggregation behavior of a PolyQ tract. Biophys J 2016;110(11):2361-6. PMID 27276254
18: Fernandez-Rhodes LE, Kokkinis AD, White MJ, et al. Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial. Lancet Neurol 2011;10(2):140-7. PMID 21216197
19: Ferrante MA, Wilbourn AJ. The characteristic electrodiagnostic features of Kennedy's disease. Muscle Nerve 1997;20:323-9. PMID 9052811
20: Ferraro PM, Agosta F, Querin G, et al. Structural brain MRI abnormalities in Kennedy’s disease. Neurology 2016;86(16):P5.015.
21: Finsterer J, Mishra A, Wakil S, Pennuto M, Soraru G. Mitochondrial implications in bulbospinal muscular atrophy (Kennedy disease). Amyotroph Lateral Scler Frontotemporal Degener 2015;17(1-2):112-8. PMID 26428534
22: Finsterer J, Stollberger C. Only some patients with bulbar and spinal muscular atrophy may develop cardiac disease. Mol Genet Metab Rep 2018;14:44-6. PMID 29326874
23: Gatchel JR, Zoghbi HY. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet 2005;6(10):743-55. PMID 16205714
24: Guber RD, Takyar V, Kokkinis A, et al. Nonalcoholic fatty liver disease in spinal and bulbar muscular atrophy. Neurology 2017;89(24):2481-90. PMID 29142082
25: Guidetti D, Sabadini R, Ferlini A, Torrente I. Epidemiological survey of X-linked bulbar and spinal muscular atrophy, or Kennedy disease, in the province of Reggio Emilia, Italy. European J Epidemiol 2001;17(6):587-91. PMID 11949733
26: Guo H, Lu M, Ma Yan, Liu X. Myoglobin: a new biomarker for spinal and bulbar muscular atrophy? Int J Neurosci 2020;1-6. PMID 3279750
27: Hama T, Hirayama M, Hara T, et al. Discrimination of spinal and bulbar muscular atrophy from amyotrophic lateral sclerosis using sensory nerve action potentials. Muscle Nerve 2012;45(2):169-74. PMID 22246870
28: Hanajima R, Terao Y, Nakatani-Enomoto S, et al. Postural tremor in X-linked spinal and bulbar muscular atrophy. Mov Disord 2009;24(14):2063-9. PMID 19746452
29: Hashizume A, Katsuno M, Suzuki K, et al. Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy: natural history-controlled study. J Neurol Neurosurg Psychiatry 2017;88(12):1026-32. PMID 28780536
30: Hirunagi T, Nakatsuji H, Sahashi K, et al. Exercise attenuates polyglutamine-mediated neuromuscular degeneration in a mouse model of spinal and bulbar muscular atrophy. J Cachexia Sarcopenia Muscle 2023. [Epub ahead of print] PMID 37937369
31: Hirunagi T, Sahashi K, Meilleur KG, Katsuno M. Nucleic acid-based therapeutic approach for spinal and bulbar muscular atrophy and related neurological disorders. Genes (Basel) 2022;13(1):109. PMID 35052449
32: Hoo FK, Sumon SH, Basri H, et al. Androgen-modulating agents for spinal bulbar muscular atrophy/Kennedy's disease. Cochrane Database Syst Rev 2015;12:CD012000.
33: Igarashi S, Tanno Y, Onodera O, et al. Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy. Neurology 1992;42:2300-2. PMID 1461383
34: Inoue K, Hemmi S, Miyaishi M, et al. Muscular fatigue and decremental response to repetitive nerve stimulation in X-linked spinobulbar muscular atrophy. Eur J Neurol 2009;16(1):76-80. PMID 19087153
35: Kang M, Gwak D, Cho H, Min Y, Park J. Effect of leuprorelin in bulbar function of spinal and bulbar muscular atrophy patients: observational study for 1 year. J Neurol 2021;268(9):3344-51. PMID 33675422
36: Katsuno M, Adachi H, Doyu M, et al. Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy. Nat Med 2003;9(6):768-73. PMID 12754502
37: Katsuno M, Adachi H, Kume A, et al. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 2002;35:843-54. PMID 12372280
38: Katsuno M, Banno H, Suzuki K, et al. Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010;9(9):875-84. PMID 20691641
39: Katsuno M, Sang C, Adachi H, et al. Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease. Proc Natl Acad Sci U S A 2005;102(46):16801-6. PMID 16260738
40: Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology 1968;18:671-80. PMID 4233749
41: Kim H, Lim YM, Lee EJ, Oh YJ, Kim KK. Correlation between the CAG repeat size and electrophysiological findings in patients with spinal and bulbar muscular atrophy. Muscle Nerve 2018;57(4):683-6. PMID 28972672
42: Kim H, Seo I, Kang M, et al. Whole-body muscle magnetic resonance imaging in 81 spinal and bulbar muscular atrophy: a prospective study. Ann Neurol 2023. [Epub ahead of print] PMID 38054838
43: Kim JY, Park KD, Kim SM, Sunwoo IN. Decremental responses to repetitive nerve stimulation in x-linked bulbospinal muscular atrophy. J Clin Neurol 2013;9(1): 32-5. PMID 23346158
