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The workshop held in the Netherlands from October 20–22, 2023, united 27 scientists from academia, healthcare, and industry representing 11 countries, alongside four patient and charity representatives. Focused on Kennedy's Disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), the workshop aimed to consolidate knowledge, align on clinical trial designs, and promote participative medicine for effective treatments. Discussions emphasized KD's molecular mechanisms, highlighting its status as a neuromuscular disorder with motor neuron degeneration. Strategies for therapeutic intervention, including AR activity modulation and targeting post-translational modifications, were proposed. The need for diagnostic, prognostic, and target engagement biomarkers was stressed. Challenges in patient stratification and clinical trial recruitment were acknowledged, with the International KD/SBMA Registry praised for its role. The workshop concluded with a patient-focused session, underscoring challenges in KD diagnosis and the vital support provided by patient associations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Kennedy disease is a rare neuromuscular disease associated with damage of androgen receptor gene and inherited by the X-linked recessive type. Its clinic features is characterized by a complex of neurological and extraneural disorders, including extremities peripheral paresis, bulbar syndrome. Some patients also have sensory polyneuropathy, cognitive impairment, endocrine and urological disorders. The article presents a clinical case of a man with Kennedy disease, symptoms debuted at age of 35. The features of the disease were significantly increase the level of blood creatinekinase, the presence of polyneuropathy. The data of a three-year observation of clinical and electromyographic manifestations, the results of laboratory tests, biopsies, and magnetic resonance imaging of muscles are presented. The possibilities of using and features of interpretation of the results of additional examination methods, the difficulties of differential diagnosis of the disease are discussed.

Abstract Background Kennedy’s disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by CAG expansions in exon 1 of the androgen receptor gene (AR). The objective of the French national diagnostic and management protocol is to provide evidence-based best practice recommendations and outline an optimised care pathway for patients with KD, based on a systematic literature review and consensus multidisciplinary observations. Results The initial evaluation, confirmation of the diagnosis, and management should ideally take place in a tertiary referral centre for motor neuron diseases, and involve an experienced multidisciplinary team of neurologists, endocrinologists, cardiologists and allied healthcare professionals. The diagnosis should be suspected in an adult male presenting with slowly progressive lower motor neuron symptoms, typically affecting the lower limbs at onset. Bulbar involvement (dysarthria and dysphagia) is often a later manifestation of the disease. Gynecomastia is not a constant feature, but is suggestive of a suspected diagnosis, which is further supported by electromyography showing diffuse motor neuron involvement often with asymptomatic sensory changes. A suspected diagnosis is confirmed by genetic testing. The multidisciplinary assessment should ascertain extra-neurological involvement such as cardiac repolarisation abnormalities (Brugada syndrome), signs of androgen resistance, genitourinary abnormalities, endocrine and metabolic changes (glucose intolerance, hyperlipidemia). In the absence of effective disease modifying therapies, the mainstay of management is symptomatic support using rehabilitation strategies (physiotherapy and speech therapy). Nutritional evaluation by an expert dietician is essential, and enteral nutrition (gastrostomy) may be required. Respiratory management centres on the detection and treatment of bronchial obstructions, as well as screening for aspiration pneumonia (chest physiotherapy, drainage, positioning, breath stacking, mechanical insufflation-exsufflation, cough assist machnie, antibiotics). Non-invasive mechanical ventilation is seldom needed. Symptomatic pharmaceutical therapy includes pain management, endocrine and metabolic interventions. There is no evidence for androgen substitution therapy. Conclusion The French national Kennedy’s disease protocol provides management recommendations for patients with KD. In a low-incidence condition, sharing and integrating regional expertise, multidisciplinary experience and defining consensus best-practice recommendations is particularly important. Well-coordinated collaborative efforts will ultimately pave the way to the development of evidence-based international guidelines.

Abstract A 61 year old man with facial diplegia, quadruparesis, tongue atrophy/fasciculations, bulbar speech, muscle weakness/wasting, hypotonia, tremor, dysdiadochokinesia, absent tendon reflexes, fasciculations, and gynecomastia, received immunoglobulins for suspected immune‐neuropathy with limited benefit. After reconsideration, Kennedy disease was diagnosed upon 44 CAG repeats in AR. In conclusion, immunoglobulins exhibit limited benefit on immune‐neuropathy in patients with coexisting KD.

