Clinical Features
Kennedy disease (KD), also known as Spinal and Bulbar Muscular Atrophy (SBMA), is a recessive, X-linked, adult-onset motor neuron disease characterized by the slow, progressive weakness of the bulbar and limb muscles. Kennedy disease predominantly affects adult males, with an estimated global incidence of 1-2/100,000. Many patients may be misdiagnosed with other neuromuscular disorders, including Amyotrophic Lateral Sclerosis (ALS).
There are reports of patients with SBMA from various ethnic backgrounds around the world, with the onset of the disease typically occurring between the ages of 30 to 60. In the early stages of the disease, symptoms are often nonspecific, such as postural tremors and muscle spasms. Postural tremors may often appear several years or even decades before muscle weakness in patients, and this phenomenon deserves increased attention from clinicians. Research suggests that its cause may be related to subclinical sensory disturbances and a decrease in motor cells. Early clinical symptoms include facial twitching, unclear or slurred speech, and muscle fasciculations, especially around the mouth and tongue.
While Kennedy disease (KD) is currently considered a lower motor neuron disease, there is also research suggesting that patients with KD may exhibit mild cognitive dysfunction. This can manifest as speech fluency disorders, abnormalities in concept formation, and decreased memory. Some patients show signs of androgen insensitivity, such as breast development, testicular atrophy, erectile dysfunction, and reduced fertility. Female carriers are typically asymptomatic. Physical examinations primarily reveal signs of lower motor neuron involvement, including mild muscle atrophy, fasciculations, slight muscle weakness (more pronounced in proximal limbs), reduced or absent tendon reflexes, and sensory deficits. Most patients have elevated serum creatine kinase (CK) levels, and some may also have comorbidities like hypertension, hyperlipidemia, mild liver function abnormalities, and impaired glucose tolerance. Electrophysiological tests in patients with KD typically show widespread chronic neurogenic changes, often accompanied by sensory and motor nerve conduction abnormalities, with sensory abnormalities being more common than motor abnormalities [1].
Figure 1. Clinical Features of Kennedy Disease [2]
Figure 2. Muscle Pathological Examination
A: Muscle biopsy from the patient stained with H&E (Hematoxylin and Eosin) shows severe fiber atrophy, atrophic fibers are distributed in a fascicular pattern, with increased interstitial fat, and no inflammatory cell infiltration is observed.
B: Muscle biopsy stained with NADH (Nicotinamide Adenine Dinucleotide) demonstrates a grouping phenomenon of type I fibers [3].
Animal Models of Spinal and Bulbar Muscular Atrophy
Given that Kennedy Disease/SBMA is caused by the genetic mutation of the X-linked androgen receptor (AR) gene, some researchers have investigated the role of the pathogenic AR protein and its specific ligand, testosterone. A method for a full-length human AR transgenic mouse model and a BAC fxAR121 transgenic (hAR) mouse models are described herein:
Full-length Human Androgen Receptor Mouse Model
To study the role of testosterone, researchers obtained transgenic mice that express full-length human AR containing 97 CAG repeats. This model not only recapitulates neurological dysfunction but also replicates gender-specific phenotypic differences, which are a distinctive feature of SBMA [4].
Humanized BAC fxAR121 Transgenic Mouse Model
Other researchers identified two overlapping BACs spanning the entire length of the AR gene and, using recombination strategies, fused these two BACs to create an AR BAC structure. This structure not only included all 8 AR exons but also encompassed 50 kb upstream of the first AR exon and 30 kb downstream of the last AR exon. Through this recombination method, the researchers introduced a CAG repeat tract of 121 repeats and designed two loxP sites on either side of AR exon 1 to construct a conditional AR CAG121 BAC (BAC fxAR121) transgenic structure. Subsequently, they obtained BAC fxAR121 transgenic mice, and their expression studies revealed that the levels of hAR RNA and mAR endogenous protein in these mice were comparable to those in YAC CAG100 (YAC AR100) mice [5]. Using this mouse model, some researchers have determined that muscles are a site of mutant AR toxicity and have proposed targeting mutant protein expression in this tissue as a therapeutic approach for the disease [6].
