Hiroshi Kawahara: A Founder of Japanese Neurology: The Origin of Neurology in Nagoya

Diseases are sometimes known by many names 1–9, which complicates the retrieval of publications. Rare and emerging diseases may be especially vulnerable to this. Health sciences librarians do not often encounter rare diseases and may be unaware of the search challenges that these diseases present. To effectively retrieve publications for research, a strategy to identify all the different names of a disease is needed so that these can be incorporated into a comprehensive search. The author was engaged in a research project to create a comprehensive bibliography of the rare disease spinal and bulbar muscular atrophy (SBMA). The project utilized a strategy to identify all of the various names for the disease. This strategy should be helpful not only for SBMA researchers, but for anyone interested in a methodology for obtaining a comprehensive list of names for a disease. Spinal and bulbar muscular atrophy (SBMA) SBMA (ORPHA481, OMIM #313200, SNOMED CT Concept ID 230253001†) is a rare progressive neuromuscular disorder of males marked by proximal muscle weakness, cramping, fasciculations (twitching of individual muscle fibers), and muscle atrophy. Symptoms have been reported to first begin to develop between the third to sixth decades of life. Prevalence of SBMA has been reported alternately as 1 in 40,000 10, 1–2 in 100,000 11, and less than 1 in 50,000 live male births 12, but it is thought to be underdiagnosed 13–15. Degeneration of anterior horn cells (lower motor neurons) in the spinal cord of affected individuals is observed. Additional symptoms may include gynecomastia (abnormal growth of breasts in males), testicular atrophy, dysarthria (difficulty speaking), and dysphagia (difficulty swallowing). At this time, there is no known cure for most such neuromuscular diseases 16. Inheritance of SBMA is by traditional X-linked genetics. The disorder is related to a genetic defect in which a trinucleotide repeat occurs in the first exon of the androgen receptor gene on the X chromosome, first identified by La Spada in 1991 17. The string of three nucleotides of a trinucleotide repeat is present in a normal gene but is an unusually long string in a defective gene. The trinucleotide repeat of SBMA is cytosine-adenine-guanine (CAG), which codes for the amino acid glutamine. The presence of the repeat in DNA translation results in a string of glutamine molecules in the resulting peptide. Normal CAG repeat length in the androgen receptor gene is 11–34. SBMA is diagnosed if the number of CAG repeats exceeds 38 18, 19. Women do not develop SBMA, but heterozygous and homozygous women may exhibit mild symptoms, particularly muscle twitching and cramping 13, 20, 21. SBMA was identified as a unique disorder in 1968 by William R. Kennedy, but the disorder existed before its discovery 22. As far back as 1897, Japanese neurologist Hiroshi Kawahara first described what appeared to be SBMA in two brothers suffering from muscle atrophy and fasciculation of the tongue and limbs, with adult onset and sex-linked recessive inheritance 23, 24. Several disorders of varying severity and outcomes resemble SBMA, and the disorder is thought to be frequently misdiagnosed 25–29. The most well known is amyotrophic lateral sclerosis. The most challenging are the spinal muscular atrophies (SMA). However, SMA is an autosomal recessive genetic disease. Symptoms of most forms of SMA arise in childhood, but SMA3 is suggested to possibly first appear in adolescence or young adulthood. SMA4 symptoms may appear after age 30 30.

Polyglutamine expansion within the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA) and is associated with misfolded and aggregated species of the mutant AR. We showed previously that nuclear localization of the mutant AR was necessary but not sufficient for SBMA. Here we show that an interdomain interaction of the AR that is central to its function within the nucleus is required for AR aggregation and toxicity. Ligands that prevent the interaction between the amino-terminal FXXLF motif and carboxyl-terminal AF-2 domain (N/C interaction) prevented toxicity and AR aggregation in an SBMA cell model and rescued primary SBMA motor neurons from 5α-dihydrotestosterone-induced toxicity. Moreover, genetic mutation of the FXXLF motif prevented AR aggregation and 5α-dihydrotestosterone toxicity. Finally, selective androgen receptor modulators, which prevent the N/C interaction, ameliorated AR aggregation and toxicity while maintaining AR function, highlighting a novel therapeutic strategy to prevent the SBMA phenotype while retaining AR transcriptional function.

