Kennedy disease or Foster Kennedy syndrome exhibits through muscle atrophy, and is untreatable. Learn more about Kennedy disease from doctors at Meri Sehat.

Kennedy's Disease

PNS SHIFA

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Syed Intisar Hussain

Overview

<p>Kennedy&#39;s disease is a rare hereditary condition. One of its synonyms is spinal and bulbar muscular atrophy (SBMA). The term &quot;bulbar&quot; describes a bulb-shaped lower brain area regulating voluntary muscular action. The condition has an impact on specific nerve cells in the brainstem and spinal cord.</p>

<p>There are several synonyms of Kennedy&#39;s disease, such as Kennedy&#39;s syndrome, spinal bulbar muscular atrophy, X-linked spinal and bulbar muscular atrophy, and X-linked spinobulbar muscular atrophy.</p>

<p>It belongs to a class of conditions known as lower motor neuron diseases, which involve disruptions in the transmission of nerve cell signals in the brainstem and spinal cord. Although it has been identified in men as young as teenagers and as old as 70, the condition often manifests between the ages of 20 and 40.</p>

<p>A defect on the X chromosome causes SBMA to develop. So, females can be carriers (2X chromosomes), but males have only one X chromosome and hence will develop Kennedy disease if they inherit the X chromosome containing the disease gene.&nbsp;</p>

<div>&nbsp;</div>

<p>The disorder known as Kennedy disease was first described in an abstract in 1966 and in a full report in 1968 by William R. Kennedy.&nbsp;It is extremely rare in females and affects about 1 in 40,000 persons worldwide. The United States, Australia, Europe, Asia, and South America have all reported cases of Kennedy&rsquo;s disease. It appears to be particularly common in the Japanese population due to a founder effect<sup><a href="#accordion">[1]</a></sup>. Roughly 3.3 per 100,000 males are affected by Kennedy&#39;s disease<sup><a href="#accordion">[2]</a></sup>.&nbsp;</p>

<div>&nbsp;</div>

Signs And Symptoms

<p>Not every individual with Kennedy&rsquo;s disease will exhibit symptoms. They typically begin to appear in individuals between the ages of 20-50. However, the affected individuals go on to achieve the maximum possible standard of living if they are provided with proper support.<br />
&nbsp;</p>

<h5><strong>Neurological Symptoms</strong></h5>

<p>People with Kennedy&#39;s disease may experience a number of neurological symptoms, such as:</p>

<ul>
	<li>Swallowing issues that influences how the patient consumes food and liquids</li>
	<li>Trembling hands&nbsp;</li>
	<li>Lack of reflexes (e.g., there is no foot movement in response to tapping on the tendon below the kneecap)</li>
	<li>Muscle weakness and wastage (loss of muscle mass) in arms, legs, and face</li>
	<li>Numbness</li>
</ul>

<p>&nbsp;</p>

<h5><strong>Muscular Symptoms</strong></h5>

<p>The pathophysiology of Kennedy&#39;s disease is heavily influenced by muscle symptoms which can severely impact patients. These consist of:</p>

<ul>
	<li>Twitching and fasciculations (rippling sensations beneath the skin)</li>
	<li>Cramping&nbsp;</li>
	<li>Tremors and trembling in specific positions&nbsp;<br />
	&nbsp;</li>
</ul>

<h5><strong>Other Symptoms</strong></h5>

<p>Aside from the neurological and muscular symptoms, Kennedy&#39;s disease patients also frequently experience the following symptoms:</p>

<ul>
	<li>Slurred speech that interferes with communication.</li>
	<li>Enlarged breast glands which cause the growth of male breast tissue.</li>
	<li>Decreased sexual drive and <a href="https://merisehat.pk/disease/erectile-dysfunction" target="_blank">erectile dysfunction</a>.</li>
	<li>Hormonal changes and a low sperm count<a href="https://www.merisehat.pk/disease/infertility-in-men" target="_blank"> impair fertility</a>.</li>
	<li>Testicular enlargement.</li>
</ul>