The study objective is to present current data on various genetic reasons of feminization.Results. Disruption of puberty in males can be associated with genetically determined defects of androgen receptor which cause partial or full insensitivity to the action of these hormones. The article presents a detailed description of the structure and function of these receptors. Additionally, polymorphism of the androgen receptors» gene is described: it consists of different number of CAG-repeats, and elongation of this locus causes hypogonadism.Conclusion. Pathology of androgen receptors can cause insufficient clinical effectiveness of testosterone drugs, therefore treatment of male hypogonadism requires evaluation of androgen receptor sensitivity prior to drug prescription and during evaluation of treatment results.

Background: Spinal and bulbar muscular atrophy (SBMA) or Kennedy disease [OMIM: 313200] is a rare X-linked neuromuscular disease. Patients commonly present with muscle cramps, tremors, leg weakness, dysarthria and dysphagia.Methods: We deeply phenotyped and evaluated the possible extent of affected systems in all patients with SBMA in Latvia (n = 5). In addition, neurophysiological studies and blood analyses were used to perform a molecular diagnosis and evaluate biochemical values. We analyzed neurofilament light (NfL) as a possible biomarker.Results: Neurological examination revealed typical SBMA clinical manifestations; all patients had small or large nerve fiber neuropathy. Three of five patients had increased neurofilament light levels.Conclusion: The study confirms the systemic involvement in patients suffering from SBMA. Increased NfL concentration was associated with either peripheral neuropathy or decreased body mass index. The complex phenotype of the disease should be kept in mind, as it could help to diagnose patients with SBMA.

Hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) is a rare degenerative disorder inherited in an autosomal dominant fashion. This disease was described first in Japanese descendants from Okinawa and Shiga prefectures in mainland Honshu in 1997. The disease is characterized by adult onset of proximal weakness and atrophy, muscle cramps, fasciculations, areflexia, high incidence of elevated creatine kinase, hyperlipidemia, and diabetes mellitus, resembling Kennedy disease, though the mode of inheritance is autosomal dominant, rather than X linked. We examined a 56-year-old male patient with clinical features suggestive of HMSN-P and positive family history in an autosomal dominant fashion. Clinical, electrophysiological, and genetic factors were also reviewed. The appearance of HMSN-P in India and elsewhere calls for clinicians in nonendemic regions to be familiar with this rare disorder, which has typically been geographically confined. [ABSTRACT FROM AUTHOR]

Background: Kennedy's disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by CAG expansions in exon 1 of the androgen receptor gene (AR). The objective of the French national diagnostic and management protocol is to provide evidence-based best practice recommendations and outline an optimised care pathway for patients with KD, based on a systematic literature review and consensus multidisciplinary observations.Results: The initial evaluation, confirmation of the diagnosis, and management should ideally take place in a tertiary referral centre for motor neuron diseases, and involve an experienced multidisciplinary team of neurologists, endocrinologists, cardiologists and allied healthcare professionals. The diagnosis should be suspected in an adult male presenting with slowly progressive lower motor neuron symptoms, typically affecting the lower limbs at onset. Bulbar involvement (dysarthria and dysphagia) is often a later manifestation of the disease. Gynecomastia is not a constant feature, but is suggestive of a suspected diagnosis, which is further supported by electromyography showing diffuse motor neuron involvement often with asymptomatic sensory changes. A suspected diagnosis is confirmed by genetic testing. The multidisciplinary assessment should ascertain extra-neurological involvement such as cardiac repolarisation abnormalities (Brugada syndrome), signs of androgen resistance, genitourinary abnormalities, endocrine and metabolic changes (glucose intolerance, hyperlipidemia). In the absence of effective disease modifying therapies, the mainstay of management is symptomatic support using rehabilitation strategies (physiotherapy and speech therapy). Nutritional evaluation by an expert dietician is essential, and enteral nutrition (gastrostomy) may be required. Respiratory management centres on the detection and treatment of bronchial obstructions, as well as screening for aspiration pneumonia (chest physiotherapy, drainage, positioning, breath stacking, mechanical insufflation-exsufflation, cough assist machnie, antibiotics). Non-invasive mechanical ventilation is seldom needed. Symptomatic pharmaceutical therapy includes pain management, endocrine and metabolic interventions. There is no evidence for androgen substitution therapy.Conclusion: The French national Kennedy's disease protocol provides management recommendations for patients with KD. In a low-incidence condition, sharing and integrating regional expertise, multidisciplinary experience and defining consensus best-practice recommendations is particularly important. Well-coordinated collaborative efforts will ultimately pave the way to the development of evidence-based international guidelines. [ABSTRACT FROM AUTHOR]