BACKGROUND Although spinal and bulbar muscular atrophy (SBMA) has been classified as a motor neuron disease, several reports have indicated the primary involvement of skeletal muscle in the pathogenesis of this devastating disease. Recent studies reported decreased intramuscular creatine levels in skeletal muscles in both patients with SBMA and transgenic mouse models of SBMA, which appears to contribute to muscle weakness. OBJECTIVE The present study aimed to examine the efficacy and safety of oral creatine supplementation to improve motor function in patients with SBMA. METHODS A randomized, double-blind, placebo-controlled, three-armed clinical trial was conducted to assess the safety and efficacy of creatine therapy in patients with SBMA. Patients with SBMA eligible for this study were assigned randomly in a 1:1:1 ratio to each group of placebo, 10 g, or 15 g daily dose of creatine monohydrate in a double-blind fashion. Participants took creatine or placebo orally 3 times a day for 8 weeks. Outcome measurements were results of neurological assessments, examinations, and questionnaires collected at baseline and at weeks 4, 8, and 16 after a washout period. The primary endpoint was the change in handgrip strength values from baseline to week 8. The secondary endpoints included the following: results of maximum voluntary isometric contraction tests of extremities; tongue pressure; results of the 15-foot timed walk test and the rise from bed test; modified quantitative myasthenia gravis score; respiratory function test results; activities of daily living assessed with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale and the Spinal and Bulbar Muscular Atrophy Functional Rating Scale; skeletal muscle mass measured with dual-energy X-ray absorptiometry; urinary 8-hydroxydeoxyguanosine levels; and questionnaires examining the quality of life, swallowing function, and fatigue. RESULTS Participant enrollment in the trial started from June 2014 and follow-up was completed in July 2015. The study is currently being analyzed. CONCLUSIONS This is the first clinical trial evaluating creatine therapy in SBMA. Given that creatine serves as an energy source in skeletal muscles, recovery of intramuscular creatine concentration is expected to improve muscle strength. CLINICALTRIAL University Hospital Medical Information Network Clinical Trials Registry UMIN000012503; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014611 (Archived by WebCite at http://www.webcitation.org/6xOlbPkg3).

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is an adult-onset, X-linked motor neuron disease characterized by muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. SBMA is caused by the expansion of a CAG triplet repeat, encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The histopathological finding in SBMA is the loss of lower motor neurons in the anterior horn of the spinal cord as well as in the brainstem motor nuclei. There is no established disease-modifying therapy for SBMA. Animal studies have revealed that the pathogenesis of SBMA depends on the level of serum testosterone, and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation and/or stabilization of the pathogenic AR. Heat shock proteins, the ubiquitin-proteasome system and transcriptional regulation are also potential targets for development of therapy for SBMA. Among these therapeutic approaches, the luteinizing hormone-releasing hormone analogue, leuprorelin, prevents nuclear translocation of aberrant AR proteins, resulting in a significant improvement of disease phenotype in a mouse model of SBMA. In a phase 2 clinical trial of leuprorelin, the patients treated with this drug exhibited decreased mutant AR accumulation in scrotal skin biopsy. Phase 3 clinical trial showed the possibility that leuprorelin treatment is associated with improved swallowing function particularly in patients with a disease duration less than 10years. These observations suggest that pharmacological inhibition of the toxic accumulation of mutant AR is a potential therapy for SBMA.

BackgroundAlthough spinal and bulbar muscular atrophy (SBMA) has been classified as a motor neuron disease, several reports have indicated the primary involvement of skeletal muscle in the pathogenesis of this devastating disease. Recent studies reported decreased intramuscular creatine levels in skeletal muscles in both patients with SBMA and transgenic mouse models of SBMA, which appears to contribute to muscle weakness.ObjectiveThe present study aimed to examine the efficacy and safety of oral creatine supplementation to improve motor function in patients with SBMA.MethodsA randomized, double-blind, placebo-controlled, three-armed clinical trial was conducted to assess the safety and efficacy of creatine therapy in patients with SBMA. Patients with SBMA eligible for this study were assigned randomly in a 1:1:1 ratio to each group of placebo, 10 g, or 15 g daily dose of creatine monohydrate in a double-blind fashion. Participants took creatine or placebo orally 3 times a day for 8 weeks. Outcome measurements were results of neurological assessments, examinations, and questionnaires collected at baseline and at weeks 4, 8, and 16 after a washout period. The primary endpoint was the change in handgrip strength values from baseline to week 8. The secondary endpoints included the following: results of maximum voluntary isometric contraction tests of extremities; tongue pressure; results of the 15-foot timed walk test and the rise from bed test; modified quantitative myasthenia gravis score; respiratory function test results; activities of daily living assessed with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale and the Spinal and Bulbar Muscular Atrophy Functional Rating Scale; skeletal muscle mass measured with dual-energy X-ray absorptiometry; urinary 8-hydroxydeoxyguanosine levels; and questionnaires examining the quality of life, swallowing function, and fatigue.ResultsParticipant enrollment in the trial started from June 2014 and follow-up was completed in July 2015. The study is currently being analyzed.ConclusionsThis is the first clinical trial evaluating creatine therapy in SBMA. Given that creatine serves as an energy source in skeletal muscles, recovery of intramuscular creatine concentration is expected to improve muscle strength.Trial RegistrationUniversity Hospital Medical Information Network Clinical Trials Registry UMIN000012503; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014611 (Archived by WebCite at http://www.webcitation.org/6xOlbPkg3).