<p>&nbsp;</p>

<p>One side of the body may occasionally be more impacted than the other. Patients can have hand and muscular tremors for many years before any weakening appears.&nbsp;Muscles start to weaken and deteriorate with time. This increases the risk of falls and injuries; mobility is not just exhausting but also challenging since the individual&rsquo;s posture and balance are affected.<br />
&nbsp;</p>

<p>Some of the main symptoms of SBMA are also seen in other neuromuscular diseases. These consist of:</p>

<ul>
	<li>Amyotrophic lateral sclerosis or Lou Gehrig&rsquo;s disease</li>
	<li>Myasthenia gravis</li>
	<li>Adrenoleukodystrophy&nbsp;</li>
</ul>

<p>&nbsp;</p>

<p>It&rsquo;s easy to confuse these conditions when their symptoms overlap; hence, a differential diagnosis of the above should also include Kennedy&#39;s disease and vice versa.</p>

<div>&nbsp;</div>

Causes

<p>The androgen receptor protein on the X chromosome is encoded by the AR gene. Mutation in the AR gene leads to Kennedy&rsquo;s syndrome. Each gene has 4 fundamental nucleotide bases in different arrangements:</p>

<p>&nbsp;</p>

<ul>
	<li>Adenine (A)</li>
	<li>Cytosine (C)&nbsp;</li>
	<li>Guanine (G)</li>
	<li>Thymine (T)&nbsp;</li>
</ul>

<p>&nbsp;</p>

<p>In diseased individuals, an abnormal section in the AR gene is seen due to the&nbsp; excessive number of CAG trinucleotide repetitions in the DNA sequence for example: an average person has 10-35 CAG repeats; a person with Kennedy illness has more than 36 CAG repeats.</p>

<p>The androgen receptor&#39;s typical job is to assist cells in processing androgens (male hormones). These receptors are present in many body tissues such as the skin, prostate, skeletal muscle, and the central nervous system motor neurons in the spinal cord and brainstem. When the androgen receptor is defective, it cannot adequately form a hormone-receptor complex and consequently signaling genes to increase protein production for various functions is hampered.</p>

<p>While the exact mechanism for neuronal impairment remains to be elucidated, there is evidence to believe that it might be due to the altered functioning of the mutant androgen receptor.&nbsp;&nbsp;</p>

<p>SBMA is caused by a gene defect on the X chromosome, resulting in an X-linked inheritance pattern. Males have a pairing of XY sex chromosomes, while females have XX chromosomes. Females with X-linked illness typically have a gene defect on 1 X chromosome (although sometimes the mild disease is probable). On the other hand, males often exhibit the full impact of the mutation on their single X chromosome since they lack a second X to safeguard them.</p>

<p>There is a 50% probability that each mother&#39;s son who carries an X-linked disease will inherit the gene defect and become ill. Every daughter has a 50% probability of acquiring the gene defect and becoming a carrier.</p>

<p>Genetic tests can help diagnose SBMA and identify SBMA carriers.</p>

<div>&nbsp;</div>

Diagnosis

<p>Kennedy&#39;s disease is diagnosed primarily on outward physical symptoms and indications. An in-person physical examination, a review of the patient&#39;s family history, and a few painless tests are typically the first stages in diagnosing a neuromuscular disorder like Kennedy&rsquo;s disease. Several tests can be used to diagnose it, including:<br />
&nbsp;</p>

<ul>
	<li>
	<h5><strong>Molecular Genetic Testing</strong></h5>
	</li>
</ul>

<p>Testing for cytosine-adenosine-guanosine (CAG) trinucleotide repeats in the AR gene using molecular genetics on a blood sample can confirm the diagnosis of the condition. The abnormal portion of the AR gene with more than 36 CAG trinucleotide repeats, confirms the disease in patients.<br />
&nbsp;</p>

