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.

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

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. INTERPRETATION: 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.

A phenotypically robust model of spinal and bulbar muscular atrophy in Drosophila.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked disorder that affects males who inherit the androgen receptor (AR) gene with an abnormal CAG triplet repeat expansion. The resulting protein contains an elongated polyglutamine (polyQ) tract and causes motor neuron degeneration in an androgen-dependent manner. The precise molecular sequelae of SBMA are unclear. To assist with its investigation and the identification of therapeutic options, we report here a new model of SBMA in Drosophila melanogaster. We generated transgenic flies that express the full-length, human AR with a wild-type or pathogenic polyQ repeat. Each transgene is inserted into the same safe harbor site on the third chromosome of the fly as a single copy and in the same orientation. Expression of pathogenic AR, but not of its wild-type variant, in neurons or muscles leads to consistent, progressive defects in longevity and motility that are concomitant with polyQ-expanded AR protein aggregation and reduced complexity in neuromuscular junctions. Additional assays show adult fly eye abnormalities associated with the pathogenic AR species. The detrimental effects of pathogenic AR are accentuated by feeding flies the androgen, dihydrotestosterone. This new, robust SBMA model can be a valuable tool toward future investigations of this incurable disease.

Characteristics of spinal and bulbar muscular atrophy in South Korea: a cross-sectional study of 157 patients.

Spinal and bulbar muscular atrophy, namely Kennedy disease, is a rare progressive neurodegenerative disorder caused by the expansion of a CAG repeat in the first exon of the androgen receptor gene on the X chromosome. We assessed the clinical history, laboratory findings, functional scales and electrophysiological data, as well as the levels of luteinizing hormone, follicle-stimulating hormone and testosterone, in 157 Korean patients with genetically confirmed spinal and bulbar muscular atrophy (mean age at data collection = 56.9 years; range = 33-83 years). Hand tremor was the first symptom noticed by patients at a median age of 35 years, followed by gynaecomastia, orofacial fasciculation, cramps and fatigability in ascending order. Clinical symptoms such as paraesthesia and dysphagia appeared during the later stages of the disease. Cane use during ambulation began at a median age of 62 years. There were statistically significant differences between patients and controls in the results of sensory nerve studies, motor conduction velocity, and distal latencies. Furthermore, among the hormone markers analysed, the level of luteinizing hormone exhibited a negative correlation with the spinal and bulbar muscular atrophy functional rating scale, Korean version. However, among the patients with a disease duration of ≤5 years, the levels of luteinizing hormone showed a significant correlation with assessments using the amyotrophic lateral sclerosis functional rating scale-revised, spinal and bulbar muscular atrophy functional rating scale, Korean version and the 6-minute walk test. In conclusion, our findings provide clinical information from a substantial number of patients with spinal and bulbar muscular atrophy in Korea that accorded with that of patients with this disease worldwide but with updated clinical features.

Clinical spectrum, biochemical profile and disease progression of Kennedy disease in an Indian cohort.

BACKGROUND: Kennedy disease (KD) is a slowly progressive lower motor neuron degenerative disease. The prevalence of KD is unknown in India. AIM: To describe the phenotypic and laboratory features of an Indian cohort of KD patients. METHODS: A retrospective study was done on seven genetically confirmed KD patients based on demographic, clinical and laboratory details. RESULTS: Mean age at onset and presentation was 37 ± 11.9 and 44.6 ± 13.5 years respectively. Progressive asymmetric proximal and distal limb weakness was the commonest symptom (57.1%). All patients had motor symptoms along with non-specific symptoms such as cramps from the onset. Easy fatigability, decremental response along with ptosis were noted in two patients, which was a novel finding. Gynaecomastia and tongue wasting with fasciculations were universal findings. All five patients with nerve conduction studies showed sensorimotor neuropathy. Magnetic resonance imaging muscle done in two patients showed a prominent moth-eaten appearance in the thigh and posterior leg compartment in one patient. The mean cytosine-adenine-guanine repeats were 44 ± 3.7, and there was no association between age of onset or severity with repeat length. Only one patient required an assistive device for ambulation after 15 years of symptom onset. CONCLUSIONS: This study showed phenotypic heterogeneity in the Indian cohort. The age of onset was earlier with a slowly progressive indolent course as compared with other ethnic cohorts. This highlights the importance of considering the KD diagnosis in patients with the indolent course and suspected ALS diagnosis even with ptosis and fatigability in an appropriate clinical context.

