Spinal Bulbar Muscular Atrophy Research Articles

Concurrence of Spinobulbar Muscular Atrophy and Seropositive Myasthenia Gravis

Concurrence of Spinobulbar Muscular Atrophy and Seropositive Myasthenia Gravis

Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.

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 motor neuron diseases (MNDs), 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 MNDs, 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.

Polyglutamine disease proteins: Commonalities and differences in interaction profiles and pathological effects.

Currently, nine polyglutamine (polyQ) expansion diseases are known. They include spinocerebellar ataxias (SCA1, 2, 3, 6, 7, 17), spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and Huntington's disease (HD). At the root of these neurodegenerative diseases are trinucleotide repeat mutations in coding regions of different genes, which lead to the production of proteins with elongated polyQ tracts. While the causative proteins differ in structure and molecular mass, the expanded polyQ domains drive pathogenesis in all these diseases. PolyQ tracts mediate the association of proteins leading to the formation of protein complexes involved in gene expression regulation, RNA processing, membrane trafficking, and signal transduction. In this review, we discuss commonalities and differences among the nine polyQ proteins focusing on their structure and function as well as the pathological features of the respective diseases. We present insights from AlphaFold-predicted structural models and discuss the biological roles of polyQ-containing proteins. Lastly, we explore reported protein-protein interaction networks to highlight shared protein interactions and their potential relevance in disease development.

Blocking the dimerization of polyglutamine-expanded androgen receptor protects cells from DHT-induced toxicity by increasing AR turnover

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular degenerative disease caused by a polyglutamine expansion in the androgen receptor (AR). This mutation causes AR to misfold and aggregate, contributing to toxicity in and degeneration of motor neurons and skeletal muscle. There is currently no effective treatment or cure for this disease. The role of an interdomain interaction between the amino- and carboxyl-termini of AR, termed the N/C interaction, has been previously identified as a component of androgen receptor-induced toxicity in cell and mouse models of SBMA. However, the mechanism by which this interaction contributes to disease pathology is unclear. This work seeks to investigate this mechanism by interrogating the role of AR homodimerization- a unique form of the N/C-interaction- in SBMA. We show that, although the AR N/C-interaction is reduced by polyglutamine-expansion, homodimers of 5α-dihydrotestosterone (DHT)-bound AR are increased. Additionally, blocking homodimerization results in decreased AR aggregation and toxicity in cell models. Blocking homodimerization results in the increased degradation of AR, which likely plays a role in the protective effects of this mutation. Overall, this work identifies a novel mechanism in SBMA pathology that may represent a novel target for the development of therapeutics for this disease.

Disruption of Neuromuscular Junction Following Spinal Cord Injury and Motor Neuron Diseases.

The neuromuscular junction (NMJ) is a crucial structure that connects the cholinergic motor neurons to the muscle fibers and allows for muscle contraction and movement. Despite the interruption of the supraspinal pathways that occurs in spinal cord injury (SCI), the NMJ, innervated by motor neurons below the injury site, has been found to remain intact. This highlights the importance of studying the NMJ in rodent models of various nervous system disorders, such as amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). The NMJ is also involved in myasthenic disorders, such as myasthenia gravis (MG), and is vulnerable to neurotoxin damage. Thus, it is important to analyze the integrity of the NMJ in rodent models during the early stages of the disease, as this may allow for a better understanding of the condition and potential treatment options. The spinal cord also plays a crucial role in the functioning of the NMJ, as the junction relays information from the spinal cord to the muscle fibers, and the integrity of the NMJ could be disrupted by SCI. Therefore, it is vital to study SCI and muscle function when studying NMJ disorders. This review discusses the formation and function of the NMJ after SCI and potential interventions that may reverse or improve NMJ dysfunction, such as exercise, nutrition, and trophic factors.

Differentially disrupted spinal cord and muscle energy metabolism in spinal and bulbar muscular atrophy.