44: Kinirons P, Rouleau GA. Administration of testosterone results in reversible deterioration in Kennedy's disease. J Neurol Neurosurg Psychiatry 2008;79(1):106-7. PMID 17056629
45: Kobayashi M. Gynecomastia on computed tomography: a helpful finding for the diagnosis of spinal and bulbar muscular atrophy. Acta Neurol Belg 2020;120(6):1491-3. PMID 32949348
46: Kurland LT. Epidemiologic investigations of amyotrophic lateral sclerosis: III. A genetic interpretation of incidence and geographic distribution. Proc Staff Meet Mayo Clin 1957;32:449-62. PMID 13465826
47: Lai TH, Liu RS, Yang BH, et al. Cerebral involvement in spinal and bulbar muscular atrophy (Kennedy's disease): a pilot study of PET. J Neurol Sci 2013;335(1-2):139-44. PMID 24120273
48: Langenbruch L, Perez-Mengual S, Glatz C, Young P, Boentert M. Disorders of sleep in spinal and bulbar muscular atrophy (Kennedy’s disease). Sleep Breath 2020;25(3):1399-405. PMID 33219909
49: Lanman TA, Bakar D, Badders NM, et al. Sexual reassignment fails to prevent Kennedy’s disease. J Neuromuscul Dis 2016;3(1):121-5. PMID 27854206
50: La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991;352:77-9. PMID 2062380
51: Lee CH, Lai PH, Liu CS, Li JY. Proton magnetic resonance spectroscopy in Kennedy disease. J Neurol Sci 2009;277(1-2):71-5. PMID 19019384
52: Lefter S, Hardiman O, Ryan AM. A population-based epidemiologic study of adult neuromuscular disease in the Republic of Ireland. Neurology 2017;88(3):304-13. PMID 27927941
53: Li M, Miwa S, Kobayashi Y, et al. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol 1998a;44:249-54. PMID 9708548
54: Li M, Nakagomi Y, Kobayashi Y, et al. Non-neural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy. Am J Pathol 1998b;153:695-701. PMID 9736019
55: 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 1995;18(3):301-8. PMID 7870107
56: Lieberman AP, Harmison G, Strand AD, et al. Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor. Hum Mol Genet 2002;11(17):1967-76. PMID 12165558
57: Lin X, Wu S. Bright tongue sign in Kennedy disease. QJM 2020;113(1):45-6. PMID 31566244
58: Lu M, Guo H, Fan D. Kennedy’s disease 1234 scale: preliminary design and test. J Clin Neurosci 2017;40:185-9. PMID 28242130
59: Lund A, Udd B, Juvonen V, et al. Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world. Eur J Hum Genet 2001;9:431-6. PMID 11436124
60: Madeira JLO, Souza ABC, Cunha FS, et al. A severe phenotype of Kennedy Disease associated with a very large CAG repeat expansion. Muscle Nerve 2018;57(1):E95-7. PMID 28877561
61: Magee KR. Familial progressive bulbar spinal muscular atrophy. Neurology 1960;10:295-305. PMID 14419783
62: Mano T, Katsuno M, Banno H, et al. Cross-sectional and longitudinal analysis of an oxidative stress biomarker for spinal and bulbar muscular atrophy. Muscle Nerve 2012;46(5):692-7. PMID 22941760
63: Mariotti C, Castellotti B, Pareyson D, et al. Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscul Disord 2000;10:391-7. PMID 10899444
64: Milioto C, Malena A, Maino E, et al. Beta-agonist stimulation ameliorates the phenotype of spinal and bulbar muscular atrophy mice and patient-derived myotubes. Sci Rep 2017;7:41046. PMID 28117338
65: Monks DA, Rao P, Johansen JA, Lewis G, Kemp MQ. Androgen receptor and Kennedy disease/spinal bulbar muscular atrophy. Horm Behav 2008;53(5):729-40. PMID 18321505
66: Nakatsuji H, Araki A, Hashizume A, et al. Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy. J Neurol 2017;264(5):839-47. PMID 28229243
67: Noto Y, Misawa S, Mori M, et al. Prominent fatigue in spinal muscular atrophy and spinal and bulbar muscular atrophy: evidence of activity-dependent conduction block. Clin Neurophysiol 2013;124(9):1893-8. PMID 23643309
68: Otto-Duessel M, Tew BY, Vonderfecht S, Moore R, Jones JO. Identification of neuron selective androgen receptor inhibitors. World J Biol Chem 2017;8(2):138-50. PMID 28588757
69: Palazzolo I, Gliozzi A, Rusmini P, et al. The role of the polyglutamine tract in androgen receptor. J Steroid Biochem Mol Biol 2008;108(3-5):245-53. PMID 17945479
70: Parboosingh JS, Figlewicz DA, Krizus A, et al. Spinobulbar muscular atrophy can mimic ALS: the importance of genetic testing in male patients with atypical ALS. Neurology 1997;49(2):568-72. PMID 9270598
71: Pelosi L, Ghosh A, Leadbetter R, Lance S, Rodrigues M, Roxburgh R. Nerve ultrasound detects abnormally small nerves in patients with spinal and bulbar muscular atrophy. Muscle Nerve 2022;65(5):599-602. PMID 35092036
