eMedicine Specialties > Neurology > Neuromuscular Diseases

Kennedy Disease

Author: Paul E Barkhaus, MD, Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center
Contributor Information and Disclosures

Updated: Jan 24, 2008

Introduction

Background

Kennedy disease (KD) is named after the author, William R. Kennedy, MD, who first described this entity in an abstract in 1966. The full report followed in 1968.¹ The history of this entity is summarized briefly here by way of a personal memoir from Dr Kennedy to the author.

Three months after completing his residency in neurology at Mayo Clinic in 1964, Dr Kennedy examined a 57-year-old man of French and Native American ancestry from Minnesota who had been having problems with weakness for over 20 years. Other affected family members were identified, and an extensive pedigree developed. Dr Kennedy recalled, "This was an exciting patient! As a resident I had reviewed the entire Mayo Clinic film collection of patients, and every muscle and nerve biopsy taken before 1964, but I had not encountered this disease. I thought I knew how to document this patient. But I had never performed a muscle biopsy, had never photographed a patient, and had never used a motion picture camera."

Two months later, a similar patient, a 68-year-old man from Iowa, was referred for evaluation. Again, the patient's family history was positive, and Dr Kennedy noted that this patient's clinical picture closely resembled that of the previous patient. Evaluation of both families included his loading an electromyograph (EMG) into a car and driving to Iowa. (The present author had a similar experience when evaluating another affected family with Dr Kennedy in northern Minnesota in 1979. Performing clinical evaluations and EMG in the field is challenging work.)

Dr Paul Delwaide, a Belgian neurologist, first used the appellation Kennedy disease in a 1979 paper. In the author's discussions over the years with Dr Kennedy, he tended to downplay the use of eponyms for diseases. When the author recently asked him again about "his disease," he admitted that now, as he grows older, "It feels kind of good."

In 1982, Harding et al reclassified the disease as X-linked bulbospinal neuronopathy to reflect the sensory conduction abnormalities noted in several of their cases.² Although the concept of the disease has been broadened, it remains an X-linked disorder with the hallmark of progressive weakness of the limb and bulbar musculature. Additional neurologic features include sensory abnormalities, tremor of the upper extremities, and a quivering chin. A number of patients also have various endocrinologic abnormalities, such as diabetes, testicular atrophy, gynecomastia, oligospermia, and erectile dysfunction.

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

Pathophysiology

KD is an inherited disorder characterized by degeneration of both motor and sensory neurons. It involves loss of lower motor neurons supplying the limb and bulbar musculature. Extraocular muscles are spared, possibly because of reduced numbers of androgen receptors in these muscles. Autopsy studies showed loss of large, medium, and small motor neurons. Loss of small motor neurons is not a typical finding in acquired amyotrophic lateral sclerosis (ALS). Subsequent investigators emphasized the loss of larger dorsal root ganglion cells, thereby establishing a sensory neuron component. Li et al suggested a pattern of central-peripheral distal axonopathy.⁴⁷

Li et al demonstrated nuclear inclusions in the spinal motor neurons of patients with KD that stained positively for androgen receptor protein when immunohistochemical methods are used.⁴⁶ Similar features have been reproduced in transgenic mice and neuronal cell culture. Walcott and Merry further studied these nuclear inclusions.⁵⁵ Although the inclusions are a neuropathologic finding in KD, their role in the disease remains unresolved.

As mentioned before, the genetic basis of the disease involves an expanded repeat of the CAG trinucleotide in the proximal portion of the q arm of the X chromosome. It is thought to encode a polyglutamine tract on the androgen receptor protein. Patients with KD have about 40-62 repeats, compared with 10-36 repeats in healthy individuals. This expanded repeat is unstable in that its length may change from generation to generation. Reports indicate that repeat lengths, which are minimally expanded, are associated with atypical presentations. Echaniz-Laguna et al reported a family with early-onset and rapidly progressive KD that showed 50-54 CAG repeats.⁵  

Although KD typically affects men, women can be symptomatic.^6,7  Greenland et al reported a heterozygous female carrier of KD who had one allele containing an expanded number of CAG repeats (44) with the normal allele showing 28 repeats (upper normal range). They felt that this particular combination of allele repeats may have led to this patient's clinical expression of the disease.⁷

Authors have suggested that anticipation occurs in KD. That is, the length of the expanded repeat and the age of onset appear to be inversely related: a longer repeat seems to indicate a younger age of onset. However, subsequent observations have not supported this suggestion. Amato et al found no correlation between the severity of disease and the length of CAG repeat.⁸ Sinnreich et al found some correlation between the number of repeats and the age of onset, but other yet-to-be determined factors are likely influential.⁹ Other investigators have also reviewed CAG repeats in KD.^10,11

A number of molecular pathophysiologic studies of the androgen receptor have been conducted to clarify its role in the pathogenies of KD.^{12,13,14,15,16,17,18,19} Androgen-receptor protein is produced in the cytoplasm and modified and bound to other molecules. When a ligand such as testosterone is present, it may be transported to the nucleus, where it may undergo further change and function.