Prior studies showed that polyglutamine-expanded androgen receptor (AR) is aberrantly acetylated and that deacetylation of the mutant AR by overexpression of nicotinamide adenine dinucleotide-dependent (NAD+-dependent) sirtuin 1 is protective in cell models of spinal and bulbar muscular atrophy (SBMA). Based on these observations and reduced NAD+ in muscles of SBMA mouse models, we tested the therapeutic potential of NAD+ restoration in vivo by treating postsymptomatic transgenic SBMA mice with the NAD+ precursor nicotinamide riboside (NR). NR supplementation failed to alter disease progression and had no effect on increasing NAD+ or ATP content in muscle, despite producing a modest increase of NAD+ in the spinal cords of SBMA mice. Metabolomic and proteomic profiles of SBMA quadriceps muscles indicated alterations in several important energy-related pathways that use NAD+, in addition to the NAD+ salvage pathway, which is critical for NAD+ regeneration for use in cellular energy production. We also observed decreased mRNA levels of nicotinamide riboside kinase 2 (Nmrk2), which encodes a key kinase responsible for NR phosphorylation, allowing its use by the NAD+ salvage pathway. Together, these data suggest a model in which NAD+ levels are significantly decreased in muscles of an SBMA mouse model and intransigent to NR supplementation because of decreased levels of Nmrk2.

Efficacy of leuprorelin in spinal and bulbar muscular atrophy: a 3-year observational study.

This study aimed to investigate the long-term effects and functional outcomes of androgen suppression therapy using leuprorelin among Korean patients with spinal and bulbar muscular atrophy (SBMA). This observational study enrolled patients with genetically confirmed SBMA who provided informed consent. Leuprorelin was administered via subcutaneous injection every 12weeks. The primary outcome measure was the change in total Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS) scores. A total of 48 SBMA patients were evaluated in this study. Among them, 39 patients underwent androgen suppression therapy over a 3-year period. The total SBMAFRS score decreased from 41.72 ± 5.55 to 36.74 ± 7.74 (p < 0.001) in patients who completed their treatment. The subgroup with a baseline SBMAFRS score of ≥ 42 had a significantly lower decline in SBMAFRS score than did those with a baseline SBMAFRS score of ≤ 41. We determined that at a baseline, SBMAFRS cutoff value of 41.5 could predict good prognosis, with a corresponding area under the curve of 0.689. Despite androgen suppression therapy, all enrolled participants exhibited a decrease in the overall SBMAFRS score. However, those with a baseline SBMAFRS of ≥ 42 showed a mild decrease in scores, indicating a more favorable prognosis. These findings suggest that a higher baseline motor function was a key prognostic indicator in SBMA treatment and that initiating early leuprorelin treatment in patients with high baseline function may lead to good clinical outcomes.

Higher than expected incident cases of spinal bulbar muscular atrophy in western Canada.

Higher than expected incident cases of spinal bulbar muscular atrophy in western Canada.

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

Spinal 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. This 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). We 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. We 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 2024;95:596-606.

Troponin T in spinal and bulbar muscular atrophy (SBMA)

Serum biomarkers that might detect clinical progression are currently lacking for Spinal and bulbar muscular atrophy (SBMA), thus limiting the effectiveness of possible future pharmacological trials. Elevation of cardiac troponin T (cTnT) unrelated to myocardial damage in a motor neuron (MN) disease as amyotrophic lateral sclerosis (ALS) was associated to disease severity.We enrolled 47 SBMA patients and 5 Spinal muscular atrophy (SMA) type 3 adult patients as control group; each SBMA patient was evaluated at baseline and at one-year follow-up visit. Demographic and clinical data including functional scores (SBMAFRS) were collected; serum was collected as standard of care and tested for cardiac troponins.Levels of cTnT but not cTnI were increased in SBMA with respect to reference values; unlike other neuromuscular diseases, SMA patients had overall normal cTnT values. Median cTnT concentrations did not change after one year and values were correlated to motor function, particularly with lower limb subdomain, at baseline only. Variations of cTnT and of SBMAFRS were unrelated.The cautiously promising results of cTnT as potential biomarker should undergo a more extensive clinical validation, including studies with longer follow-up period. When evaluating SBMA patients for a potential cardiac damage cTnI testing should be coupled or preferred to cTnT.

Spinal bulbar muscular atrophy-Kennedy's disease.

A middle age man complained of progressive bilateral hand tremor and occasional muscle cramps. Examination showed tongue muscle atrophy and limb muscle fasciculation with resting and postural tremor in the upper extremities. Deep tendon reflexes were decreased. He had bilateral breast enlargement. Nerve conduction study and Electromyography revealed chronic sensory-motor neuropathy. DNA analysis identified an expanded number of CAG trinucleotide repeats in the androgen receptor gene consistent with a diagnosis of Kennedy's disease (KD). KD, also known as Spinal Bulbar Muscular Atrophy (SBMA), is a rare X-linked recessive lower motor neuron disorder characterized by proximal and bulbar muscle wasting due to degeneration of motor neurons in the brain stem and spinal cord. KD can present with non-specific symptoms initially and may be misdiagnosed as Amyotrophic Lateral Sclerosis or other neurological conditions. Molecular genetic testing enables the diagnosis by identifying the CAG trinucleotide repeat expansion.