<ul>
	<li>
	<h5><strong>Blood Test To Check For Increased Serum Creatine Kinase (CK)&nbsp;</strong></h5>
	</li>
</ul>

<p>People with Kennedy&#39;s syndrome typically have more of this specific enzyme circulating in their blood than the general population. The physician may prescribe a quick blood test for an enzyme called creatine kinase (CK) as this enzyme emerges from degenerating muscles.&nbsp;Despite being generic (since CK levels are increased in many neuromuscular disorders), this test is frequently helpful.<br />
&nbsp;</p>

<ul>
	<li>
	<h5><strong>Genetic Tests Using Blood Samples&nbsp;</strong></h5>
	</li>
</ul>

<p>Even if a person has no symptoms or is a carrier, this test can determine whether Kennedy&#39;s disease gene is present. Genetic assistance and counseling are crucial.&nbsp;<br />
&nbsp;</p>

<ul>
	<li>
	<h5><strong>Clinical Evaluation And Follow-Up</strong></h5>
	</li>
</ul>

<p>There may be a need for annual tests to measure muscular strength.<br />
&nbsp;</p>

<ul>
	<li>
	<h5><strong>Electromyography (EMG)&nbsp;</strong></h5>
	</li>
</ul>

<p>EMG is a test in which a small needle is inserted into a muscle to measure and evaluate electrical activity in the muscle. Kennedy&rsquo;s disease can be considered when an EMG is abnormal and shows complex repetitive discharges, quivering muscles and fasciculations.<br />
&nbsp;</p>

<h5><strong>Differential Diagnosis Of Kennedy Disease&nbsp;</strong></h5>

<p>Kennedy&rsquo;s disease has similar symptoms to other diseases e.g.Amyotrophic lateral sclerosis (ALS), Adrenoleukodystrophy (ALD), etc. Hence differential diagnoses can help rule out other diseases.&nbsp;&nbsp;</p>

<p>&nbsp;</p>

<p>Less likely differential diagnoses include conditions with lower motor neuron presentations, such as:<br />
&nbsp;</p>

<ul>
	<li>Hirayama disease</li>
	<li>Multifocal motor neuropathy</li>
	<li>Spinal muscular atrophy (SMA)</li>
	<li>Post-polio syndrome (PPS)</li>
	<li>Progressive bulbar palsy (PBP)</li>
	<li>Progressive muscular atrophy (PMA)</li>
	<li>Spinal cord ischemia</li>
	<li>Myelopathies&nbsp;</li>
	<li>Charcot-Marie-Tooth disease</li>
</ul>

<p>&nbsp;</p>

<p>Most of these conditions have specific radiological, molecular or electrophysiological features which help to distinguish them from KD. The other differential diagnoses depend on the initial constellation of clinical signs or symptoms, which are often extra-neurological.</p>

<div>&nbsp;</div>

Treatment

<p>There is currently no known treatment for the disease, and no drugs have been shown to halt the disease&#39;s progression or reverse it. Treatments are available, nevertheless, to control symptoms and lessen their intensity.</p>

<p>It&#39;s critical to realize that SBMA is a chronic condition. In other words, it will get worse with time. Most SBMA patients eventually require live-in caretakers.<br />
&nbsp;</p>