Figure 3. Reduction of Mutant AR Expression in Muscle has Beneficial Effects in SBMA Mouse Model [6]
Treatment Options for SBMA
Symptomatic Treatment
Symptomatic treatment helps alleviate symptoms such as tremors, endocrine abnormalities, muscle spasms, respiratory failure, and swallowing difficulties. Patients diagnosed with SBMA should undergo long-term follow-up and observation. For painful spasms, options include magnesium, tizanidine, baclofen, gabapentin, sodium valproate, and carbamazepine. If the patient has diabetes, treatment should follow current clinical guidelines. In cases of malnutrition due to swallowing difficulties, percutaneous endoscopic gastrostomy can be considered. For a small portion of patients experiencing respiratory function impairment, non-invasive positive pressure ventilation can improve symptoms. In advanced cases with respiratory failure, the decision to use mechanical ventilation should be made based on the patient's wishes [7].
Specific Treatment
For polyglutamine (PolyQ) diseases, including Kennedy disease (KD)/SBMA, multiple mechanisms may contribute to neuronal dysfunction and eventual cell death. These mechanisms include:
1. Misfolding of disease-causing proteins leading to altered protein function.
2. Toxic interactions of mutant proteins engaging in harmful protein-protein interactions.
3. Formation of toxic oligomers.
4. Transcriptional dysregulation.
5. Mitochondrial dysfunction resulting in impaired bioenergetics and oxidative stress.
6. Impaired axonal transport.
7. Abnormal neural signaling, including excitotoxicity.
8. Disrupted cellular protein homeostasis.
9. RNA toxicity.
Although these molecular mechanisms hold potential as therapeutic targets, there is currently no standard treatment for SBMA due to the unclear pathogenic mechanisms. Existing treatments are mostly at the experimental stage in animal models. These experimental/potential treatment approaches include:
1. Testosterone deprivation has been applied in clinical trials. Some experiments have shown that the histopathology of male mouse models of Kennedy disease demonstrate a positive correlation between AR protein expression levels and testosterone levels. To support this notion, surgical castration in mouse models of Kennedy disease has demonstrated improved motor function. Similar results have been seen in preclinical studies with leuprorelin, a luteinizing hormone-releasing hormone (LHRH) agonist that suppresses pituitary release of gonadotropins, thereby inhibiting testosterone release from the testes. This drug has been used for various hormone-dependent conditions, including prostate cancer and endometriosis. In male mouse models of Kennedy disease, leuprorelin successfully inhibited the pathogenic aggregation of AR in the nucleus, resulting in a significant improvement in the neuromuscular phenotype. The testosterone-blocking effect of leuprorelin was further confirmed by a reduction in the weight of the prostate and seminal vesicles. Kennedy disease mouse models treated with leuprorelin showed longer lifespans, larger size, and better motor performance compared to control mice. Phase 2 clinical trials of leuprorelin showed that serum testosterone levels in humans decreased to the levels achieved by surgical castration approximately 2-4 weeks after treatment. Patients treated with leuprorelin exhibited reduced accumulation of mutant AR in scrotal skin biopsies and improved swallowing function compared to the placebo group. Autopsy results from patients who received leuprorelin treatment indicated that testosterone deprivation inhibited nuclear accumulation of AR in spinal cord and brainstem motor neurons. These observations suggest that leuprorelin, through administration, inhibits the toxic accumulation of mutant AR in the neuromuscular system of Kennedy disease.
2. Androgen receptor (AR) co-regulators have also been considered as alternative therapeutic targets because they control the function and distribution of cellular AR. The compound 5-Hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (AsC-J9), extracted from ginger and curry, disrupts the interaction between AR and its co-regulators. Recent research has found that AsC-J9 selectively degrades AR protein and reduces its intracellular aggregation. This significantly improves motor function in AR-97Q transgenic mice with Kennedy disease, increasing the average lifespan from 28 weeks to 39 weeks. Moreover, Kennedy disease mouse models treated with AsC-J9 exhibit nearly normal serum testosterone levels, significant improvements in sexual function, and enhanced fertility after treatment.
