History
See the list below:
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A typical constellation of complaints in Kennedy disease (KD) is an insidious onset of easy fatigability, muscle cramps, and weakness in the limbs.
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As the disease progresses, disability commensurately increases until the patient is wheelchair bound.
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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.
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Postural tremor and tremor in the upper extremities usually begins late in the course of the illness.
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Sensory complaints may be present, but they are rarely isolated findings.
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Patients may have complaints related to endocrinopathy, particularly diabetes. Because the onset of the disease is relatively late, complaints such as infertility or reduced libido may not be appreciated readily. Battaglia et al reported a case in which endocrinopathy was the presenting manifestation of KD. [49]
Physical
Neurologic findings
Cognition is unimpaired.
Examination of the cranial nerves usually shows evidence of weakness in the facial, palatal, and tongue muscles. (See images below.) The weakness may be so profound that the mouth hangs open and is tremulous. In the index case Kennedy et al reported, the facial weakness became so severe that the patient held his chin up with his hands to chew. Jaw drop may be a prominent feature. [50] Although eye movements are typically spared, there has been one case report of abnormal extra-ocular motility in KD. [12]
The forehead of this patient with Kennedy disease 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.
Contraction of perioral musculature may elicit twitching movements of the chin (quivering-chin phenomenon). This also may be seen when the patient is at rest, ie, not activating his facial muscles.
The voice changes and may become nasal. The tongue usually shows scalloping (irregularity of the borders) or a deep furrowing in the midline as the bundles of muscle forming the glossal group become wasted and separate at the midline. Laryngospasm may occur. [51] (See image below.)
Note the scalloping of the borders of the tongue, which strongly suggests wasting. In addition, the marked wasting of the large group of glossal muscles on each side has caused them to separate and form a midline furrow.
Although bulbar involvement usually follows limb involvement, it is occasionally the presenting weakness.
Muscle strength may show a classic pattern of proximal-greater-than-distal impairment, beginning in the legs. However, Ferrante and Wilbourn showed variation in distribution of initial weakness ranging from symmetry to asymmetry, from proximal to distal predominant weakness, and from upper extremity to lower extremity. [52]
In mild to moderately severe cases, prominence of bony landmarks should be sought to confirm wasting. If the patient is ambulatory, proximal weakness may cause a hyperlordotic standing posture and internally rotated arms, ie, simian stance, in which the thumbs point medially or toward the patient rather than straight forward (see image below).
Note wasting in the thighs and shoulders. The arms hang down and are rotated internally so that the thumbs point toward the patient (ie, simian posture) rather than forward, as in a healthy individual. This observation strongly suggests weakness in shoulder girdle muscles.
Fasciculations, or spontaneous discharges of single motor units, are seen easily in affected musculature. The patient should be evaluated at complete rest in a warm environment. In particular, care should be taken not to mistake postural movements in the tongue for fasciculations.
In weak muscles, minimal isometric activation or contraction of muscle may result in large, coarse, and regular movement of a portion of the muscle that superficially may resemble a fasciculation. This is sometimes (and unfortunately) called contraction fasciculation. In normal muscle, isometric activation or contraction of muscle is not associated with what appears to be a coarse and jerking movement.
In patients with chronic denervation-reinnervation in whom motor units are markedly enlarged (ie, a single motor neuron innervates more than twice the number of muscle fibers), these appear as twitches associated with activation.
Although not to be confused with fasciculations per se, these clinical findings are important, as their presence indicates a chronic neurogenic process until proven otherwise.
The quivering-chin phenomenon, when seen with facial muscle activation, may be the result of the activation of the few enlarged motor units.
Muscle stretch responses are variable; they range from normal to depressed and are usually absent in the ankles. Generally, no upper motor neuron dysfunction occurs in KD; however, Pachatz et al show evidence for subclinical involvement using transcranial magnetic stimulation, [53] but this finding was not confirmed in a subsequent study. [14]
Sensation is often clinically normal to the modalities of vibration perception, position sense, sharp touch, and light touch, despite the demonstration of abnormalities in morphology and autonomic testing. [11, 54, 55, 56] If sensation is impaired, it is important to distinguish a pattern that might suggest a diabetic polyneuropathy.