Ellerby et al demonstrated that caspases, or "cysteine protease cell-death executioners", may act on the gene product (ie, androgen-receptor protein) resulting from the trinucleotide-repeat expansions, which act as substrates. Caspase cleavage affects proteins with the abnormal expanded polyglutamine tracts, resulting in cell death. Ellerby et al concluded that caspase cleavage is an important step in cytotoxicity (ie, neuronal cell death).²⁰ High circulating levels of androgens in men might precipitate the motor neuron degeneration observed in KD.²¹

In summary, the locus of the mutation is at the Xq11-q12 band of the long arm of the X chromosome, and the gene product is an androgen-receptor protein with a polyglutamine tail at the N -terminal end. The exact mechanism by which the neuronal degeneration occurs remains unknown, but the abnormal protein presumably alters the function of the androgen receptor.

An alternate mechanism of how the expanded repeat causes KD may be a toxic-gain-of-function effect by mutant gene products. The motor neuron loss imputed to the abnormal (or mutant) androgen receptor is not a simple, passive loss of function. Instead, it is a transformed protein that is actively adverse (or toxic) to cell function. This mechanism is analogous to genetic defects in other, but dissimilar, neurologic disorders, including Huntington disease and some spinocerebellar ataxias (SCAs, types 1, 2, 3, 6, and 7), which also are associated with tandem repeats.

Frequency

United States

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

International

The incidence is unknown, but frequencies similar to those in the United States are anticipated in areas reporting the disease, including Europe, Japan, Australia, and Brazil. Some regions, such as western Finland and Japan, may have a high prevalence.^22,23

Mortality/Morbidity

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

Race

No racial predilection is known.

Sex

• KD is a disease of the X chromosome; therefore, only males express the full phenotype. Affected men cannot pass the genetic trait on to their sons, but their daughters have a 50% risk of being carriers. Carrier females have a 50% risk of having sons with the disease gene and a 50% risk of having daughters who are carriers.
• A study of 8 heterozygous female patients with proven tandem CAG repeats showed that 50% had subclinical phenotypic expression.⁶ Their clinical findings were normal, except for muscle cramps and finger tremors. Laboratory investigations showed abnormalities ranging from chronic reinnervation changes on EMG to abnormal findings on muscle biopsy. Such women are considered manifesting carriers.

Age

• The typical age of onset is 40-60 years.
• The disease may appear as early as the mid-20s.
• Doyu et al²⁴ reported an 84-year-old man without a family history who had difficulty climbing stairs and muscle cramps in his calves for 10 years. Clinical, endocrinologic, and electrophysiologic results suggested KD. Genetic polymerase chain reaction (PCR) testing for KD revealed CAG repeats but in the low range of abnormality. Expression of the disease in this man was mild. This case emphasizes the importance of testing individuals, even those without a family history, for possible spontaneous mutations when the results of careful clinical evaluation and laboratory testing are compatible with KD.

Clinical

History

• A typical constellation of complaints in Kennedy disease (KD) is an insidious onset of easy fatigability, muscle cramps, and weakness in the limbs.
• As the disease progresses, disability commensurately increases until the patient is wheelchair bound.
• Involvement of the bulbar musculature may be expressed as difficulty in chewing, swallowing, and speaking. The last often results in a nasal quality of the person's speech because of palatal weakness.
• Postural tremor and tremor in the upper extremities usually begins late in the course of the illness.
• Sensory complaints may be present, but they are rarely isolated findings.
• Patients may have complaints related to endocrinopathy. Because the onset of the disease is relatively late, complaints such as infertility or reduced libido may not be appreciated readily. Battaglia et al reported a case in which endocrinopathy was the presenting manifestation of KD.²⁵