These findings suggest that AsC-J9 has the potential to be a therapeutic agent for Kennedy disease by selectively targeting AR protein degradation and improving motor function and hormone levels.
3. Activation of cellular defense mechanisms is another promising therapeutic approach for Kennedy disease. In mouse models of Kennedy disease, Heat Shock Proteins (Hsps) are stress-induced molecular chaperones that belong to various families, including Hsp100, Hsp90, Hsp70, Hsp60, Hsp40, and small Hsps. High levels of Hsp expression in mouse models of polyglutamine diseases, including Kennedy disease, can inhibit the toxic aggregation of misfolded proteins typical of PolyQ diseases and prevent cell death through various pathways. Therefore, increasing their expression levels through drug-induced methods could be a new approach to treat Kennedy disease and other polyglutamine(PolyQ) diseases.
Tropifexor (GA) can strongly induce Hsp expression in various tissues. When administered orally to Kennedy disease transgenic mice, GA significantly upregulates the expression of Hsp70 in the central nervous system and inhibits the aggregation of pathogenic AR proteins within the cell nucleus, leading to a significant improvement in neuro-muscular-related symptoms.
On the other hand, inhibiting Hsp90 has been shown to suppress neurodegeneration by activating the ubiquitin-proteasome system in Kennedy disease. Treatment with a potent Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AG), in cellular and mouse models of Kennedy disease promotes the degradation of pathogenic AR proteins within proteasomes.
4. Transcriptional dysregulation is another target for intervention. Inhibition of Histone Deacetylases (HDAC) activity can increase histone acetylation, consequently enhancing gene transcription levels. HDAC inhibitors have been considered to have therapeutic potential in polyglutamine (PolyQ) diseases. Sodium butyrate was the first discovered HDAC inhibitor, and oral administration of sodium butyrate can upregulate histone acetylation in neural tissues in mouse models of Kennedy disease, improving the symptoms and pathological phenotype of the model [8].
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References:
[1]Kouyoumdjian JA, Morita Mda P, Araujo RG, et al. X-linked spinal and bulbar muscular atrophy (Kennedy disease) with long-term electrophysiological evaluation: case report [J ]. Arq Neuropsiquiatr, 2005, 63(1) : 154-159.
[2]https://zhuanlan.zhihu.com/p/305781133
[3] Yu Liqiang, Fang Qi, Jiang Jue'an, Xu Lizhen (2015). Clinical, pathological, and genetic characteristics of Kennedy disease. Clinical Neurology Journal, 28(4), 296-298.
[4]Masahisa Katsuno,Hiroaki Adachi,Masahiro Waza,Haruhiko Banno,Keisuke Suzuki,Fumiaki Tanaka,Manabu Doyu,Gen Sobue. Pathogenesis, animal models and therapeutics in Spinal and bulbar muscular atrophy (SBMA)[J]. Experimental Neurology,2006,200(1).
[5]Constanza J. Cortes,Shuo-Chien Ling,Ling T. Guo,Gene Hung,Taiji Tsunemi,Linda Ly,Seiya Tokunaga,Edith Lopez,Bryce L. Sopher,C. Frank Bennett,G. Diane Shelton,Don W. Cleveland,Albert R. La Spada. Muscle Expression of Mutant Androgen Receptor Accounts for Systemic and Motor Neuron Disease Phenotypes in Spinal and Bulbar Muscular Atrophy[J]. Neuron,2014,82(2).
[6]Carlo Rinaldi,Laura C. Bott,Kenneth H. Fischbeck. Muscle Matters in Kennedy Disease[J]. Neuron,2014,82(2).
[7]https://www.nrdrs.org.cn/app/rare/disease-list-article.html?index=109
[8] Ma Junfang, Cui Liying, Cui Bo (2015). Clinical characteristics, pathogenesis, and therapeutic progress of Kennedy disease. Chinese Journal of Neurology, 48(4), 344-347.