72: Popescu C. Monozygotic twins discordant for Kennedy disease: a case report. J clin Neuromuscul Dis 2019;21(2):112-16. PMID 31743255
73: Priesler N, Andersen G, Thøgersen F, et al. Effect of aerobic training in patients with spinal and bulbar muscular atrophy (Kennedy disease). Neurology 2009;72(4):317-23. PMID 19171827
74: Puls I, Oh SJ, Sumner CJ, et al. Distal spinal and bulbar muscular atrophy caused by dynactin mutation. Ann Neurol 2005;57:687-94. PMID 15852399
75: Poort JE, Rheuben MB, Breedlove SM, Jordan CL. Neuromuscular junctions are pathological but not denervated in two mouse models of spinal bulbar muscular atrophy. Hum Mol Genet 2016;25(17):3768-83. PMID 27493028
76: Querin G, Soraru G, Pradat PF. Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy. Rev Neurol (Paris) 2017;173(5):326-37. PMID 28473226
77: Ranganathan S, Harmison GG, Meyertholen K, Pennuto M, Burnett BG, Fishbeck KH. Mitochondrial abnormalities in spinal and bulbar muscular atrophy. Hum Mol Genet 2009;18(1):27-42. PMID 18824496
78: Ramzan F, McPhail M, Rao P, et al. Distinct etiological roles for myocytes and motor neurons in a mouse model of Kennedy's disease/spinobulbar muscular atrophy. J Neurosci 2015;35(16):6444-51. PMID 25904795
79: Rhodes LE, Freeman BK, Auh S, et al. Clinical features of spinal and bulbar muscular atrophy. Brain 2009;132(Pt12):3242-51. PMID 19846582
80: Rocchi C, Greco V, Urbani A, et al. Subclinical autonomic dysfunction in spinobulbar muscular atrophy (Kennedy disease). Muscle Nerve 2011;44(5):737-40. PMID 22006688
81: 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. J Neurol Sci 1979;41:343-57. PMID 108363
82: Shimada N, Sobue G, Doyu M, et al. X-linked recessive bulbospinal neuronopathy: clinical phenotypes and CAG repeat size in androgen receptor gene. Muscle Nerve 1995;18:1378-84. PMID 7477059
83: Sinnreich M, Sorenson EJ, Klein CJ. Neurologic course, endocrine dysfunction and triplet repeat size in spinal bulbar muscular atrophy. Can J Neurol Sci 2004;31:378-80. PMID 15376484
84: Soraru G, D'Ascenzo C, Polo A, et al. Spinal and bulbar muscular atrophy: skeletal muscle pathology in male patients and heterozygous females. J Neurol Sci 2008;264(1-2):100-5. PMID 17854832
85: Sorenson EJ, Klein CJ. Elevated creatine kinase and transaminases in asymptomatic SBMA. Amyotroph Lateral Scler 2007;8(1):62-4. PMID 17364438
86: Sperfeld AD, Bretschneider V, Flaith L, et al. MR-pathologic comparison of the upper spinal cord in different motor neuron diseases. Eur Neurol 2005b;53(2):74-7. PMID 15785072
87: Sperfeld AD, Hanemann O, Ludolf AC, Kassubek J. Laryngospasm: an underdiagnosed symptom of X-linked spinobulbar muscular atrophy. Neurology 2005a;64:753-54. PMID 15728312
88: Sperfeld AD, Karitzky J, Brummer D, et al. X-linked bulbospinal neuronopathy. Arch Neurol 2002;59:1921-6. PMID 12470181
89: Steinmetz K, Rudic B, Borggrefe M, et al. J wave syndromes in patients with spinal and bulbar muscular atrophy. J Neurol 2022;269(7):3690-9. PMID 35132468
90: Takeuchi Y, Katsuno M, Banno H, et al. Walking capacity evaluated by the 6-minute walk test in spinal and bulbar muscular atrophy. Muscle Nerve 2008;38(2):964-71. PMID 18642379
91: Takeyama K, Ito S, Yamamoto A, et al. Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron 2002;35:855-64. PMID 12372281
92: 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 1994;241(4):196-203. PMID 8195817
93: Thurtell MJ, Pioro EP, Leigh RJ. Abnormal eye movements in Kennedy disease. Neurology 2009;72(17):1528-30. PMID 19398709
94: Torii R, Hashizume A, Yamada S, et al. Clinical features of female carriers and prodromal male patients with spinal and bulbar muscular atrophy. Neurology 2023;100(1):e84-93. PMID 36180235
95: Udd B, Juvonen V, Hakamies L, et al. High prevalence of Kennedy's disease in Western Finland—is the syndrome underdiagnosed. Acta Neurol Scand 1998;98:128-33. PMID 9724012
96: Vucic S, Kiernan MC. Cortical excitability testing distinguishes Kennedy's disease from amyotrophic lateral sclerosis. Clin Neurophysiol 2008;119(5):1088-96. PMID 18313980
97: Weydt P, Sagnelli A, Rosenbohm A, et al. Clinical trials in spinal and bulbar muscular atrophy-past, present, and future. J Mol Neurosci 2016;58(3):379-87. PMID 26572537
98: Yuan M, Chen W, Zhou H, et al. Kennedy disease misdiagnosed as polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome: a case report. Med Princ Pract 2016;25(3):286-9. PMID 26618536