Physical

• Neurologic findings
  • Cognition is unimpaired.
  • Examination of the cranial nerves usually shows evidence of weakness in the facial, palatal, and tongue muscles. The weakness may be so profound that the mouth hangs open and is tremulous. In the index case Kennedy et al reported, the facial weakness became so severe that the patient held his chin up with his hands to chew (see Media files 1-4). Jaw drop may be a prominent feature.²⁶
  • Contraction of perioral musculature may elicit twitching movements of the chin (quivering-chin phenomenon). This also may be seen when the patient is at rest, ie, not activating his facial muscles.
  • The voice changes and may become nasal. The tongue usually shows scalloping (irregularity of the borders) or a deep furrowing in the midline as the bundles of muscle forming the glossal group become wasted and separate at the midline (see Media file 5). Laryngospasm may occur.²⁷
  • Although bulbar involvement usually follows limb involvement, it is occasionally the presenting weakness.
  • Muscle strength may show a classic pattern of proximal-greater-than-distal impairment, beginning in the legs. However, Ferrante and Wilbourn showed variation in distribution of initial weakness ranging from symmetry to asymmetry, from proximal to distal predominant weakness, and from upper extremity to lower extremity.²⁸
  • In mild to moderately severe cases, prominence of bony landmarks should be sought to confirm wasting. If the patient is ambulatory, proximal weakness may cause a hyperlordotic standing posture and internally rotated arms, ie, simian stance, in which the thumbs point medially or toward the patient rather than straight forward (see Media file 1).
  • Fasciculations, or spontaneous discharges of single motor units, are seen easily in affected musculature. The patient should be evaluated at complete rest in a warm environment. In particular, care should be taken not to mistake postural movements in the tongue for fasciculations.
  • In weak muscles, minimal isometric activation or contraction of muscle may result in large, coarse, and regular movement of a portion of the muscle that superficially may resemble a fasciculation. This is sometimes (and unfortunately) called contraction fasciculation. In normal muscle, isometric activation or contraction of muscle is not associated with what appears to be a coarse and jerking movement.
    • In patients with chronic denervation-reinnervation in whom motor units are markedly enlarged (ie, a single motor neuron innervates more than twice the number of muscle fibers), these appear as twitches associated with activation.
    • Although not to be confused with fasciculations per se, these clinical findings are important, as their presence indicates a chronic neurogenic process until proven otherwise.
    • The quivering-chin phenomenon, when seen with facial muscle activation, may be related to this.
  • Muscle stretch responses are variable; they range from normal to depressed and are usually absent in the ankles. Generally, no upper motor neuron dysfunction occurs in KD; however, Pachatz et al show evidence for subclinical involvement using transcranial magnetic stimulation.²⁹
  • Sensation is often normal to the modalities of vibration perception, position sense, sharp touch, and light touch. When sensation is impaired, distinguishing a pattern that might suggest a diabetic polyneuropathy is important.
• General findings
  • Gynecomastia is probably the most common nonneurologic finding on examination, but it is not a criterion for diagnosis (see Media file 2).
  • Testicular atrophy, oligospermia and/or azoospermia, and erectile dysfunction may be present and typically occur in advanced cases.
  • In a clinical study, Sinclair et al found that men with KD may have a reduced risk of androgenetic alopecia compared with a cohort of white males of European descent without KD.³⁰

Causes

• Other diagnostic considerations Table 1. Primary Differential Diagnoses

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  Table

  Disease	Differentiating Characteristics or Tests
  ALS	Upper motor neuron involvement with tendency for distal-greater-than-proximal weakness
  Spinal muscular atrophy	See Table 2
  Fascioscapulohumeral muscular dystrophy	Autosomal dominant pattern with myopathic findings on muscle biopsy and EMG, positive genetic marker
  Myasthenia gravis - Adult acquired form	Extraocular muscle frequently involved, EMG consistent with neuromuscular transmission disorder, acetylcholine receptor antibodies frequently positive
  Oculopharyngeal muscular dystrophy	Autosomal dominant pattern, late onset, predominant involvement of bulbar muscle with ptosis and mild ophthalmoparesis, EMG and muscle biopsy results consistent with myopathic process, positive genetic marker
  Hexosaminidase A deficiency	Rectal biopsy, enzyme assay
  Sandhoff disease	Rectal biopsy, enzyme assay
  Syphilis (neurovascular form)	Positive serology
  Lead neuropathy	Index of suspicion based on potential exposure; anemia; elevated serum, blood, and urine lead levels
  Motor neuron disease with macroglobulinemia	Monoclonal gammopathy
  Autosomal dominant cerebellar ataxia type I	Amyotrophy occasionally prominent finding in SCAs, particularly types II and III; other clinical and laboratory findings suggest condition other than a pure motor-neuron process; appropriate tests of genetic markers for SCA
  Polymyositis	Elevated serum creatine kinase, EMG and muscle-biopsy results consistent with inflammatory myopathy
  Cervical spondylosis	Rostral cervical segmental myotomes (eg, C5, C6) commonly affected, but pattern on EMG testing is highly localizing; possible pyramidal-tract signs if spondylosis compresses spinal cord at same segmental level; no evidence of lower motor-neuro involvement in legs; imaging (eg, cervical MRI, myelography with low-dose CT) findings correlated with suspected lesion

