Molecular pathogenesis of spinal bulbar muscular atrophy (Kennedy's disease) and avenues for treatment

Fischbeck, Kenneth H.

doi:10.1097/wco.0000000000000856

Cited by 12 publications

(10 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Various studies using animal models have shown that circulating testosterone aggravates the neuromuscular phenotype, and testosterone deprivation is beneficial in SBMA, suggesting testosterone-dependent pathophysiology. 14,15 This view is in line with the fact that the early-stage signs of SBMA, i.e., hand tremors and muscle cramps, emerge as early as postpuberty. However, a few studies reported that female carriers also manifest, albeit mild, clinical symptoms such as weakness, muscle cramps, and hand tremors.…”

supporting

confidence: 64%

Clinical Features of Female Carriers and Prodromal Male Patients With Spinal and Bulbar Muscular Atrophy

et al. 2023

View full text Add to dashboard Cite

Objective:To assess the clinical and electrophysiological features of female carriers and early-stage male subjects with spinal and bulbar muscular atrophy (SBMA) to elucidate the early pathophysiological changes of the disease.Methods:Female carriers, early-stage male subjects with SBMA and age-matched male and female healthy controls were recruited. The results of motor functional scales, motor unit number estimation, dual-energy X-ray absorptiometry, and peripheral blood tests were compared between female carriers and healthy female controls and between SBMA subjects and healthy male controls. Electromyography was also investigated in female carriers.Results:We enrolled 21 female carriers and 11 early-stage male subjects. Seventeen female and 14 male age-matched healthy controls were also enrolled. Female carriers experienced early-stage symptoms such as muscle cramps more frequently than healthy female controls. Decreased motor unit number estimation and electromyography abnormalities including high amplitude or polyphasic potentials were observed in female carriers together with mild muscle weakness in neck flexion and a slow walking speed. Changes of muscle-related markers, including serum creatine kinase and dual-energy X-ray absorptiometry, were clearly detected in male early-stage subjects with SBMA, but not in female carriers.Conclusion:The present study revealed that female carriers of SBMA manifest mild muscular weakness associated with changes in neurogenic biomarkers. Conversely, male patients showed neurogenic and myopathic changes even at the early-stage. These results suggest a testosterone-independent neurodegenerative pathophysiology in female SBMA carriers.

show abstract

supporting

confidence: 64%

Clinical Features of Female Carriers and Prodromal Male Patients With Spinal and Bulbar Muscular Atrophy

et al. 2023

View full text Add to dashboard Cite

show abstract

“…In a previous clinical trial involving insulinlike growth factor-1 mimetic, thigh muscle volume was used as a primary endpoint and was suggested as a potential marker for monitoring disease progression. 23,24 Therefore, in the clinical setting, an MRI of the thigh may be used as a predictor of gait capacity in patients with SBMA.…”

Section: Discussionmentioning

confidence: 99%

“…Our study revealed that the MRI section of the thigh comprising the gracilis, sartorius, semimembranosus, vastus intermedius, and vastus medialis, as well as the patient's age, provided the most comprehensive and a reasonable explanation for the results of the 6MWT in patients with SBMA (see Table 2). In a previous clinical trial involving insulinlike growth factor‐1 mimetic, thigh muscle volume was used as a primary endpoint and was suggested as a potential marker for monitoring disease progression 23,24 . Therefore, in the clinical setting, an MRI of the thigh may be used as a predictor of gait capacity in patients with SBMA.…”

Section: Discussionmentioning

confidence: 99%

Whole‐Body Muscle Magnetic Resonance Imaging in 81 Patients with Spinal and Bulbar Muscular Atrophy: A Prospective Study

Kim,

Seo,

Kang

et al. 2023

Annals of Neurology

View full text Add to dashboard Cite

ObjectiveSpinal and bulbar muscular atrophy (SBMA) is characterized by slow, progressive bulbar and limb muscle weakness; however, the pattern of progression of muscle fat infiltration remains unclear. We assessed the progression of muscle involvement in 81 patients with SBMA using whole‐body muscle magnetic resonance imaging (MRI), alongside clinical and laboratory findings.MethodsThis prospective study included patients with genetically confirmed SBMA who underwent whole‐body muscle MRI. We analyzed muscle fat infiltration and the pattern of involved muscles using cluster analysis, visualizing the sequential progression of fat infiltration. Muscle clusters demonstrated correlation with clinical scales and laboratory findings. Additionally, linear regression analysis was performed to identify the MRI section most strongly associated with 6‐minute walk test (6MWT).ResultsWe included 81 patients with SBMA (age = 54.3 years). After categorizing the patients into 6 clusters based on the pattern of muscle fat infiltration, we observed that muscle involvement began in the posterior calf and progressed to the posterior thigh, pelvis, trunk, anterior thigh, medial thigh, anterior calf, and upper extremity muscles. These muscle clusters correlated significantly with disease duration (τ = 0.47, p < 0.001), 6MWT (τ = −0.49, p < 0.001), and serum creatinine level (τ = −0.46, p < 0.001). The whole‐body MRI indicated the thigh as the section most significantly correlated with 6MWT.InterpretationWe used whole‐body muscle MRI to determine the sequential progression of the fat infiltration in SBMA. Our findings may enable the identification of objective and reliable imaging outcome measures in the study of the natural history or future clinical trials of SBMA. ANN NEUROL 2023

show abstract

“…The mechanisms underlying the neurodegenerative gain of function in SBMA are not fully understood [114]. Nuclear accumulation and aggregation of polyQ-ARs may contribute to motor neuron degeneration through a variety of molecular mechanisms involving disruption of multiple processes such as transcriptional regulation, protein homeostasis, intracellular trafficking, mitochondrial function and cellular signalling [115].…”

Section: Spinal Bulbar Muscular Atrophy (Sbma)mentioning

confidence: 99%

Antisense oligonucleotides (ASOs) in motor neuron diseases: a road to cure in light and shade

Cantara,

Simoncelli,

Ricci

2024

Preprint

View full text Add to dashboard Cite

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins and decrease levels of toxic proteins. ASOs are being developed for the treatment of several diseases, including motor neuron diseases (MNDs), a group of neurodegenerative disorders characterised by the loss of motor neurons, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MND, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.

show abstract

Molecular pathogenesis of spinal bulbar muscular atrophy (Kennedy's disease) and avenues for treatment

Cited by 12 publications

References 57 publications

Clinical Features of Female Carriers and Prodromal Male Patients With Spinal and Bulbar Muscular Atrophy

Clinical Features of Female Carriers and Prodromal Male Patients With Spinal and Bulbar Muscular Atrophy

Whole‐Body Muscle Magnetic Resonance Imaging in 81 Patients with Spinal and Bulbar Muscular Atrophy: A Prospective Study

Antisense oligonucleotides (ASOs) in motor neuron diseases: a road to cure in light and shade

Contact Info

Product

Resources

About