<ol>
	<li>Gynecomastia and erectile dysfunction are symptoms of SBMA that are frequently treated with testosterone, although this can potentially worsen the condition. Another option for patients with SBMA who have gynecomastia is breast reduction surgery.</li>
	<li>Symptoms are frequently treated with prescription medications for tremors and cramping in the muscles. These might alleviate discomfort and agony but do not impact how SBMA works.</li>
	<li>Physical Therapy And Lifestyle Adjustments (occupational therapy and speech therapy) are commonly used to adapt to the progressing disease and maintain an individual&rsquo;s skills for e.g., it is advised to practice safe and efficient swallowing techniques with a speech-language pathologist (SLP) or dysphagia specialist.</li>
	<li>Swallowing issues frequently contribute to early mortality in SBMA patients as a result of complications, including pneumonia or asphyxiation. Splitting food into tiny pieces prevents a person from choking because swallowing and chewing is easier.&nbsp;</li>
	<li>Respiratory therapy in this case may be beneficial if the patient is frequently finding it a challenge to breathe. Additionally, breathing might be a little bit simpler with the help of ventilation devices, like a bi-level positive air pressure device.</li>
	<li>In order to walk securely and prevent injuries from falls, it may be necessary to use a mobility aid (e.g., cane, wheelchair, braces and walkers etc.) as the leg muscles can weaken over time. Physical therapy may assist a person with SBMA.</li>
</ol>

<div>&nbsp;</div>

<p>&nbsp;</p>

<h5><strong>1. Endocrine Changes</strong></h5>

<p>Endocrine issues usually appear before neurological symptoms and result from partial androgen insensitivity. Gynecomastia may be present in as many as 73&ndash;78% of male Kennedy&rsquo;s disease patients. It usually manifests itself after puberty and is brought on by a diminished sensitivity to testosterone. Additionally, typical symptoms include erectile dysfunction and reduced libido<sup><a href="#accordion">[6]</a></sup>.<br />
&nbsp;</p>

<h5><strong>2. Bone Involvement</strong></h5>

<p>In a study, 36% of individuals had lumbar and/or femoral osteopenia (low bone mass) and 5% of individuals had femoral osteoporosis as determined by bone osteo-densitometry. The mean bone mineral density (BMD) of Kennedy&rsquo;s disease patients was reduced in the femur and conserved in the lumbar vertebrae compared to healthy participants<sup><a href="#accordion">[6]</a></sup>.&nbsp;</p>

<p>Lower limb weakness might result in relative inactivity due to decreased BMD. However, there is no connection between lumbar BMD and motor impairment. It&rsquo;s also interesting to note that nearly 65% of Kennedy&rsquo;s disease patients have vitamin D insufficiency<sup><a href="#accordion">[6]</a></sup>.<br />
&nbsp;</p>

<h5><strong>3. Cardiac Involvement</strong></h5>

<p>It has been repeatedly documented that potentially fatal conduction problems appear as Brugada-type ECG changes with ST elevation in the precordial V1 to V3 leads, generating a distinctive &quot;coved&quot; upward convex ST pattern. This could be connected to severe ventricular tachyarrhythmias that could be a risk factor for sudden cardiac death. The frequency of Brugada-type ECG abnormalities was 4% in one of the most extensive datasets of 144 Kennedy&rsquo;s disease patients and was associated with 2 episodes of sudden cardiac death<sup><a href="#accordion">[6]</a></sup>.<br />
&nbsp;</p>

<h5><strong>4. Genito-Urinary Disorders</strong></h5>

<p>Using the International Prostate Symptom Score (IPSS) questionnaire, a major study found that 73 Kennedy disease patients had genitourinary diseases far more frequently than an average person. 30% of patients had moderate dysuria, whereas 10% had severe dysuria. 3 individuals additionally needed a suprapubic catheter<sup><a href="#accordion">[6]</a></sup>.</p>

<p>Although the precise mechanism is still unknown, several theories have been presented, including the possibility that androgen insensitivity could contribute to bladder obstruction, straight detrusor and perineal muscle dysfunction, and dysautonomia. Erectile dysfunction is more prevalent in Kennedy&rsquo;s disease, but its prevalence has only been examined in a few studies<sup><a href="#accordion">[6]</a></sup>.</p>

<div>&nbsp;</div>

<p>As SBMA is an X-linked hereditary condition that causes spinal and bulbar muscular atrophy, its risk factor includes having a parent with an abnormal portion of the AR gene.&nbsp;<br />
&nbsp;</p>

