Spinal And Bulbar Muscular Atrophy Patients Research Articles

Central neurodegeneration in Kennedy’s disease accompanies peripheral motor dysfunction

Spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease (KD), is a rare hereditary neuromuscular disorder demonstrating commonalities with amyotrophic lateral sclerosis (ALS). The current study aimed to define functional and central nervous system abnormalities associated with SBMA pathology, their interaction, and to identify novel clinical markers for quantifying disease activity. 27 study participants (12 SBMA; 8 ALS; 7 Control) were recruited. SBMA patients underwent comprehensive motor and sensory functional assessments, and neurophysiological testing. All participants underwent whole-brain structural and diffusion MRI. SBMA patients demonstrated marked peripheral motor and sensory abnormalities across clinical assessments. Increased abnormalities on neurological examination were significantly associated with increased disease duration in SBMA patients (R2 = 0.85, p < 0.01). Widespread juxtacortical axonal degeneration of corticospinal white matter tracts were detected in SBMA patients (premotor; motor; somatosensory; p < 0.05), relative to controls. Increased axial diffusivity was significantly correlated with total neuropathy score in SBMA patients across left premotor (R2 = 0.59, p < 0.01), motor (R2 = 0.63, p < 0.01), and somatosensory (R2 = 0.61, p < 0.01) tracts. The present series has identified involvement of motor and sensory brain regions in SBMA, associated with disease duration and increasing severity of peripheral neuropathy. Quantification of annualized brain MRI together with Total Neuropathy Score may represent a novel approach for clinical monitoring.

Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology.

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor (AR) gene, which encodes a ligand-dependent transcription factor. The mutant AR protein, characterized by polyglutamine expansion, is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in SBMA patients. These aggregates alter protein-protein interactions and compromise transcriptional activity. In this study, we reported that in both cultured N2a cells and mouse brain, mutant AR with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-derived neurotrophic factor (MANF). Overexpression of MANF ameliorated the neurotoxicity of mutant AR through the inhibition of mutant AR aggregation. Conversely, knocking down endogenous MANF in the mouse brain exacerbated neuronal damage and mutant AR aggregation. Our findings suggest that inhibition of MANF expression by mutant AR is a potential mechanism underlying neurodegeneration in SBMA.

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.

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.

Incidence and prevalence of Spinal and bulbar muscular atrophy in South Korea: a nationwide population-based study.

Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is a rare X-linked neuromuscular disorder predominantly affecting males and caused by a mutation in the androgen receptor gene. The epidemiology and comorbidities associated with SBMA in different ethnicities remain poorly understood. This study investigated the prevalence, incidence, and comorbidities associated with SBMA in the South Korean population using the Health Insurance Review and Assessment Service (HIRA) database. We retrospectively reviewed diagnosed cases of SBMA (G12.25 code of the Korean Classification of Diseases-7th edition) registered from January 1, 2016, to December 31, 2019, to calculate incidence and prevalence rates and concomitant comorbidities. Additionally, we surveyed SBMA patients (questionnaire group) visiting our clinic in 2022 to compare comorbidities with the HIRA data. The mean incidence rate of SBMA in the Korean population was 0.36/100,000 males from 2018 to 2019, while the prevalence rate was approximately 0.46/100,000 males from 2016 to 2019. The most common comorbidities identified in HIRA were gastritis and duodenitis (99.7%), gastroesophageal reflux (90.5%), hyperlipidemia (88.4%), and liver disorders (75.2%), which showed similar results in the questionnaire group. Additionally, gastric cancer was the most common type of cancer reported in SBMA in South Korea; although indeterminate, age-related factors may contribute to the development of cancer in these patients. Our findings provide valuable insights into the epidemiology and associated comorbidities of SBMA within the Korean population, which could inform clinical practice and future clinical research.

Patient Reported Impact of Symptoms in Spinal Bulbar Muscular Atrophy (PRISM-SBMA) (S33.007)

Patient Reported Impact of Symptoms in Spinal Bulbar Muscular Atrophy (PRISM-SBMA) (S33.007)