Objectives: According to recent publications, some patients with spinal and bulbar muscular atrophy (BSMA) develop cardiac disease, manifesting as ST-segment abnormalities, Brugada-syndrome, dilative cardiomyopathy, or sudden cardiac death. Here we present neurological and cardiac data of a BSMA patient who was followed up for 10 y. Case report: In a male patient aged 47 y, BSMA was diagnosed at age 37 y upon the typical clinical presentation (postural tremor since age 12 y, dysarthria since age 15 y, muscle cramps since age 29 y, general myalgias since age 32 y, general fasciculations since age 34 y, myoclonic jerks, easy fatigability, dyspnea upon exercise since age 36 y) and a CAG-repeat expansion of 47 ± 1 repeats in the androgen-receptor gene detected at age 37 y. During the next 10 y he additionally developed mild but slowly progressive diffuse weakness on the upper limbs and mild proximal weakness on the lower limbs. Cardiologic exam, ECG, and echocardiography were normal at ages 37 y, 41 y, 44 y, and 47 y. Conclusions: Cardiac involvement may only develop in some BSMA patients within 10 y, whereas neurologic abnormalities slowly progress within 10 y of observation. Cardiac disease may develop at a later stage with progression of age and disease.

Bulboespinal muscular atrophy or Kennedy disease is a rare condition of the motor neuron. Patients with this condition, in addition to presenting motor problems that substantially affect their autonomy, will present to a greater or lesser extent affectations related to the musculature of the phonoarticulator mechanism, causing problems in the production of speech, voice and the function of swallowing. Evaluation and intervention by the phoniatric specialist is essential to establish intervention strategies aimed at communication skills and safe food ingestion. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) includes a number of disorders causing degeneration of lower and upper motor neurons and findings in the bulbar region and at least two spinal regions or UMN and LMN in three spinal regions. ALS is typically presented with bulbar or asymmetric limb weakness, loss of ability to speak, to swallow and to breathe. Kennedy disease is a form of MND that is associated with bulbar involvement and X linked recessive inheritance. The symptoms include muscular cramps, a limb-girdle distribution of muscle weakness, bulbar symptoms and distinguishing clinical features include facial and perioral fasciculations in particular. This is a case study of a 43-year-old man who suffered from recurrent muscle cramping and progressive symmetric lower extremity weakness, with a prominent fatigable component to this weakness, shoulder weakness, difficulty swallowing and facial twitching. EMNG showed widespread reinnervation changes and fasciculations in arms, legs, tongue, and thoracic paraspinals, with minimal fibrillation potentials. Motor NCS were normal or borderline in amplitude, and sensory responses were absent in upper and lower limbs. Genetic testing was positive (45 CAG). Kennedy disease may be underdiagnosed, owing in part to misdiagnosis and to the mild symptoms exhibited by some patients. The electro-physiological examinations are the key point to the diagnosis of Kennedy disease. In our case, we found the symmetric weakness, sensory abnormalities on electrophysiological testing, prominent facial fasciculations, and gynecomastia which were not characteristic of the ALS, and indicated that was one of MND syndromes such as Kennedy disease and that was confirmed by genetic testing. [ABSTRACT FROM AUTHOR]

Abstract Patients with motor neuron diseases may present to primary care clinic or may be initially encountered in the inpatient setting. Timely diagnosis of these conditions is a key factor in early intervention and therapy, and accuracy of diagnosis is of extreme importance, in particular for amyotrophic lateral sclerosis with its poor prognosis. The aim of this review article is to provide a clinical and diagnostic framework for the diagnosis and evaluation of motor neuron disease for primary care physicians. [ABSTRACT FROM AUTHOR]