Immp2l Enhances the Structure and Function of Mitochondrial Gpd2 Dehydrogenase.

'Inner mitochondrial membrane peptidase 2 like' (IMMP2L) is a nuclear-encoded mitochondrial peptidase that has been conserved through evolutionary history, as has its target enzyme, 'mitochondrial glycerol phosphate dehydrogenase 2' (GPD2). IMMP2L is known to cleave the mitochondrial transit peptide from GPD2 and another nuclear-encoded mitochondrial respiratory-related protein, cytochrome C1 (CYC1). However, it is not known whether IMMP2L peptidase activates or alters the activity or respiratory-related functions of GPD2 or CYC1. Previous investigations found compelling evidence of behavioural change in the Immp2lKD-/- KO mouse, and in this study, EchoMRI analysis found that the organs of the Immp2lKD-/- KO mouse were smaller and that the KO mouse had significantly less lean mass and overall body weight compared with wildtype littermates (p < 0.05). Moreover, all organs analysed from the Immp2lKD-/- KO had lower relative levels of mitochondrial reactive oxygen species (mitoROS). The kidneys of the Immp2lKD-/- KO mouse displayed the greatest decrease in mitoROS levels that were over 50% less compared with wildtype litter mates. Mitochondrial respiration was also lowest in the kidney of the Immp2lKD-/- KO mouse compared with other tissues when using succinate as the respiratory substrate, whereas respiration was similar to the wildtype when glutamate was used as the substrate. When glycerol-3-phosphate (G3P) was used as the substrate for Gpd2, we observed ~20% and ~7% respective decreases in respiration in female and male Immp2lKD-/- KO mice over time. Together, these findings indicate that the respiratory-related functions of mGpd2 and Cyc1 have been compromised to different degrees in different tissues and genders of the Immp2lKD-/- KO mouse. Structural analyses using AlphaFold2-Multimer further predicted that the interaction between Cyc1 and mitochondrial-encoded cytochrome b (Cyb) in Complex III had been altered, as had the homodimeric structure of the mGpd2 enzyme within the inner mitochondrial membrane of the Immp2lKD-/- KO mouse. mGpd2 functions as an integral component of the glycerol phosphate shuttle (GPS), which positively regulates both mitochondrial respiration and glycolysis. Interestingly, we found that nonmitochondrial respiration (NMR) was also dramatically lowered in the Immp2lKD-/- KO mouse. Primary mouse embryonic fibroblast (MEF) cell lines derived from the Immp2lKD-/- KO mouse displayed a ~27% decrease in total respiration, comprising a ~50% decrease in NMR and a ~12% decrease in total mitochondrial respiration, where the latter was consistent with the cumulative decreases in substrate-specific mediated mitochondrial respiration reported here. This study is the first to report the role of Immp2l in enhancing Gpd2 structure and function, mitochondrial respiration, nonmitochondrial respiration, organ size and homeostasis.

Spinal and bulbar muscular atrophy combined with hypertrophic cardiomyopathy and Brugada-pattern electrocardiographic changes: A case report.

Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked recessive neurodegenerative disorder caused by the excessive expansion of cytosine-adenine-guanine repeat sequences in the androgen receptor gene encoded on the Xq11-12 chromosome. SBMA primarily affects adult males and is characterized by weakness and atrophy of the proximal limb muscles, often involving the bulbar muscles. In addition to neuromuscular deficits, nonneuronal symptoms such as hypertension, hyperlipidemia, and liver dysfunction are often observed in patients with SBMA. Previous studies have suggested that SBMA patients have been diagnosed with hypertrophic cardiomyopathy (HCM), while gene detection is lacked. Moreover, according to current reports, SBMA patients can carry Brugada syndrome or HCM respectively, while three kinds of diseases have not been reported to exist in the same patient. Here, we report the first case of a male diagnosed with SBMA combined with HCM and two types of Brugada-pattern electrocardiographic changes, with a heterozygous missense mutation in the TTN gene.

A female carrier of spinal and bulbar muscular atrophy diagnosed with DNAJB6-related distal myopathy.