Bicalutamide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice

Spinal and bulbar muscular atrophy (SBMA) is characterized by motor neuron (MN) degeneration that leads to slowly progressive muscle weakness. It is considered a neuromuscular disease since muscle has a primary role in disease onset and progression. SBMA is caused by a CAG triplet repeat expansion in the androgen receptor (AR) gene. The translated poly-glutamine (polyQ) tract confers a toxic gain of function to the mutant AR altering its folding, causing its aggregation into intracellular inclusions, and impairing the autophagic flux. In an in vitro SBMA neuronal model, we previously showed that the antiandrogen bicalutamide and trehalose, a natural disaccharide stimulating autophagy, block ARpolyQ activation, reduce its nuclear translocation and toxicity and facilitate the autophagic degradation of cytoplasmic AR aggregates. Here, in a knock-in SBMA mouse model (KI AR113Q), we show that bicalutamide and trehalose ameliorated SBMA pathology. Bicalutamide reversed the formation of the AR insoluble forms in KI AR113Q muscle, preventing autophagic flux blockage. We demonstrated that apoptosis is activated in KI AR113Q muscle, and that both compounds prevented its activation. We detected a decrease of mtDNA and an increase of OXPHOS enzymes, already at early symptomatic stages; these alterations were reverted by trehalose. Overall, bicalutamide and/or trehalose led to a partial recovery of muscle morphology and function, and improved SBMA mouse motor behavior, inducing an extension of their survival. Thus, bicalutamide and trehalose, by counteracting ARpolyQ toxicity in skeletal muscle, are valuable candidates for future clinical trials in SBMA patients.

Acoustic Change Over Time in Spastic and/or Flaccid Dysarthria in Motor Neuron Diseases

This study aims to investigate acoustic change over time as biomarkers to differentiate among spastic-flaccid dysarthria associated with amyotrophic lateral sclerosis (ALS), spastic dysarthria associated with primary lateral sclerosis (PLS), flaccid dysarthria associated with spinal and bulbar muscular atrophy (SBMA), and to explore how these acoustic parameters are affected by dysarthria severity. Thirty-three ALS patients with mixed flaccid-spastic dysarthria, 17 PLS patients with pure spastic dysarthria, 18 SBMA patients with pure flaccid dysarthria, and 70 controls, all French speakers, were included in the study. Speakers produced vowel-glide sequences targeting different vocal tract shape changes. The mean and coefficient of variation of the total squared change of mel frequency cepstral coefficients were used to capture the degree and variability of acoustic changes linked to vocal tract modifications over time. Differences in duration of acoustic events were also measured. All pathological groups showed significantly less acoustic change compared to controls, reflecting less acoustic contrast in sequences. Spastic and mixed spastic-flaccid dysarthric speakers showed smaller acoustic changes and slower sequence production compared to flaccid dysarthria. For dysarthria subtypes associated with a spastic component, reduced degree of acoustic change was also associated with dysarthria severity. The acoustic parameters partially differentiated among the dysarthria subtypes in relation to motor neuron diseases. While similar acoustic patterns were found in spastic-flaccid and spastic dysarthria, crucial differences were found between these two subtypes relating to variability. The acoustic patterns were much more variable in ALS. This method forms a promising clinical tool as a diagnostic marker of articulatory impairment, even at mild stage of dysarthria progression in all subtypes.

Quantitative and Morphological Assessment of Computed Tomography-depicted Gynecomastia in Spinal and Bulbar Muscular Atrophy

To evaluate the prevalence, size, and characteristics of gynecomastia on thoracic computed tomography (CT) in patients with spinal and bulbar muscular atrophy (SBMA) or amyotrophic lateral sclerosis (ALS), compared to those of patients with myasthenia gravis (as controls). A total of 189 male patients (SBMA [n=15]; ALS [n=76]; control [n=98]) who underwent thoracic computed tomography were included. The size of breast glandular tissue diameters, and characteristic of CT-depicted gynecomastia were compared. On multivariate logistic regression analysis, mean breast glandular tissue diameter (adjusted odds ratio [aOR] 1.13, 95% confidence interval [CI] 1.08-1.19), maximum breast glandular tissue diameter (aOR 1.14, 95% CI 1.08-1.20), prevalence of CT-depicted gynecomastia (aOR 21.71, 95% CI 5.39-87.38), dendritic or diffuse pattern of gynecomastia (aOR 35.30, 95% CI 8.02-155.40), and bilateral gynecomastia (aOR 41.96, 95% CI 10.20-172.69) were positively associated with SBMA, but not ALS. On receiver operating characteristic (ROC) analysis, the area under the curve of the mean breast tissue diameter for predicting SBMA was 0.92 with the optimal cutoff value of 16.5 mm. The ROC analysis showed that a maximum breast tissue diameter of 18.6 mm can also effectively distinguish SBMA from controls. These findings suggest that the evaluation of breast glandular tissue on thoracic CT could be a screening examination to distinguish SBMA patients and assist in its differential diagnosis.

Nerve ultrasound detects abnormally small nerves in patients with spinal and bulbar muscular atrophy.