Objective Spinal and bulbar muscular atrophy (SBMA) causes oral and pharyngeal dysphagia; however, esophageal involvement remains unclear. This study aimed to clarify esophageal involvement in SBMA by using chest computed tomography (CT). Methods Patients with SBMA who visited our hospital between 2014 and 2025 and underwent chest CT were included. Male stroke patients served as controls. The maximum thoracic esophageal diameter was measured on chest CT in patients with SBMA and stroke. A videofluoroscopic swallowing study (VFSS) was performed in the SBMA group. Results Fifty-seven patients (12 with SBMA and 45 with stroke) were included in the study. The upper thoracic esophageal diameter was larger in the SBMA group (15.4 vs. 11.1 mm; p=0.035). In the middle segment, the diameter was larger in the SBMA group (13.1 vs. 5.1 mm; p=0.004). In the lower segment, the diameter tended to be larger in the SBMA group, but the difference was not statistically significant. Multiple regression analyses showed that age (B=0.13, 95% confidence interval [CI]=0.02-0.24; p=0.026) and SBMA (B=5.35, 95% CI 1.09-9.60; p=0.015) independently predicted upper thoracic esophageal dilation. SBMA was an independent predictor in the middle segment (B=5.11, 95% CI 1.28-8.94; p=0.01). VFSS was performed in 8 patients with SBMA. Esophageal residue after swallowing thickened liquid was observed in six patients. Conclusion SBMA was associated with upper and middle thoracic esophageal dilation on chest CT. Esophageal dysfunction warrants attention along with oral and pharyngeal dysphagia.

No data are available regarding the occurrence of sleep disorders in spinal and bulbar muscular atrophy (SBMA). We investigated the sleep-wake cycle in SBMA patients compared with healthy subjects. Nine SBMA outpatients and nine age-matched and sex-matched healthy controls were evaluated. Subjective quality of sleep was assessed by means of the Pittsburgh Sleep Quality Index (PSQI). The Epworth Sleepiness Scale was used in order to evaluate excessive daytime sleepiness. All participants underwent a 48-h polysomnography followed by the multiple sleep latency test. Time in bed, total sleep time and sleep efficiency were significantly lower in SBMA than controls. Furthermore, the apnea-hypopnea index (AHI) was significantly higher in SBMA than controls. Obstructive sleep apnea (OSA: AHI >5/h) was evident in 6/9 patients (66.6 %). REM sleep without atonia was evident in three patients also affected by OSA and higher AHI in REM; 2/9 (22.2 %) SBMA patients showed periodic limb movements in sleep. The global PSQI score was higher in SBMA versus controls. Sleep quality in SBMA is poorer than in controls. OSA is the most common sleep disorder in SBMA. The sleep impairment could be induced both by OSA or/and the neurodegenerative processes involving crucial areas regulating the sleep-wake cycle.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy. The cause of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, within the first exon of the androgen receptor (AR) gene. SBMA exclusively occurs in males, whereas both heterozygous and homozygous females are usually asymptomatic. In a transgenic mouse model of SBMA, neuromuscular symptoms are markedly pronounced in the male mice, but far less severe in the female counterparts. Androgen deprivation through both surgical and chemical castration substantially suppresses nuclear accumulation of the pathogenic AR, and thereby improves symptoms in the male mice. Since the nuclear translocation of AR is ligand-dependent, testosterone appears to show toxic effects by accelerating nuclear translocation of the pathogenic AR. In a phase 2 clinical trial, 12-month treatment with leuprorelin significantly diminished the serum level of creatine kinase, and suppressed nuclear accumulation of the pathogenic AR. The ligand-dependent accumulation of the pathogenic AR, an initial step in the neurodegenerative process in SBMA, is followed by several downstream molecular events such as transcriptional dysregulation, axonal transport disruption, and mitochondrial insufficiency, indicating that both upstream and downstream molecular abnormalities should be corrected.