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Robert W Pratt MD

Dr. Pratt of the University of Colorado has no relevant financial relationships to disclose.
See Profile

Editor

Louis H Weimer MD

Dr. Weimer of Columbia University has no relevant financial relationships to disclose.
See Profile

Former Authors

Martin SuttonBrown MD (original author), Cory Toth MD (original author), Stuart Lubarsky MD, and Colin Chalk MD

Patient Profile

Age range of presentation: 6 to 64 years
Sex preponderance: male>female,>1:1
Heredity: X-linked recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Anterior horn cell disease- Motor neuron disease: 335.2

Anterior horn cell disease- Spinal muscular atrophy: 335.1
ICD-10: Motor neuron disease: G12.2

Spinal muscular atrophy, unspecified: G12.9
OMIM: Kennedy disease: #313200

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Kennedy disease

Associated Disorders

diabetes mellitus
dysarthria
dysphagia
gynecomastia

Differential Diagnosis

amyotrophic lateral sclerosis
limb-girdle muscular dystrophy
inflammatory, endocrine, or toxic myopathies
fascioscapulohumeral muscular dystrophy
oculopharyngeal muscular dystrophy
- myopathy
- chronic inflammatory demyelinating polyradiculoneuropathy
- spinal muscular atrophy type 1
- spinal muscular atrophy type 2
- Lambert Eaton myasthenic syndrome
- myasthenia gravis
- scapuloperoneal neuropathies or neuronopathies
- cervical spondylosis
- hereditary forms of motor dominant neuropathies
- POEMS syndrome
- Adult-onset Sandhoff disease

Kennedy disease …

Kennedy disease

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Diagnostic workup

Management

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Neuropathies associated with cytomegalovirus infection

Distal myopathies

Chronic inflammatory demyelinating polyradiculoneuropathy

Amyotrophic lateral sclerosis

Amiodarone neuropathy

Autoimmune autonomic neuropathy

Leukodystrophies

Neuroacanthocytosis

Kennedy disease

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Diagnostic workup

Management

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neuropathies associated with cytomegalovirus infection

Distal myopathies

Chronic inflammatory demyelinating polyradiculoneuropathy

Amyotrophic lateral sclerosis

Amiodarone neuropathy

Autoimmune autonomic neuropathy

Leukodystrophies

Neuroacanthocytosis

This is an article preview.
Start a Free Account
to access the full version.