General findings
Gynecomastia is probably the most common nonneurologic finding on examination, but it is not a criterion for diagnosis (see image below).
Testicular atrophy, oligospermia and/or azoospermia, and erectile dysfunction may be present and typically occur in advanced cases.
In a clinical study, Sinclair et al found that men with KD may have a reduced risk of androgenetic alopecia compared with a cohort of white males of European descent without KD. [57]
Causes
Table 1. Primary Differential Diagnoses of Kennedy Disease (Open Table in a new window)
Disease
|
Differentiating Characteristics or Tests
|
ALS |
Upper motor neuron involvement with tendency for distal-greater-than-proximal weakness [58] |
Spinal muscular atrophy |
See Table 2 below |
Fascioscapulohumeral muscular dystrophy |
Autosomal dominant pattern with myopathic findings on muscle biopsy and EMG, positive genetic marker |
Myasthenia gravis - Adult acquired form |
Extraocular muscle frequently involved, EMG consistent with neuromuscular transmission disorder, acetylcholine receptor antibodies frequently positive |
Oculopharyngeal muscular dystrophy |
Autosomal dominant pattern, late onset, predominant involvement of bulbar muscle with ptosis and mild ophthalmoparesis, EMG and muscle biopsy results consistent with myopathic process, positive genetic marker |
Hexosaminidase A deficiency |
Rectal biopsy, enzyme assay |
Sandhoff disease |
Rectal biopsy, enzyme assay |
Syphilis (neurovascular form) |
Positive serology |
Lead neuropathy |
Index of suspicion based on potential exposure; anemia; elevated serum, blood, and urine lead levels |
Motor neuron disease with macroglobulinemia |
Monoclonal gammopathy [59] |
Autosomal dominant cerebellar ataxia type I |
Amyotrophy occasionally prominent finding in SCAs, particularly types II and III; other clinical and laboratory findings suggest condition other than a pure motor-neuron process; appropriate tests of genetic markers for SCA |
Polymyositis |
Elevated serum creatine kinase, EMG and muscle-biopsy results consistent with inflammatory myopathy |
Cervical spondylosis |
Rostral cervical segmental myotomes (eg, C5, C6) commonly affected, but pattern on EMG testing is highly localizing; possible pyramidal-tract signs if spondylosis compresses spinal cord at same segmental level; no evidence of lower motor-neuro involvement in legs; imaging (eg, cervical MRI, myelography with low-dose CT) findings correlated with suspected lesion |
Facial onset sensory and motor neuropathy (FOSMN syndrome) [60, 61] |
Slow progressing, trigeminal-onset sensory loss that may spread to upper limbs and torso, associated with lower motor syndrome with prominent bulbar involvement |
Table 2. Patterns of Hereditary Spinal Muscular Atrophies that May Resemble Kennedy Disease (Open Table in a new window)
Pattern
|
Characteristics*
|
Bulbar hereditary motor neuropathy affecting lowest 6 cranial nerves (Fazio-Londe disease) |
Autosomal recessive, onset in childhood, limbs not affected; when associated with deafness, pattern called Vialleto-van Laere disease, which may be X-linked or autosomal dominant |
Scapuloperoneal hereditary motor neuropathy |
Variable transmission: dominant, recessive, X-linked; pattern of weakness as described; bulbar muscles spared |
Fascioscapulohumeral hereditary motor neuropathy |
Autosomal dominant, pattern of weakness as described |
Hereditary motor neuronopathy with oculopharyngeal involvement |
Described in Japanese individuals; autosomal recessive or dominant; ophthalmoplegia, dysarthria, and dysphagia |
Hereditary proximal motor neuropathy |
Variable dominant or recessive inheritance; onset usually in first 2 decades; bulbar muscles spared |
Hereditary distal motor neuropathy |
Usually recessive inheritance; onset usually in first 2 decades; bulbar muscles spared; autosomal-dominant distal spinal muscular atrophy linked to chromosome 7 (same locus as that of hereditary sensorimotor neuropathy type 2D) [62] |
*In none of these diseases are results of test for the KD marker positive, and associated endocrinopathy or sensory nerve conduction abnormality should be absent. |
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Other conditions associated with KD include the following:
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Lipid disorders
Type II hyperlipoproteinemia
Type IV hyperlipoproteinemia
Hypobetalipoproteinemia
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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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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.