<ul>
	<li>Affected males with X-linked disorders will always pass the gene to their daughters, but will only pass their normal Y chromosome to their sons. Therefore, all of the daughters of an affected male will be carriers for the disease, but the sons of an affected male will not have the disease.&nbsp;</li>
	<li>However, sons of female carriers have a 50% chance of inheriting the disease, while daughters have a 50% chance of becoming carriers.</li>
</ul>

<div>&nbsp;</div>

<p>&nbsp;</p>

<h5><strong>Effect Of Aerobic Training In Patients With Spinal And Bulbar Muscular Atrophy</strong></h5>

<p>Researchers looked at how patients with spinal and bulbar muscular atrophy responded to aerobic exercise (SBMA)<sup><a href="#accordion">[7]</a></sup>. For 12 weeks, 8 SBMA patients cycled on a regular basis. Measures of maximum oxygen uptake (Vo2max), maximum work capacity (Wmax), muscle morphology, citrate synthase (CS) activity, body composition, EMG, static strength, lung function, plasma proteins, and hormones were taken before and after training. Following the training, an evaluation of the gains in activities of daily living was carried out.</p>

<p>Patients with spinal and bulbar muscular atrophy did not benefit much from routine, moderate-intensity aerobic exercise (SBMA). High plasma creatine kinase levels and evidence of muscle regeneration point to a primary myopathic condition which, along with motor neuron insufficiency, may blunt the effects of exercise training in SBMA patients.<br />
&nbsp;</p>

<h5><strong>The Spinal And Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS)</strong></h5>

<p>The scale has been proposed to assess the degree of function in people with Kennedy&#39;s disease. The functional aspects of the disease are divided into 4 subscales by this scale:<br />
&nbsp;</p>

<ul>
	<li>Bulbar-Related Subscale</li>
	<li>Breathing Related Subscale</li>
	<li>Lower-Limb Related Subscale</li>
	<li>Upper-Limb Related Subscale</li>
</ul>

<p>&nbsp;</p>

<p>The SBMAFRS exhibits good validity, but inadequate sensitivity to change over time. Further prospective cohort studies are warranted to capture SBMAFRS&rsquo; ability to capture longitudinal responsiveness.<br />
&nbsp;</p>

<h5><strong>Biomarkers Under Research&nbsp;</strong></h5>

<p>&nbsp;</p>

<p><strong>1. Disease Mechanism, Biomarker, And Therapeutics For Spinal And Bulbar Muscular Atrophy (SBMA)</strong></p>

<p>Lower motor neurons are significantly impacted in the central nervous system. Still, pathophysiology in patient and animal models also shows that skeletal muscle fibers are involved, including a loss of fast-twitch type 2 fibers, a rise in slow-twitch type 1 fibers, and a metabolic switch from glycolysis to oxidation<sup><a href="#accordion">[3]</a></sup>.</p>

<p>Biochemical indicators, including the blood creatinine level and MRI examination of muscle and fat, are potential biomarkers to monitor the course of the disease. Reportedly, the serum creatinine level begins to decline before there is any sign of muscle weakness, such as hand tremors, which is a prodromal symptom of the disease.</p>

<p>An essential stage in the pathophysiology is an androgen-dependent nuclear accumulation of the polyglutamine-expanded AR, which offers treatment options through hormonal modulation and gene silencing with antisense oligonucleotides. Additionally, animal studies point to a mitochondrial deficit, altered autophagy, and hyperactivation of Src as the underlying causes of SBMA&#39;s neuromuscular degeneration and alternate treatment options.<br />
&nbsp;</p>

<p><strong>2. 6-MWT&nbsp;</strong>&nbsp;</p>

<p>In one study, Kennedy&#39;s disease patients were given the 6-Minute Walk Test or 6MWT and it was discovered that there was a considerable reduction in walking distance between those with the disease and a control group (n=35). According to the study&#39;s findings, the 6MWT could be employed as a biomarker for disease development<sup><a href="#accordion">[4]</a></sup>.&nbsp;<br />
&nbsp;</p>