Mutations in the DNAJB6 gene cause limb girdle muscular dystrophy D1 (LGMD D1) and distal myopathy with rimmed vacuoles. With the discovery of new mutations, the phenotypic spectrum of DNAJB6-related myopathy has been extended, making the diagnosis more complicated. In this study, we describe a female carrier of spinal and bulbar muscular atrophy (SBMA) diagnosed with DNAJB6-related distal myopathy. The c.292_294delGAT (p. Asp98del) mutation in the DNAJB6 gene and a 49 CAG repeat expansion in the androgen receptor (AR) gene were identified. According to the clinical manifestations of distal-dominant lower limb involvement, a myogenic pattern in the electrophysiological study, and rimmed vacuoles on muscle pathology, the patient was ultimately diagnosed with DNAJB6-related distal myopathy. A functional study in a zebrafish model indicated that the c.292_294delGAT (p. Asp98del) mutation contributed to muscle structure defects. This study offers useful insights for the differential diagnosis of a condition in which patients carry pathogenic variants in different genes.

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

INTRODUCTION/AIMS: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Identification of UBA1 as the causative gene of an X-linked non-Kennedy spinal-bulbar muscular atrophy.

BACKGROUND AND PURPOSE: Spinal-bulbar muscular atrophy (SBMA) (Kennedy's disease) is a motor neuron disease. Kennedy's disease is nearly exclusively caused by mutations in the androgen receptor encoding gene (AR). The results of studies aimed at identification of the genetic cause of a disease that best approximates SBMA in a pedigree (four patients) without mutations in AR are reported. METHODS: Clinical investigations included thorough neurological and non-neurological examinations and testing. Genetic analysis was performed by exome sequencing using standard protocols. UBA1 mutations were modeled on the crystal structure of UBA1. RESULTS: The clinical features of the patients are described in detail. A missense mutation in UBA1 (c.T1499C; p.Ile500Thr) was identified as the probable cause of the non-Kennedy SBMA in the pedigree. Like AR, UBA1 is positioned on chromosome X. UBA1 is a highly conserved gene. It encodes ubiquitin-like modifier activating enzyme 1 (UBA1) which is the major E1 enzyme of the ubiquitin-proteasome system. Interestingly, UBA1 mutations can also cause infantile-onset X-linked spinal muscular atrophy (XL-SMA). The mutation identified here and the XL-SMA causative mutations were shown to affect amino acids positioned in the vicinity of UBA1's ATP binding site and to cause structural changes. CONCLUSION: UBA1 was identified as a novel SBMA causative gene. The gene affects protein homeostasis which is one of most important components of the pathology of neurodegeneration. The contribution of this same gene to the etiology of XL-SMA is discussed.

Kennedy's disease presented with mastication fatigue combined with positive titin antibody: a case report.

BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is an X-linked recessive hereditary neuromuscular disorder caused by the expanded trinucleotide repeat in the androgen receptors gene. The major clinical manifestations of SBMA consist of weakness in the bulbar and limb muscles, fasciculations, tremors, cramps, sensory impairment, and gynecomastia. However, atypical SBMA cases may lead to misdiagnosis. Muscular fatigue and decremental responses to repetitive nerve stimulation (RNS), despite being observed in some SBMA patients, are usually occurred in MG patients, and patient with the symptom of mastication fatigue was rarely reported. In addition, cardiological investigations have been performed in SBMA patients and several ECG alterations were identified. Here we report an SBMA patient presenting with a rare onset symptom of mastication fatigue, who has been detected with a positive titin antibody in the serum and showed a WPW pattern electrocardiogram. CASE PRESENTATION: The patient showed mildly progressive fatigue in the muscles of mastication over 3 years. Neurological examination showed facial muscle weakness and a wasting tongue with fasciculations, but the weakness, wasting, or fasciculations were not obvious in the limbs. 3-Hz RNS showed a decremental response in bilateral orbicularis oculi. The test of titin antibody was positive in the serum, and the electrocardiogram showed a WPW pattern ECG. Genetic analysis revealed an increased number (39 repeats) of tandem CAG repeats in the AR gene, which confirmed the diagnosis of SBMA. The fatigue symptom was significantly improved after oral pyridostigmine bromide treatment. CONCLUSION: This case calls for more attention to muscular fatigue as the onset symptoms of Kennedy's disease. ECG screening is of importance in SBMA patients and further studies are needed to investigate the titin antibody in SBMA patients as well as other neurogenic disorders.

Ultrasonographic evaluation reveals thinning of cervical nerve roots and peripheral nerves in spinal and bulbar muscular atrophy.