  Disease	Differentiating Characteristics or Tests
  ALS	Upper motor neuron involvement with tendency for distal-greater-than-proximal weakness
  Spinal muscular atrophy	See Table 2
  Fascioscapulohumeral muscular dystrophy	Autosomal dominant pattern with myopathic findings on muscle biopsy and EMG, positive genetic marker
  Myasthenia gravis - Adult acquired form	Extraocular muscle frequently involved, EMG consistent with neuromuscular transmission disorder, acetylcholine receptor antibodies frequently positive
  Oculopharyngeal muscular dystrophy	Autosomal dominant pattern, late onset, predominant involvement of bulbar muscle with ptosis and mild ophthalmoparesis, EMG and muscle biopsy results consistent with myopathic process, positive genetic marker
  Hexosaminidase A deficiency	Rectal biopsy, enzyme assay
  Sandhoff disease	Rectal biopsy, enzyme assay
  Syphilis (neurovascular form)	Positive serology
  Lead neuropathy	Index of suspicion based on potential exposure; anemia; elevated serum, blood, and urine lead levels
  Motor neuron disease with macroglobulinemia	Monoclonal gammopathy
  Autosomal dominant cerebellar ataxia type I	Amyotrophy occasionally prominent finding in SCAs, particularly types II and III; other clinical and laboratory findings suggest condition other than a pure motor-neuron process; appropriate tests of genetic markers for SCA
  Polymyositis	Elevated serum creatine kinase, EMG and muscle-biopsy results consistent with inflammatory myopathy
  Cervical spondylosis	Rostral cervical segmental myotomes (eg, C5, C6) commonly affected, but pattern on EMG testing is highly localizing; possible pyramidal-tract signs if spondylosis compresses spinal cord at same segmental level; no evidence of lower motor-neuro involvement in legs; imaging (eg, cervical MRI, myelography with low-dose CT) findings correlated with suspected lesion

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

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  Table

  Pattern	Characteristics*
  Bulbar hereditary motor neuropathy affecting lowest 6 cranial nerves (Fazio-Londe disease)	Autosomal recessive, onset in childhood, limbs not affected; when associated with deafness, pattern called Vialleto-van Laere disease, which may be X-linked or autosomal dominant
  Scapuloperoneal hereditary motor neuropathy	Variable transmission: dominant, recessive, X-linked; pattern of weakness as described; bulbar muscles spared
  Fascioscapulohumeral hereditary motor neuropathy	Autosomal dominant, pattern of weakness as described
  Hereditary motor neuronopathy with oculopharyngeal involvement	Described in Japanese individuals; autosomal recessive or dominant; ophthalmoplegia, dysarthria, and dysphagia
  Hereditary proximal motor neuropathy	Variable dominant or recessive inheritance; onset usually in first 2 decades; bulbar muscles spared
  Hereditary distal motor neuropathy	Usually recessive inheritance; onset usually in first 2 decades; bulbar muscles spared; autosomal-dominant distal spinal muscular atrophy linked to chromosome 7 (same locus as that of hereditary sensorimotor neuropathy type 2D) 31

  Pattern	Characteristics*
  Bulbar hereditary motor neuropathy affecting lowest 6 cranial nerves (Fazio-Londe disease)	Autosomal recessive, onset in childhood, limbs not affected; when associated with deafness, pattern called Vialleto-van Laere disease, which may be X-linked or autosomal dominant
  Scapuloperoneal hereditary motor neuropathy	Variable transmission: dominant, recessive, X-linked; pattern of weakness as described; bulbar muscles spared
  Fascioscapulohumeral hereditary motor neuropathy	Autosomal dominant, pattern of weakness as described
  Hereditary motor neuronopathy with oculopharyngeal involvement	Described in Japanese individuals; autosomal recessive or dominant; ophthalmoplegia, dysarthria, and dysphagia
  Hereditary proximal motor neuropathy	Variable dominant or recessive inheritance; onset usually in first 2 decades; bulbar muscles spared
  Hereditary distal motor neuropathy	Usually recessive inheritance; onset usually in first 2 decades; bulbar muscles spared; autosomal-dominant distal spinal muscular atrophy linked to chromosome 7 (same locus as that of hereditary sensorimotor neuropathy type 2D) 31

  *In none of these diseases are results of test for the KD marker positive, and associated endocrinopathy or sensory nerve conduction abnormality should be absent.
• Other associated conditions with KD
  • Lipid disorders
    • Type II hyperlipoproteinemia
    • Type IV hyperlipoproteinemia
    • Hypobetalipoproteinemia
  • Endocrinopathy
    • Testicular atrophy
    • Oligospermia or azoospermia secondary to testicular atrophy
    • Gynecomastia
    • Diabetes mellitus
    • Elevated serum estradiol and gonadotropin
    • Pituitary microadenoma rare

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