Drosophila melanogaster as a Model Organism to Facilitate Rare Disease Diagnosis and Therapeutic Research

Cancer is one of the leading causes of death worldwide accounting for around 10 million deaths in 2020. Cancer is caused by abnormal growth of cells in any part of the body. Genetic causes of cancer can be due to mutations in the genes. Rare mutations in genes show rare types of tumors like Neurofibromatosis and Tuberous sclerosis. The study of model organisms has been pivotal in understanding the causes of various diseases. The studies involve a variety of different methods and out of them the WES (Whole Exome Sequencing) model of research is the most common. Herein lies the future of integrating human genomics with studies in model organisms. It is essential to maintain and expand the current Drosophila melanogaster databases this houses the genomic, molecular, and cell biological knowledge on the organism. This can be done by collaboration with the NIH. The understanding of the characteristics of cancer cells plays an important role in terms of how to go about with research tumor and normal host cell motility plays a multifaceted role in the metastasis of cancer by allowing the tumor to spread to distant organs, migrate to blood and lymphatic arteries, breach the basement membrane, and escape from the original tumor. The ability to migrate towards favourable environments is a fundamental and evolutionarily conserved cellular behaviour from unicellular organisms to humans. Both normal and cancer cells migrate using diverse modes including amoeboid, mesenchymal, epithelial, collective and individual. Simple model organisms also exhibit these diverse modes of motility and offer experimental advantages such as low cost, amenability to large-scale genetic and pharmacological screening and live imaging of cells interacting within their native environments. This article goes into detail about how drosophila can be used as a model organism to study various diseases such as Duchenne Muscular Dystrophy, Parkinsons disease, Prions diseases, Polyglutamine disorders, Huntington's disease, Machado-Josephs disease, Kennedy disease, Amyotrophic lateral sclerosis, Leigh Disease, Nieman-Pick Disease and a few rare tumours

Patient-Reported Impact of Symptoms in Spinal and Bulbar Muscular Atrophy

Background and ObjectivesThe aim of this study was to determine the frequency and relative importance of symptoms experienced by patients with spinal and bulbar muscular atrophy (SBMA).MethodsWe conducted a cross-sectional study of 232 participants with SBMA. Participants provided input regarding 18 themes and 208 symptoms that affect patients with SBMA. Participants were asked about the relative importance of each symptom, and analysis was conducted to determine how age, education, disease duration, CAG repeat length, and ambulation status relate to symptom prevalence.ResultsHip, thigh, or knee weakness (96.5%), fatigue (96.5%), problems with hands and fingers (95.7%), and limitations with walking (95.7%) were the themes with the highest prevalence in the study population. Ambulatory status was associated with the prevalence of 9 of the 14 themes, and CAG repeat length and education were each associated with 4 of 14 themes. The prevalence of fatigue was reduced in those with a lower CAG repeat length and increased with a longer disease duration. Younger patients reported a higher prevalence of emotional issues.DiscussionThere are a diversity of themes that are important to patients with SBMA. These themes have a variable level of importance to the population with SBMA and represent clinically meaningful outcome measures for future therapeutic interventions.

Double trouble: Kennedy disease and immune-mediated necrotizing myopathy in a Cree male.

Double trouble: Kennedy disease and immune-mediated necrotizing myopathy in a Cree male.

The value of serum creatinine as biomarker of disease progression in spinal and bulbar muscular atrophy (SBMA)

Serum creatinine has been indicated as a potential marker of motor function in SBMA and results form previous longitudinal studies pointed to its decline over time. This is a longitudinal retrospective study investigating creatinine changes over a 36-month-period in 73 patients with SBMA. Severity and progression of the disease was assessed according to serum creatine kinase (CK) values, manual muscle testing (MMT), SBMA functional rating scale (SBMAFRS) score, 6-min-walk test (6MWT) value, and spirometry (forced vital capacity, fVC%) obtained at the baseline and at each of the annual follow-up visits. Baseline serum creatinine concentrations positively correlated with 6MWT, the MMT megascore score of both the upper (ULM) and lower (LLM) limbs and SBMAFRS. No correlation was found with CK or fVC% values. Similar correlation results were achieved at all the subsequent time points. Longitudinal assessments conducted by the generalized estimating equations (GEE) method returned significant changes for SBMAFRS (− 1.41 points per year, p < 0.001), ULM and LLM (− 0.69, p = 0.01; and − 1.07, p < 0.001, respectively), 6MWT (− 47 m, p < 0.001) but not for creatinine (− 0.82, p > 0.05). We also observed that creatinine levels at baseline did not correlate with changes in the other measures from baseline at each annual visit. Our data do not support a role for serum creatinine as sensitive biomarker of disease progression, and possibily prognosis, in SBMA.