BACKGROUND: Ultrasonography (US) is a noninvasive and patient-friendly tool for the evaluation of peripheral nerves. In motor neuron diseases, amyotrophic lateral sclerosis (ALS) has been reported to show the atrophy of peripheral nerves on US. However, the US findings are still unclear in spinal and bulbar muscular atrophy (SBMA), an adult-onset lower motor neuron disease caused by an abnormal CAG repeat expansion in the androgen receptor gene. METHODS: We prospectively recruited and evaluated 11 patients with genetically confirmed SBMA and 9 patients with ALS diagnosed according to the revised El Escorial ALS criteria or the Awaji electrodiagnostic criteria. The C5-C7 cervical nerve roots and the median and ulnar nerves were evaluated ultrasonographically. RESULTS: The cross-sectional areas (CSAs) of the C6 and C7 nerve roots, the median nerve in the upper arm and forearm, and the ulnar nerve in the upper arm were smaller in patients with SBMA than those in patients with ALS (p < 0.05), whereas the CSAs of the C5 nerve root and the ulnar nerve in the forearm were not smaller. CONCLUSIONS: US showed that the peripheral nerves in patients with SBMA were thinner than those in patients with ALS despite similar degrees of weakness and motor neuron loss. Possible causes include additional sensory nerve involvement and longer disease duration in patients with SBMA than those in patients with ALS.

Wide range of reduced penetrance alleles in spinal and bulbar muscular atrophy: a model-based approach.

BACKGROUND: Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is an X-linked motor neuron disorder caused by an expanded CAG repeat in the gene coding for the androgen receptor (AR). The range and significance of reduced penetrance alleles in SBMA has not been fully determined to date. We presently sought to determine the range of reduced penetrance alleles in SBMA. METHODS: Through systematic literature review and meta-analysis, we collected and analysed data from 2576 patients with SBMA and compared the distributions of the CAG repeat number (CAG)n in the AR gene between patients and 112 248 control alleles of the general population. RESULTS: Our analysis revealed an unexpectedly high frequency of expanded SBMA-associated alleles, with (CAG)n ≥35 present in 107/100,000 and (CAG)n ≥38 present in 27/100,000 of the general population. Consequently, we suggest an updated model describing the distribution of expanded alleles in the general population. We argue against the established cut-off principle for the penetrance of SBMA and suggest that penetrance gradually increases from 35 to approximately 46 (CAG)n, above which it reaches a plateau approaching maximum value. CONCLUSION: Asymptomatic men of the general population with no/unknown SBMA family history are free of risk when carrying (CAG)n ≤34, are at intermediate but increasing risk for developing SBMA when carrying (CAG)n ≈35-46 and have close to 100% risk of developing the disease when carrying (CAG)n ≥47. The above observations should be helpful and clinically useful when providing genetic counselling to individuals and families bearing SBMA-associated alleles.

[Evaluation of vestibular-evoked myogenic potential for functional integrity of the brain stem in Kennedy's disease].

Objective: To investigate whether vestibular-evoked myogenic potentials(VEMPs) can be used to assess brainstem involvement in patients with Kennedy's disease (KD). Method: This was a case-control study.Twenty consecutive patients with genetically confirmed KD and 20 age-and sex-matched healthy subjects were enrolled from November 2018 to September 2020.All subjects were tested for three types of VEMPs, including cervical VEMP (c-VEMP) recorded by the sternocleidomastoid muscle (parameter:p13, n23), masseter VEMP (m-VEMP) recorded by the masseter muscle(parameter: p11), and ocular VEMP (o-VEMP) recorded by the inferior oblique muscle (parameter n10, p15).The latency of each wave, interside peak latency and interpeak latency of c-VEMP, the corrected amplitude and amplitude asymmetry ratio were recorded. Bilateral sternocleidomastoid muscle (SCMM) electromyography (EMG) was performed. The spinal cord and bulbous muscular atrophy functional rating scale (SBMAFRS) was used for assessment. Results: The mean p13 latency of c-VEMP was (15.5±1.4)ms, which was longer than that of the control group[(13.3±0.9)ms](P<0.05); the mean n23 latency was(25.5±1.4)ms, which was also longer than that of the control group[(22.5±1.0)ms] (P<0.05); the difference of bilateral p13[(2.3±0.6)ms] was significantly higher than that of the control group(P<0.05). The abnormal rates of c-, m-, o-VEMP in KD patients were 75%(15/20), 30%(6/20) and 20%(4/20), respectively. There was a significant positive correlation between c-VEMP latency and course of disease in KD patients(left: r=0.715, 0.695, right: r= 0.708, 0.715, both P<0.05). However, c-VEMP latency was negatively correlated with SBMAFRS score (left: r=-0.701, -0.694, right: r=-0.644, -0.685, both P<0.05). Abnormal rates of SCMM EMG in KD group were as follows: 15%(3/20)of patients showed spontaneous potential in resting state and 45% (9/20) of patients exhibited simple recruitment. Conclusions: The c-VEMP latency is a sensitive tool for detecting lower brainstem involvement in patients with KD, and the degree of damage increases with prolongation of disease course. The o-and m-VEMP abnormalities indicate that some KD patients develop upper brainstem damage.