<p>In a different investigation, the following outcome measures were used to assess 34 patients with Kennedy&#39;s disease:<br />
&nbsp;</p>

<ul>
	<li>Modified Norris Scale</li>
	<li>Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R)</li>
	<li>6-Minute Walk Test</li>
	<li>Grip Strength using a hand dynamometer</li>
	<li>Modified Quantitative Myasthenia Gravis Score</li>
	<li>5-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5)</li>
</ul>

<p>&nbsp;</p>

<p>Except for the ALSAQ-5, all outcome variables in this study&#39;s longitudinal examination over a 3-year period demonstrated a statistically significant difference in disease progression.<br />
&nbsp;</p>

<h5><strong>Treatment Options Under Research&nbsp;</strong></h5>

<ol>
	<li>Mixed outcomes have been found in studies using anti-androgen medications to prevent the effects of the AR gene. The evidence for utilizing these medications to treat the condition is still insufficient.</li>
	<li>The Muscular Dystrophy Association claims that a novel class of medications known as selective androgen receptor modulators (SARMs) is now being investigated. According to experts, the severity of SBMA may one day be prevented or lessened thanks to these medications.</li>
	<li>A 2013 study found that the medicine clenbuterol seems to increase SBMA patients&#39; stamina levels. Clenbuterol is a drug with steroid-like characteristics primarily used to treat asthma<sup><a href="#accordion">[5]</a></sup>. However, further research is needed prior to its utilization in the mainstream therapeutic outline.&nbsp;</li>
</ol>

<div>&nbsp;</div>

Key Points

<ul>
	<li>Kennedy&#39;s disease is a rare genetic neuromuscular illness that results in progressive weakness and atrophy of the muscles, especially the arms and legs.</li>
	<li>It is caused by a genetic mutation in the androgen receptor gene on the X chromosome.</li>
	<li>Unfortunately, there is currently no cure but symptomatic management can help improve the patient&rsquo;s quality of life.&nbsp;</li>
	<li>With supportive treatment, patients with Kennedy&rsquo;s disease are usually able to lead productive lives.</li>
	<li>Several facets of the disease are under research: medications, biomarkers, etc.&nbsp;</li>
</ul>

<div>&nbsp;</div>

[1] Breza M, Koutsis G. Kennedy’s disease (spinal and bulbar muscular atrophy): a clinically oriented review of a rare disease. J Neurol. 2019;266(3):565–73.

[2] Finsterer J. Perspectives of Kennedy’s disease. J Neurol Sci. 2010;298(1–2):1–10.

[3] Hashizume A, Fischbeck KH, Pennuto M, Fratta P, Katsuno M. Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA). J Neurol Neurosurg \& Psychiatry. 2020;91(10):1085–91.

[4] Takeuchi Y, Katsuno M, Banno H, Suzuki K, Kawashima M, Atsuta N, et al. Walking capacity evaluated by the 6-minute walk test in spinal and bulbar muscular atrophy. Muscle \& nerve. 2008;38(2):964–71.

[5] Querin G, D’Ascenzo C, Peterle E, Ermani M, Bello L, Melacini P, et al. Pilot trial of clenbuterol in spinal and bulbar muscular atrophy. Neurology. 2013;80(23):2095–8

[6] Pradat P-F, Bernard E, Corcia P, Couratier P, Jublanc C, Querin G, et al. The French national protocol for Kennedy’s disease (SBMA): consensus diagnostic and management recommendations. Orphanet J Rare Dis. 2020;15(1):1–21

[7] Preisler N, Andersen G, Thøgersen F, Crone C, Jeppesen TD, Wibrand F, et al. Effect of aerobic training in patients with spinal and bulbar muscular atrophy (Kennedy disease). Neurology. 2009;72(4):317–23.