Sensory impairment secondary to dorsal root ganglion neuronopathy is common, although often subclinical, in X-linked spinal and bulbar muscular atrophy (SBMA). We investigated the hypothesis that nerves of SBMA patients show the same morphological changes on ultrasound as other inherited sensory neuronopathies and that these changes are distinct from those in axonal neuropathy. We compared the ultrasound cross-sectional areas (CSAs) of median, ulnar, sural, and tibial nerves of prospectively recruited SBMA patients with those of patients with acquired axonal neuropathy and healthy controls. We also compared the individual nerve CSAs of SBMA and neuropathy patients with our laboratory reference values. There were 7 SBMA patients, 18 neuropathy patients, and 42 healthy controls. The nerve CSAs of the SBMA patients were significantly smaller than those of patients in the other two groups. The changes were most prominent in the upper limbs (p < .001), with the nerves of the SBMA patients being on average approximately half the size of the controls and a third the size of the neuropathy patients. On individual analysis, the ultrasound abnormality was sufficiently characteristic to be detected in all but one SBMA patient. These ultrasound changes are similar to those reported in other inherited sensory neuronopathies and clearly different from the ultrasound findings in axonal neuropathy. Smaller nerves are possibly a distinctive finding in SBMA that may distinguish it from other motor neuron syndromes. Further studies are warranted to confirm this and determine the optimal sonographic protocol.

Correlation Between Maximal Tongue Pressure and Swallowing Function in Spinal and Bulbar Muscular Atrophy.

Background: Spinal and bulbar muscular atrophy (SBMA) is an X-lined motor neuron disease characterized by progressive muscle weakness, bulbar palsy, and dysphagia. Dysphagia is associated with tongue weakness, which is a common manifestation of SBMA. This study aimed to investigate the correlations between tongue pressure and dysphagia in patients with SBMA.Materials and Methods: Thirty-nine genetically confirmed SBMA patients underwent a videofluoroscopic swallowing study (VFSS) and tongue pressure assessment. Then, we analyzed the maximal tongue pressure (MTP), oral transit time, penetration-aspiration scale (PAS), videofluoroscopic dysphagia scale (VDS), amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and 6-min walk test (6MWT). Pearson and Spearman correlation coefficients were calculated to analyze the association of the MTP with clinical, swallowing, and functional parameters.Results: In the correlation analysis, MTP was negatively correlated with disease duration (r = −0.396, p = 0.013) and VDS (r = −0.426, p = 0.007), and positively correlated with ALSFRS-R (r = 0.483, p = 0.002) and 6MWT (r = 0.396, p = 0.013). The bulbar (r = 0.367, p = 0.022) and gross motor (r = 0.486, p = 0.002) domains of the ALSFRS-R were correlated with MTP.Conclusion: Tongue pressure assessment can be used as a safe and easy tool to assess swallowing function in SBMA patients. Moreover, MTP reflects functional states, including activities of daily living and gait performance, showing it to be a potential biomarker for physical performance in SBMA.

Dysregulation of Muscle-Specific MicroRNAs as Common Pathogenic Feature Associated with Muscle Atrophy in ALS, SMA and SBMA: Evidence from Animal Models and Human Patients.

Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of SOD1-mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients’ sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.

Effect of leuprorelin inbulbar function of spinal and bulbar muscular atrophypatients: observational study for 1year.

This study aimed to investigate the effect of androgen suppression therapy using leuprorelin focused on the bulbar function of patients with spinal and bulbar muscular atrophy (SBMA). Genetically confirmed SBMA patients who consented to participate in this observational study were enrolled. Leuprorelin was subcutaneously injected every 12weeks. Videofluoroscopic swallowing study was performed at baseline and after androgen suppression therapy for 1 year. The primary outcome measures were the changes in the vallecular residue and pyriform sinus residue. The videofluoroscopic swallowing study data were analyzed and interpreted by two experienced physiatrists. A total of 40 patients with SBMA were analyzed in this study. The inter-rater reliability testing showed good agreement for the pharyngeal residue (ICC = 0.84) and videofluoroscopic dysphagia scale (ICC = 0.75). The vallecular residue and pyriform sinus residue after swallowing 9mL yogurt were significantly reduced (26.8 ± 22.6 to 14.6 ± 14.5, p < 0.001, 14.9 ± 16.9 to 7.6 ± 9.9, p < 0.001, respectively). The swallowing subscore of amyotrophic lateral sclerosis functional rating scale-revised improved after androgen suppression therapy (3.3 ± 0.5 to 3.5 ± 0.6, p = 0.041). Leuprorelin significantly reduced the pharyngeal residue in patients with SBMA after 1 year of treatment without any serious adverse events and longitudinal studies are needed to confirm these results.