A 61 year old man with facial diplegia, quadruparesis, tongue atrophy/fasciculations, bulbar speech, muscle weakness/wasting, hypotonia, tremor, dysdiadochokinesia, absent tendon reflexes, fasciculations, and gynecomastia, received immunoglobulins for suspected immune‐neuropathy with limited benefit. After reconsideration, Kennedy disease was diagnosed upon 44 CAG repeats in AR. In conclusion, immunoglobulins exhibit limited benefit on immune‐neuropathy in patients with coexisting KD. [ABSTRACT FROM AUTHOR]

The X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is a rare X-linked, recessive, lower motor neuron disease, characterized by weakness, atrophy, and fasciculations of the appendicular and bulbar muscle. The disease is caused by an expansion of the CAG repetition in the androgen receptor gene. Patients with Kennedy's disease have more than 39 CAG repetitions. We report a case of 57-year-old man, resident of Monte Dourado (PA, Brazil) who complained of brachiocrural paresis evolving for 3 years along with fasciculations and tremors of extremities. In addition, he also developed dysarthria, dysphagia, and sexual dysfunction. The patient clinical picture included gait impairment, global hyporeflexia, proximal muscle atrophy of upper limbs, deviation of the uvula to right during phonation and tongue atrophy with fasciculations. The patient reported that about 30 years ago he had undergone gynecomastia surgery. His electroneuromyography suggested spinal muscular atrophy, and nuclear magnetic resonance imaging showed tapering of the cervical and thoracic spinal cord. Patient's creatine kinase level was elevated. In view of the findings, an exam was requested to investigate Kennedy's disease. The exam identified 46 CAG repetitions in the androgen receptor gene, which confirmed the diagnostic suspicion. This was the first case of Kennedy's disease diagnosed and described in the Brazilian Amazon. To our knowledge only other four papers were published on this disease in Brazilian patients. A brief review is also provided on etiopathogenic, clinical and diagnostic aspects. [ABSTRACT FROM AUTHOR]

Introduction: The effects of spinal bulbar muscular atrophy (SBMA) on quality of life (QoL) are not well understood. This study describes symptoms from the patient's perspective and the impact these symptoms have on QoL.Methods: We conducted open-ended interviews with 21 adult men with genetically confirmed SBMA. Using a qualitative framework technique, we coded and analyzed interviews to identify symptoms and resulting themes.Results: From these interviews, 729 quotations were extracted. We identified 200 SBMA-specific symptoms and 20 symptomatic themes. Weakness was mentioned by all interviewees. Symptoms within the domain of mental health and the specific themes of emotional issues and psychological impact were also frequently mentioned.Discussion: Numerous symptoms affect QoL for patients with SBMA. We identified previously unrecognized symptoms that are important to address in enhancing clinical care for patients with SBMA and in developing tools to evaluate efficacy in future clinical trials. Muscle Nerve 57: 40-44, 2018. [ABSTRACT FROM AUTHOR]

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is a rare neurodegenerative disorder presenting with insidious onset of weakness in bulbar and limb muscles. Information regarding long-term clinical and functional progression has been limited, especially for the Taiwanese population. The purpose of the study aimed to investigate early diagnosis and long-term prognosis of SBMA. Methods: We retrospectively analyzed 21 genetically confirmed SBMA patients who visited our hospital between 1993 and 2010, focusing on clinical symptoms, nerve conduction studies, and functional disability. We also analyzed the relationship between length of cytosine-adenine-guanine (CAG) repeats and age of disease onset. Results: Weakness developed at a mean age of 39 ± 7 years (mean ± standard deviation). The length of CAG repeats and age at onset of weakness showed inverse (but nonsignificant) correlation. The most common symptoms at initial presentation were hand tremor (86%), limb weakness (86%), and perioral fasciculation (76%). Creatine kinase (CK) was elevated in 17 out of 18 patients. Initial nerve conduction studies showed statistical difference from normal controls, especially decreased amplitudes of compound motor action potential (CMAP) and sensory nerve action potential (SNAP). Functional disability showed very slow progression, with only three patients becoming wheelchair-dependent during follow-up at a median age of 72 years. Conclusion: Patients with SBMA may present with a myriad of symptoms, including limbs weakness, tremor, muscle atrophy, and perioral fasciculations. Elevated serum CK and decreased CMAP and SNAP amplitudes were supportive laboratory findings of SBMA. Disease progression was gradual, and most patients remained functionally independent many years after the onset of weakness.