More than autophony: a case of Kennedy's disease presenting with autophony as an early clinical manifestation.

As autophony can be accompanied by several conditions, it is important to find co-morbidities. This paper reports a patient with Kennedy's disease (spinobulbar muscular atrophy, an X-linked, hereditary, lower motor neuron disease) having autophony as the first symptom. A 62-year-old male presented to the otorhinolaryngology department with autophony that began 2 years previously and worsened after losing weight 3 months prior to presentation. Otoscopic examination demonstrated inward and outward movement of the tympanic membrane, synchronised with respiration. Although he had no other symptoms, facial twitching was found on physical examination. In the neurology department, lower motor neuron disease, with subtle weakness of the tongue, face and upper limbs, and gynaecomastia, were confirmed. He was diagnosed with Kennedy's disease based on genetic analysis. Autophonia was presumed to be attributed to bulbofacial muscle weakness due to Kennedy's disease, and worsened by recent weight loss. Patients with autophony require a thorough history-taking and complete physical examination to assess the nasopharynx and the integrity of lower cranial function.

P90 Spinal Bulbar Muscular Atrophy (SBMA): a cross-sectional analysis of wearable sensors during the 6-minute walk (6MWT) and timed up and go (TUG) tests

P90 Spinal Bulbar Muscular Atrophy (SBMA): a cross-sectional analysis of wearable sensors during the 6-minute walk (6MWT) and timed up and go (TUG) tests

P439 Clinical and genetic characterisation of Kennedy's disease in India

P439 Clinical and genetic characterisation of Kennedy's disease in India

Functional Implications of Protein Arginine Methyltransferases (PRMTs) in Neurodegenerative Diseases.

During the aging of the global population, the prevalence of neurodegenerative diseases will be continuously growing. Although each disorder is characterized by disease-specific protein accumulations, several common pathophysiological mechanisms encompassing both genetic and environmental factors have been detected. Among them, protein arginine methyltransferases (PRMTs), which catalyze the methylation of arginine of various substrates, have been revealed to regulate several cellular mechanisms, including neuronal cell survival and excitability, axonal transport, synaptic maturation, and myelination. Emerging evidence highlights their critical involvement in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum, Huntington's disease (HD), spinal muscular atrophy (SMA) and spinal and bulbar muscular atrophy (SBMA). Underlying mechanisms include the regulation of gene transcription and RNA splicing, as well as their implication in various signaling pathways related to oxidative stress responses, apoptosis, neuroinflammation, vacuole degeneration, abnormal protein accumulation and neurotransmission. The targeting of PRMTs is a therapeutic approach initially developed against various forms of cancer but currently presents a novel potential strategy for neurodegenerative diseases. In this review, we discuss the accumulating evidence on the role of PRMTs in the pathophysiology of neurodegenerative diseases, enlightening their pathogenesis and stimulating future research.

Advancing Epidemiology and Genetic Approaches for the Treatment of Spinal and Bulbar Muscular Atrophy: Focus on Prevalence in the Indigenous Population of Western Canada.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a debilitating neuromuscular disease characterized by progressive muscular weakness and neuronal degeneration, affecting 1-2 individuals per 100,000 globally. While SBMA is relatively rare, recent studies have shown a significantly higher prevalence of the disease among the indigenous population of Western Canada compared to the general population. The disease is caused by a pathogenic expansion of polyglutamine residues in the androgen receptor protein, which acts as a key transcriptional regulator for numerous genes. SBMA has no cure, and current treatments are primarily supportive and focused on symptom management. Recently, a form of precision medicine known as antisense therapy has gained traction as a promising therapeutic option for numerous neuromuscular diseases. Antisense therapy uses small synthetic oligonucleotides to confer therapeutic benefit by acting on pathogenic mRNA molecules, serving to either degrade pathogenic mRNA transcripts or helping to modulate splicing. Recent studies have explored the suitability of antisense therapy for the treatment of SBMA, primarily focused on gene therapy and antisense-mediated mRNA knockdown approaches. Advancements in understanding the pathogenesis of SBMA and the development of targeted therapies offer hope for improved quality of life for individuals affected by this debilitating condition. Continued research is essential to optimize these genetic approaches, ensuring their safety and efficacy.