Disorders of sleep in spinal and bulbar muscular atrophy (Kennedy's disease).

Spinal and bulbar muscular atrophy (SBMA) is a progressive, X-linked lower motor neuron disorder exclusively affecting men. Since knowledge on sleep disorders in SBMA is scarce compared to other motoneuron diseases, this retrospective case-control study aimed to investigate sleep and sleep-related breathing in patients with SBMA. In 23 non-ventilated patients with SBMA (median age 52 years), clinical disease characteristics, forced vital capacity and diagnostic polysomnographies were retrospectively evaluated. In 16 patients, overnight transcutaneous capnometry was available. Twenty-three male control subjects with chronic insomnia were matched for age and body mass index. In patients with SBMA obstructive sleep apnoea (OSA, apnoea-hypopnoea index/AHI > 5/h) was more frequent than in control subjects (14/23 or 61% vs. 6/23 or 26%, p = 0.02), and median AHI was significantly higher in patients (9.0/h vs. 3.4/h, p < 0.01). Among SBMA patients, the AHI was not related to age or body mass index. Alveolar hypoventilation as reflected by nocturnal hypercapnia was found in 3/16 patients. Rapid eye movement (REM) sleep without atonia was present in 44% of SBMA patients but only in 4% of controls (p < 0.01). During REM and non-REM sleep, no behavioural abnormalities were observed in either group. Periodic limb movements in sleep (index > 15/h) were frequent in SBMA patients but rarely disrupted sleep. In patients with SBMA, sleep-disordered breathing may comprise both OSA and nocturnal hypoventilation. REM sleep without atonia may also be found, but its clinical significance remains unclear. In patients complaining of sleep-related symptoms, cardiorespiratory polysomnography and transcutaneous capnometry are recommended.

SMA - CLINICAL: P.82 Importance of pharyngeal residue as a marker of treatment in Korean spinal and bulbar muscular atrophy patients

Currently, there is no biomarker or effective treatment for Spinal and bulbar muscular atrophy (SBMA) patients. A recent clinical trial using Leuprorelin showed a modest effect on dysphagia, and an increased survival rate in SBMA. The aim of our study was to find an early marker of treatment efficiancy using Leuprorelin in 40 Korean SBMA patients. The Videofluoroscopic swallowing study (VFSS) and amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) were performed at baseline and after androgen suppression therapy for one year in these patients.

Reliability and Validity of the Korean Version of the Spinal and Bulbar Muscular Atrophy Functional Rating Scale.

Background and PurposeThe Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS) is a reliable and valid instrument for evaluating the functional status of patients with spinal and bulbar muscular atrophy (SBMA). This study aimed to validate a Korean version of the SBMAFRS in an SBMA population.MethodsWe applied the SBMAFRS to 64 SBMA patients at their regular follow-up clinical visits. The patients underwent clinical evaluations that included the 6-minute walking test (6MWT), forced vital capacity (FVC), manual muscle test, and the Penetration-Aspiration Scale (PAS). To estimate the stability of the SBMAFRS, the scale was reapplied to a subset of 31 randomly selected patients within 4 weeks of the initial test. The convergent validity was evaluated, and correlations were examined between SBMAFRS items and the muscular force, the total and subscores on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), FVC, PAS score, age at onset, disease duration, and 6MWT results.ResultsThe internal consistency of the scale was confirmed by a high Cronbach's alpha (total raw alpha=0.867, total standardized alpha=0.863). The test-retest reliability as assessed by Spearman's rho was also high. The total score and subscores of the SBMAFRS were strongly correlated with the respective items and subscores of the ALSFRS-R, respiratory function, and the 6MWT.ConclusionsWe have performed a validation study of the Korean version of a disease-specific functional rating scale for SBMA patients. The SBMAFRS is a useful tool for clinical practice and as a potential outcome measure for Korean SBMA patients.