Objective: The aim of this paper was to report the first case of Kennedy disease misdiagnosed as polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome.Clinical Presentation and Intervention: A 58-year-old Chinese man presented with limb numbness, progressive limb proximal weakness, lymph node and thyroid enlargement, edema, pigmentation in the lower limb, and obvious gynecomastia, which was initially diagnosed as POEMS syndrome and was treated with dexamethasone and small doses of cyclophosphamide without any improvement after 6 months. Finally, the patient diagnosis was confirmed as Kennedy disease (KD) by gene analysis.Conclusion: This case suggests that clinicians should pay more attention to the differential diagnosis between KD and POEMS syndrome. Gene analysis was helpful in detecting this rare confusing disease in this patient. [ABSTRACT FROM AUTHOR]

Spinal and Bulbar Muscular Atrophy (SBMA), also known as Kennedy's disease, is a rare adult-onset lower motor neuron disorder with a classic X-linked inheritance pattern. It is caused by the abnormal expansion of the CAG-repeat tract in the androgen receptor gene. Despite important progress in the understanding of the molecular pathogenesis and the availability of a broad set of model organisms, successful translation of these insights into clinical interventions remains elusive. Here we review the available information on clinical trials in SBMA and discuss the challenges and pitfalls that impede therapy development. Two important factors are the variability of the complex neuro-endocrinological phenotype and the comparatively low incidence of the disease that renders recruitment for clinical trials demanding. We propose that these challenges can be and need to be overcome by fostering closer collaborations between clinical research centers, the patient communities and the industry and non-industry sponsors of clinical trials. [ABSTRACT FROM AUTHOR]

There is no curative treatment for most neuromuscular disorders. Exercise, as a treatment for these diseases, has therefore received growing attention. When executed properly, exercise can maintain and improve health and reduce the risk of cardiovascular disease, obesity, and diabetes. In persons with muscle wasting due to neuromuscular conditions, however, a common belief has been that physical activity could accelerate degeneration of the diseased muscle and a careful approach to training has therefore been suggested. In this review, we describe the current knowledge about physical training in patients with neuromuscular diseases associated with weakness and wasting. We review studies that have investigated different types of exercise in both myopathies and motor neuron diseases, with particular emphasis on training of persons affected by spinobulbar muscular atrophy (SBMA). Finally, we provide suggestions for future investigations of training in this condition. [ABSTRACT FROM AUTHOR]

Pathomechanisms of spinal and bulbar muscular atrophy (SBMA) have been extensively investigated and are partially understood, but no effective treatment is currently available for this disabling disorder. Its rarity, the slow disease progression, and lack of sensitive-to-change outcome measures render design and conduction of clinical trials a challenging task. Therefore, it is fundamental to strengthen the network of clinical centers interested in SBMA for clinical trial readiness. We propose to create and maintain an International SBMA Registry where as many well-characterized patients as possible can be included, with the following aims: facilitate planning of clinical trials and recruitment of patients, define natural history of the disease, characterize epidemiology, develop standards of care, and inform the community of patients about research progresses and ongoing trials. We also aim at developing harmonized and coordinated biorepositories. The experience obtained during the last years in the field of other neuromuscular disorders and of Huntington disease offers valuable precedents. [ABSTRACT FROM AUTHOR]

We report the case of a 54-year-old right-handed man who presented with a 2-year history of progressive upper-limb weakness with mild dysarthria and prominent involuntary perioral abnormal movements that were characterized as fasciculations. Electromyography disclosed motor neuron disease. The diagnosis of Kennedy's disease was established by polymerase chain reaction. Perioral abnormal movements and fasciculations may represent important clinical clues to the diagnosis of Kennedy's disease, particularly when associated with proximal muscle atrophy and gynecomastia. In suspected cases, genetic testing for elevated CAG repeats in the androgen receptor Xq12 gene is warranted. [ABSTRACT FROM AUTHOR]