C9orf72 hexanucleotide repeat expansion found in suspected spinobulbar muscular atrophy (SBMA).

INTRODUCTION: The expansion of a hexanucleotide GGGGCC repeat (G4C2) in the C9orf72 locus is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In addition, C9orf72 expansion has also been detected in patients with a clinical manifestation of Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), and ataxic disorders. MATERIAL AND METHODS: A total of 1,387 patients with clinically suspected ALS, HD or spinal and bulbar muscular atrophy (SBMA) were enrolled, and the prevalence of C9orf72 expansions was estimated. RESULTS: The hexanucleotide expansion accounted for 3.7% of the ALS patients, 0.2% of the HD suspected patients with excluded HTT mutation, and 1.3% of the suspected SBMA patients with excluded mutation in AR gene. CONCLUSIONS: This is the first report revealing the presence of C9orf72 expansion in patients with a suspected SBMA diagnosis. Consequently, we advise testing for C9orf72 expansion in patients presenting with the SBMA phenotype and a genetically unsolved diagnosis.

Clenbuterol-sensitive delayed outward potassium currents in a cell model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by polyglutamine (polyQ) expansions in the androgen receptor (AR) gene. SBMA is characterized by selective dysfunction and degeneration of motor neurons in the brainstem and spinal cord through still unclear mechanisms in which ion channel modulation might play a central role as for other neurodegenerative diseases. The beta2-adrenergic agonist clenbuterol was observed to ameliorate the SBMA phenotype in mice and patient-derived myotubes. However, the underlying molecular mechanism has yet to be clarified. Here, we unveil that ionic current alterations induced by the expression of polyQ-expanded AR in motor neuron-derived MN-1 cells are attenuated by the administration of clenbuterol. Our combined electrophysiological and pharmacological approach allowed us to reveal that clenbuterol modifies delayed outward potassium currents. Overall, we demonstrated that the protection provided by clenbuterol restores the normal function through the modulation of KV2-type outward potassium currents, possibly contributing to the protective effect on motor neuron toxicity in SBMA.

Acetylcholinesterase inhibitor responsive myasthenia in a Filipino male with X-linked recessive spinal and bulbar muscular atrophy.

We report a 51-year-old male diagnosed with X-linked recessive spinal and bulbar muscular atrophy (SBMA) by genetic testing who presented with 30 years history of progressive proximal and bulbar weakness responsive to cholinesterase inhibitor. Although the anti-acetylcholine receptor antibody (anti-AChR Ab) was negative, the myasthenic state was confirmed by decremental response in repetitive nerve stimulation and increased jitter frequency and blocking in single fiber-electromyography. While myasthenia gravis and SBMA may co-exist independently in an individual having the signs and symptoms of both conditions, the absence of anti-AChR Ab may imply that myasthenia can be an exaggerated activity-induced fatigue or weakness from the latter.

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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Myoglobin: a new biomarker for spinal and bulbar muscular atrophy?

OBJECTIVES: There is a primary muscular affection in spinal and bulbar muscular atrophy (SBMA). Myoglobin (Myo) is mainly distributed in the myocardium and skeletal muscle. The purpose of the study was to explore the significance of serum Myo detection in the diagnosis and clinical evaluation of SBMA. MATERIALS AND METHODS: In this study, serum creatine kinase (CK), Myo, and Troponin T (cTNT) levels were assessed in 80 patients with SBMA and were compared with those of 60 patients with amyotrophic lateral sclerosis (ALS). All measurement data were analyzed using the t-test and enumeration data using the χ2-test. RESULTS: The rate of abnormal Myo levels in the SBMA group was 100%, however, none of the patients with ALS had an abnormal Myo level. There was no overlap between the two groups. The Myo levels in patients with SBMA were correlated with the course of the disease. Further, their CK level was significantly elevated compared with that in patients with ALS, however, there was an overlap between the two groups. The serum cTNT level in patients with SBMA was not significantly different from that in patients with ALS. CONCLUSION: Myo, as a simple, inexpensive, and readily available biochemical indicator, is likely to be used for the differentiation between SBMA and ALS, and used as a new biomarker for the clinical evaluation of 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.