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Prominence of breast tissue consistent with gynecomastia in Kennedy disease.
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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 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).
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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 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.
Tables
Disease
|
Differentiating Characteristics or Tests
|
ALS |
Upper motor neuron involvement with tendency for distal-greater-than-proximal weakness [58] |
Spinal muscular atrophy |
See Table 2 below |
Fascioscapulohumeral muscular dystrophy |
Autosomal dominant pattern with myopathic findings on muscle biopsy and EMG, positive genetic marker |
Myasthenia gravis - Adult acquired form |
Extraocular muscle frequently involved, EMG consistent with neuromuscular transmission disorder, acetylcholine receptor antibodies frequently positive |
Oculopharyngeal muscular dystrophy |
Autosomal dominant pattern, late onset, predominant involvement of bulbar muscle with ptosis and mild ophthalmoparesis, EMG and muscle biopsy results consistent with myopathic process, positive genetic marker |
Hexosaminidase A deficiency |
Rectal biopsy, enzyme assay |
Sandhoff disease |
Rectal biopsy, enzyme assay |
Syphilis (neurovascular form) |
Positive serology |
Lead neuropathy |
Index of suspicion based on potential exposure; anemia; elevated serum, blood, and urine lead levels |
Motor neuron disease with macroglobulinemia |
Monoclonal gammopathy [59] |
Autosomal dominant cerebellar ataxia type I |
Amyotrophy occasionally prominent finding in SCAs, particularly types II and III; other clinical and laboratory findings suggest condition other than a pure motor-neuron process; appropriate tests of genetic markers for SCA |
Polymyositis |
Elevated serum creatine kinase, EMG and muscle-biopsy results consistent with inflammatory myopathy |
Cervical spondylosis |
Rostral cervical segmental myotomes (eg, C5, C6) commonly affected, but pattern on EMG testing is highly localizing; possible pyramidal-tract signs if spondylosis compresses spinal cord at same segmental level; no evidence of lower motor-neuro involvement in legs; imaging (eg, cervical MRI, myelography with low-dose CT) findings correlated with suspected lesion |
Facial onset sensory and motor neuropathy (FOSMN syndrome) [60, 61] |
Slow progressing, trigeminal-onset sensory loss that may spread to upper limbs and torso, associated with lower motor syndrome with prominent bulbar involvement |
Pattern
|
Characteristics*
|
Bulbar hereditary motor neuropathy affecting lowest 6 cranial nerves (Fazio-Londe disease) |
Autosomal recessive, onset in childhood, limbs not affected; when associated with deafness, pattern called Vialleto-van Laere disease, which may be X-linked or autosomal dominant |
Scapuloperoneal hereditary motor neuropathy |
Variable transmission: dominant, recessive, X-linked; pattern of weakness as described; bulbar muscles spared |
Fascioscapulohumeral hereditary motor neuropathy |
Autosomal dominant, pattern of weakness as described |
Hereditary motor neuronopathy with oculopharyngeal involvement |
Described in Japanese individuals; autosomal recessive or dominant; ophthalmoplegia, dysarthria, and dysphagia |
Hereditary proximal motor neuropathy |
Variable dominant or recessive inheritance; onset usually in first 2 decades; bulbar muscles spared |
Hereditary distal motor neuropathy |
Usually recessive inheritance; onset usually in first 2 decades; bulbar muscles spared; autosomal-dominant distal spinal muscular atrophy linked to chromosome 7 (same locus as that of hereditary sensorimotor neuropathy type 2D) [62] |
*In none of these diseases are results of test for the KD marker positive, and associated endocrinopathy or sensory nerve conduction abnormality should be absent. |
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