Spinal and bulbar muscular atrophy (SBMA) is characterized by progressive muscle weakness linked to a polyglutamine expansion in the androgen receptor (AR). Current evidence indicates that mutant AR causes SBMA by acting in muscle to perturb its function. However, information about how muscle function is impaired is scant. One fundamental question is whether the intrinsic strength of muscles, an attribute of muscle independent of its mass, is affected. In the current study, we assess the contractile properties of hindlimb muscles in vitro from chronically diseased males of three different SBMA mouse models: a transgenic (Tg) model that broadly expresses a full-length human AR with 97 CAGs (97Q), a knock-in (KI) model that expresses a humanized AR containing a CAG expansion in the first exon, and a Tg myogenic model that overexpresses wild-type AR only in skeletal muscle fibers. We found that hindlimb muscles in the two Tg models (97Q and myogenic) showed marked losses in their intrinsic strength and resistance to fatigue, but were minimally affected in KI males. However, diseased muscles of all three models showed symptoms consistent with myotonic dystrophy type 1, namely, reduced resting membrane potential and deficits in chloride channel mRNA. These data indicate that muscle dysfunction is a core feature of SBMA caused by at least some of the same pathogenic mechanisms as myotonic dystrophy. Thus mechanisms controlling muscle function per se independent of mass are prime targets for SBMA therapeutics. [ABSTRACT FROM AUTHOR]

Relatamos, pela primeira vez em nosso meio, dois pacientes com atrofia muscular bulbo espinhal de início tardio (doença de Kennedy), caracterizada por fraqueza, atrofia muscular, tremores e manifestações endocrinológicas, com sinais eletromiográficos de desnervação. Esta entidade diferencia-se das demais doenças do neurônio motor pela sua peculiar herança ligada ao sexo, anormalidades endocrinas (ginecomastia, atrofia testicular e oligoespermia), tendo prognóstico relativamente favorável. Discutimos a caracterização clínica dos doentes apresentados, o aspecto fisiopatológico e a evolução.We report two cases of Kennedy's disease (muscle weakness, amyotrophy, intentional tremor, endocrine abnormalities, and denervation signs at electromyography). This entity must be differentiated from other motor neuron disorders by the genetic pattern (X-liked recessive), gynecomastia, testicular atrophy, oligospermia and good prognosis. A discussion about the clinical pattern and evolution is made.

ABSTRACT Introduction Testosterone (T) induces motor dysfunction in transgenic (Tg) mice that overexpress wild-type androgen receptor (AR) in skeletal muscles. Because many genes implicated in motor neuron disease are expressed in skeletal muscle, mutant proteins may act in muscle to cause dysfunction in motor neuron disease. Methods We examined contractile properties of the extensor digitorum longus (EDL) and soleus (SOL) muscles in vitro after 5 and 3 days of T treatment in motor-impaired Tg female mice. Results Both muscles showed deficits in tetanic force after 5 days of T treatment, without losses in muscle mass, protein content, or fiber number. After 3 days of T treatment, only SOL showed a deficit in tetanic force comparable to that of 5 days of treatment. In both treatments, EDL showed slowed twitch kinetics, whereas SOL showed deficits in the twitch/tetanus ratio. Conclusions These results suggest calcium-handling mechanisms in muscle fibers are defective in motor-impaired mice. Muscle Nerve 47: 823-834, 2013 [ABSTRACT FROM AUTHOR]

