Additional Investigation After the Muscle and Nerve Biopsy Diagnosis

Based on the predominant motor weakness involving the facial, bulbar, and limb muscles, the chronicity of the neurogenic changes on needle EMG, and the nerve and muscle biopsy findings, a motor neuron disease, spinobulbar muscular atrophy (Kennedy’s disease), was strongly suspected. The chronic myopathic changes on muscle biopsy were felt to represent pseudomyothic changes. The subsequent gene test showed an abnormal expansion of the CAG tandem repeat (47 CAG repeats) (normal: 11–33; borderline: 34–39) in the androgen receptor gene, confirming the diagnosis of Kennedy’s disease.

Final Diagnosis

Kennedy’s disease

Patient Follow-up

The patient was referred to a motor neuron disease clinic for multidisciplinary care. His weakness slowly progressed over the course of 2 years.

Discussion

Kennedy’s disease, also known as spinobulbar muscular atrophy , is a rare X-linked recessive hereditary motor neuron disease [1]. It is caused by an expansion of the CAG tandem repeat in the androgen receptor gene [2]. The disease affects lower motor neurons in the brainstem and spinal cord with resultant slowly progressive facial, bulbar, and limb weakness [3]. In addition to the weakness, patients may also show evidence of sensory neuropathy and signs of androgen deficiency such as poor sexual function, reduced fertility, and gynecomastia [3, 4].

The mean age at onset is 40s [5, 6]. There is a wide range of age at symptom onset, which inversely correlates with the size of the CAG repeat expansion [7, 8]. The disease onset is insidious. The initial symptom in a majority of the patients is caused by proximal leg weakness with difficulty getting up from a low chair or difficulty climbing stairs. This is followed by bulbar, facial, and other limb muscle weakness that manifests dysarthria, dysphagia, and weakness in the upper limbs. Patients may note fasciculations and cramping in the affected muscles as well as postural hand or leg tremors. They may also report sexual dysfunction and reduced fertility. Cardiac and respiratory muscles are usually not affected. Besides dysarthria, muscle atrophy, and weakness, examination often detects tongue atrophy and fasciculations, quivering chin (perioral fasciculations-myokymia), diffusely diminished tendon reflexes, and gynecomastia. It is also not uncommon to detect asympatomatic distal sensory loss as seen in our patient. It has been shown that bulbar symptoms, gynecomastia, and insulin resistance, but not the disease progression rate, correlate with the length of the CAG repeat [5, 9]. Serum CK level is mildly or moderately elevated from 200 s to 2,000 s U/L in a majority of the patients, and CK elevation is also seen in other motor neuron diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and post-polio syndrome [10–13]. CK elevation is more significant in Kennedy’s disease than in ALS [10], which may lead to a misdiagnosis of a primary myopathy. The etiology of CK elevation in motor neuron diseases is not fully understood. EMG in Kennedy’s disease typically shows diffuse active denervation changes including fibrillations and positive sharp waves, and more prominent chronic denervation-reinnervation changes including reduced recruitment and giant motor unit potentials [14]. In most of the patients with Kennedy’s disease, including our patient, NCS shows a sensory neuropathy [14], a feature that distinguishes Kennedy’s disease from other motor neuron diseases such as ALS, primary muscular atrophy, and adult-onset spinal muscular atrophy (SMA). The abnormality is caused primarily by distally accentuated sensory axonopathy with dorsal root ganglion cells less affected [15]. Kennedy’s disease does not affect upper motor neurons with no upper motor neuron signs, another useful feature that differentiates Kennedy’s disease from ALS.

The diagnosis of Kennedy’s disease is made by genetic testing, which is commercially available. The disease diagnosis, however, is often delayed by several years [6] due to the insidious onset, slow progression of weakness, co-existing sensory neuropathy, CK elevation, lack of gynecomastia or a positive family history in some patients, and lack of awareness. Although a muscle biopsy is not needed for the diagnosis of Kennedy’s disease, it is sometimes done before a high clinical suspicion for Kennedy’s disease is raised to rule out other disorders which can affect both motor and sensory nerves/neurons. As illustrated here, a sural nerve biopsy in Kennedy’s disease shows chronic axonal neuropathy , consistent with the findings by another study [15]. A muscle biopsy in Kennedy’s disease can be difficult to interpret as seen in our case [4]. Biopsy of a muscle with relatively preserved strength or mild weakness often shows prominent neurogenic changes, such as esterase-positive denervated fibers, pyknotic nuclear clumps, target or targetoid fibers, grouped atrophy, and rare fiber type grouping. Biopsy of a muscle with significant weakness usually shows chronic myopathic changes in addition to the neurogenic changes, such as increased fiber size variation, increased number of internalized nuclei, fiber splitting, and endomysial fibrosis [10, 16]. Occasional necrotic fibers, regenerating fibers, rimmed vacuoles, and minimal inflammation may also be seen [10]. The chronic myopathic changes have been reported in other motor neuron diseases, such as ALS and post-polio syndrome [17, 18]. They are attributed to long-standing denervation to represent pseudomyopathic changes [19]. In Kennedy’s disease, the accumulation of mutant androgen receptor protein may also contribute to the myopathic changes [16]. It has been shown that type grouping of normal-sized fibers is common in peripheral neuropathy but rare in motor neuron diseases, and that grouped atrophy in motor neuron diseases or motor neuropathies usually consists of mixed type 1 and type 2 atrophic fibers [20].

The disease progression in Kennedy’s disease is slow as compared with other motor neuron diseases such as ALS. The median age of using a wheelchair is 60 years [5], and the lifespan is not significantly affected [7]. Due to the bulbar involvement, the risk of chocking and aspiration pneumonia is high. Currently, there is no effective disease-modifying therapy. The management is mainly supportive to prevent falls and aspiration pneumonia by rehabilitation and swallow evaluation with diet modification. Genetic counseling should be provided.

The exact pathogenic mechanism of the CAG repeat expansion in the androgen receptor gene remains elusive. The available evidence supports that the neurodegeneration is caused by the androgen-dependent gain of toxic functions [21, 22]. Upon ligand binding, the mutant androgen receptor proteins translocate from cytoplasm to nucleus causing toxic aggregations and cell dysfunction [22]. The CAG repeat encodes a polyglutamine tract. There are widespread nuclear and cytoplasmic inclusions containing mutant polyglutamine androgen receptor in patients with Kennedy’s disease [23]. Suppressing peripheral and muscle expression of mutant polyglutamine androgen receptor has been shown effective in treating a mouse model of Kennedy’s disease [24, 25]. Clinical trials in human patients with Kennedy’s disease have been targeting the androgen receptor ligand to reduce its binding to the receptor and subsequent toxicity. Leuprorelin, but not dustasteride, showed a mild benefit in delaying the functional decline [26, 27]. Clenbuterol, a β2-adrenoceptor agonist, also appeared beneficial in a pilot study [28]. Future therapy development may also target the CAG repeat expansion.

Pearls