We examined the effect of aerobic exercise in patients with spinal and bulbar muscular atrophy (SBMA). SBMA is caused by a defect androgen receptor. This defect causes motor neuron death, but considering the important function of androgens in muscle, it is possible that muscle damage in SBMA also occurs independently of motor neuron damage. Eight patients with SBMA engaged in regular cycling exercise for 12 weeks. Maximum oxygen uptake (Vo(2max)), maximal work capacity (W(max)), muscle morphology, citrate synthase (CS) activity, body composition, EMG, static strength measurements, lung function, plasma proteins, and hormones were evaluated before and after training. Evaluation of improvements in activities of daily living (ADL) was conducted after training. W(max) increased by 18%, and CS activity increased by 35%. There was no significant change in Vo(2max) or any of the other variables examined before and after training, and the patients with SBMA did not feel improvements in ADL. Frequent, moderate-intensity aerobic conditioning is of little beneficial effect in patients with spinal and bulbar muscular atrophy (SBMA). High levels of plasma creatine kinase and muscle regeneration indicate a primary myopathic affection, which, in parallel with the motor neuron deficiency, may attenuate the response to exercise training in patients with SBMA.

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.

ObjectiveTo determine whether blood biomarkers of neuronal damage (neurofilament light chain [NfL]), muscle damage (creatine kinase [CK]), and muscle mass (creatinine) are altered in spinal and bulbar muscular atrophy (SBMA) and can be used as biomarkers for disease severity.MethodsIn this multicenter longitudinal prospective study, plasma and serum were collected from 2 cohorts of patients with SBMA in London, United Kingdom (n = 50), and Padova, Italy (n = 43), along with disease (amyotrophic lateral sclerosis [ALS]) and healthy controls, and levels of plasma and serum NfL, CK, and creatinine were measured. Disease severity was assessed by the SBMA Functional Rating Scale and the Adult Myopathy Assessment Tool at baseline and 12 and 24 months.ResultsBlood NfL concentrations were increased in ALS samples, but were unchanged in both SBMA cohorts, were stable after 12 and 24 months, and were not correlated with clinical severity. Normal NfL levels were also found in a well-established mouse model of SBMA. Conversely, CK concentrations were significantly raised in SBMA compared with ALS samples, and were not correlated to the clinical measures. Creatinine concentrations were significantly reduced in SBMA, and strongly and significantly correlated with disease severity.ConclusionsWhile muscle damage and muscle mass biomarkers are abnormal in SBMA, axonal damage markers are unchanged, highlighting the relevant primary role of skeletal muscle in disease pathogenesis. Creatinine, but not CK, correlated with disease severity, confirming its role as a valuable biomarker in SBMA.

This study aimed to explore the reliability and validity of tongue pressure measurement as a quantitative evaluation of swallowing function in patients with spinal and bulbar muscular atrophy (SBMA). This study enrolled 47 genetically confirmed patients with SBMA and 38 age- and sex-matched healthy controls. In both groups we measured tongue pressure using an intraoral pressure probe and assessed questionnaires that evaluated swallowing functions. We then analyzed the relationship between tongue pressure, functional scales, and the muscle weakness of other regions. Levels of tongue pressure were decreased in patients with SBMA within 3 years from the onset of the disease compared to healthy controls (SBMA 15.3 ± 6.4 kPa; healthy controls 37.3 ± 9.6 kPa; p < 0.001). Test-retest analysis showed a high reliability in patients with SBMA (intraclass correlation coefficient = 0.986). Tongue pressure showed a strong correlation with bulbar-related functional scales. Decrease of tongue pressure was detected in patients who reported no subjective dysphagia, and repetition of swallowing compensated for tongue weakness in such subjects. In patients with SBMA, tongue pressure more strongly correlates with the strength of pharyngeal, neck, and upper limb musculatures than with that of the lower limbs. Tongue pressure measurement is reliable and reflects swallowing function in patients with SBMA. The muscle strength of the tongue appears to decrease in SBMA before the awareness of subjective dysphagia, suggesting that tongue pressure measurement is a novel biomarker of SBMA and is applicable to early-stage detection.

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.

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

The aim of this study was to determine the frequency and relative importance of symptoms experienced by patients with spinal and bulbar muscular atrophy (SBMA). We 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. Hip, 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. There 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.