Nasometric Scores in spinal and bulbar muscular atrophy - Effects of palatal lift prosthesis on dysarthria and dysphagia

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disease affecting only males characterized by progressive muscular atrophy and weakness in bulbar and limb muscles. The present study aimed to evaluate the features of velopharyngeal dysfunction (VPD) in SBMA subjects by an acoustic analysis of speech. Twenty-three genetically confirmed patients with SBMA were enrolled and assessed their speech by measuring the nasalance score with a Nasometer II. The nasalance scores of the SBMA group was higher than that of healthy controls (p = .035) and significantly correlated with the total score of the revised amyotrophic lateral sclerosis functional rating scale (rs = −0.520, p = .011). On the basis of the results of the VPD study, the efficacy of a palatal lift prosthesis (PLP) was assessed in two patients with SBMA to treat their VPD. The PLP improved dysarthria in both cases, although the impact of the prosthesis on dysphagia was not consistent. The present study suggested that the nasalance score is a useful quantitative measurement to evaluate VPD in patients with SBMA. A PLP may improve dysarthria in SBMA patients by reducing VPD, but the clinical application of this procedure should be considered carefully in view of its possible negative effect on dysphagia.

Preliminary design and validation of the "6-K-scale" for bulbar symptoms evaluation in SBMA.

Spinal and bulbar muscular atrophy (SBMA) is a late onset, X-linked neuromuscular disease. Bulbar symptoms are a main characteristic of the disease but a tool for their clinical evaluation still does not exist. The aim of this study was to design and test a new scale (6-K-scale) for evaluation of bulbar function in SBMA. We considered 60 genetically confirmed SBMA patients and built a scale to evaluate the V, VII, IX, X, and XII cranial nerves (CN) and the ansa cervicalis. Functional status was evaluated through the Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS), 6-min-walk-test (6MWT), Adult Myopathy Assessment Tool (AMAT) scale, and FVC%. Twenty patients underwent a re-test after 3weeks, while 31 were tested longitudinally after 6months. Validation of the scale included reliability assessment and factorial analysis. To evaluate convergent validity, correlations between the 6-K-scale and functional parameters were performed. Internal consistency as measured by Cronbach's alpha was high (0.85) as was test-retest reliability. Principal component analysis yielded a six-factor solution accounting for 71.7% of the variance. The scale score was strongly correlated with the functional parameters. In conclusion, we designed and validated a new scale for bulbar evaluation in SBMA patients. This scale will be a useful tool in the clinical practice as well as a possible outcome measure in clinical trials.

Gene expression analysis reveals early dysregulation of disease pathways and links Chmp7 to pathogenesis of spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA) results from a CAG repeat expansion within the androgen receptor gene (AR). It is unclear why motor neurons selectively degenerate and there are currently no treatments for this debilitating disease. To uncover the causative genes and pathways involved in motor neuron dysfunction, we undertook transcriptomic profiling of primary embryonic motor neurons from SBMA mice. We show that transcriptional dysregulation occurs early during development in SBMA motor neurons. One gene found to be dysregulated, Chmp7, was also altered in vivo in spinal cord before symptom onset in SBMA mice, and crucially in motor neuron precursor cells derived from SBMA patient stem cells, suggesting that Chmp7 may play a causal role in disease pathogenesis by disrupting the endosome-lysosome system. Furthermore, genes were enriched in SBMA motor neurons in several key pathways including p53, DNA repair, WNT and mitochondrial function. SBMA embryonic motor neurons also displayed dysfunctional mitochondria along with DNA damage, possibly resulting from DNA repair gene dysregulation and/or mitochondrial dysfunction. This indicates that a coordinated dysregulation of multiple pathways leads to development of SBMA. Importantly, our findings suggest that the identified pathways and genes, in particular Chmp7, may serve as potential therapeutic targets in SBMA.

Insights into the genetic epidemiology of spinal and bulbar muscular atrophy: prevalence estimation and multiple founder haplotypes in the Veneto Italian region.

Literature data on spinal and bulbar muscular atrophy (SBMA) epidemiology are limited and restricted to specific populations. The aim of our study was to accurately collect information about SBMA patients living in the Veneto region in Italy to compute reliable epidemiological data. Androgen receptor (AR) lineages were genotyped to evaluate the presence of a founder effect. A prevalence survey considering all SBMA patients diagnosed in the Italian Veneto region on 31 January 2018 was carried out. The presence of different haplotypes obtained genotyping 15 polymorphic markers (single nucleotide polymorphisms and short tandem repeats) around the AR gene was evaluated. Based on 68 patients, the punctual prevalence of the disease on 31 January 2018 was 2.58/100000 (95% confidence interval 1.65-3.35) in the male population. Five different haplotypes were identified, confirming the existence of multiple founder effects. It was also observed that, within the same haplotype, patients had a similar CAG repeat number (P-value<0.001). A reliable estimation of SBMA prevalence in the Italian Veneto region was calculated which does not seem to be affected by a strong founder effect. Moreover, our data suggest that the length of the CAG expansion could be preserved in patients harbouring the same haplotype.