Background/Purpose: Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is a rare neurodegenerative disorder presenting with insidious onset of weakness in bulbar and limb muscles. Information regarding long-term clinical and functional progression has been limited, especially for the Taiwanese population. The purpose of the study aimed to investigate early diagnosis and long-term prognosis of SBMA. Methods: We retrospectively analyzed 21 genetically confirmed SBMA patients who visited our hospital between 1993 and 2010, focusing on clinical symptoms, nerve conduction studies, and functional disability. We also analyzed the relationship between length of cytosine-adenine-guanine (CAG) repeats and age of disease onset. Results: Weakness developed at a mean age of 39 ± 7 years (mean ± standard deviation). The length of CAG repeats and age at onset of weakness showed inverse (but nonsignificant) correlation. The most common symptoms at initial presentation were hand tremor (86%), limb weakness (86%), and perioral fasciculation (76%). Creatine kinase (CK) was elevated in 17 out of 18 patients. Initial nerve conduction studies showed statistical difference from normal controls, especially decreased amplitudes of compound motor action potential (CMAP) and sensory nerve action potential (SNAP). Functional disability showed very slow progression, with only three patients becoming wheelchair-dependent during follow-up at a median age of 72 years. Conclusion: Patients with SBMA may present with a myriad of symptoms, including limbs weakness, tremor, muscle atrophy, and perioral fasciculations. Elevated serum CK and decreased CMAP and SNAP amplitudes were supportive laboratory findings of SBMA. Disease progression was gradual, and most patients remained functionally independent many years after the onset of weakness. [ABSTRACT FROM AUTHOR]

BACKGROUND Kennedy disease (KD) clinically presents as progressive lower motor neuron disease with minimal or no sensory impairment. However, electrophysiological studies found abnormal somatosensory-evoked potentials even in absence of clinical deficits. Little is known about possible influences of this sensory neuropathy on the central somatosensory processing. METHODS In this study, the cortical topography of index finger representation was studied in 7 patients with genetically proven KD compared to healthy control subjects by means of magnetoencephalography using an established stimulation paradigm. Data analysis was carried out with synthetic aperture magnetometry (SAM). Additionally, the latency and source amplitude of the earliest cortical somatosensory-evoked field (SEF) component were determined based on traditional single dipole source analysis. RESULTS In KD patients the latency of the SEF was prolonged (48.6 vs. 37.4 ms, P < .005). There was no significant difference in dipole source amplitude, but stimulus-related SAM activation of the contralateral sensorimotor cortex (pseudo-t-values –.107 vs. –.199, P < .05), including maximum activity (53.5%), was reduced. CONCLUSIONS These results implicate that even subclinical sensory neuropathy leads to possible functional reorganization of the sensorimotor cortex in KD patients and reinforces the view that in KD the somatosensory system is extensively involved. [ABSTRACT FROM AUTHOR]

Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: Double discharges (DDs) of the motor unit are frequent in amyotrophic lateral sclerosis (ALS) and Kennedy’s disease (KD). This likely reflects changes in the intrinsic properties of motor neurons but in ALS changes in corticomotoneuronal inputs may also contribute. We determined the corticomotoneuronal contribution to DDs. Methods: DD prevalence, intra-doublet interval (IDI) of DDs and their timing with respect to transcranial magnetic stimulation (TMS)-induced primary peaks (PPs) in the peristimulus time histogram (PSTH) were measured in 23 ALS patients (96 motor units), 11 patients with KD (45 motor units) and 13 control subjects (60 motor units). Results: In patients with KD more motor units (82%) fired DDs than in ALS patients (51%) and control subjects (63%); (p =0.013). DDs occurred before (pre-peak), during (peak), and after (post-suppression) the peristimulus time histogram (PSTH) primary peak. The prevalence of pre-peak DD in KD was 4.06-fold higher (95% CI 0.53–2.81; p =0.0014) than in controls. In contrast the prevalence of ALS peak DDs was 4.79-fold higher (95% CI 1.09–21.10; p =0.041) than in controls. Both pre-peak and peak IDIs were significantly prolonged in ALS compared with controls (p <0.003). Motor unit action potential (MUAP) amplitude, size of the excitatory postsynaptic potential (EPSP) and interspike interval (ISI) all correlated significantly with pre-peak, but not peak DD prevalence. Conclusions: A high peak DD prevalence with prolonged IDIs in ALS are consistent with complex, multiple descending corticomotoneuronal volleys, indicating that the upper motor neuron contributes to the generation of DDs in ALS. Significance: Although double discharges are a manifestation of reinnervating motor neurons in ALS the corticomotoneuronal descending input is also influential and probably accounts for some of the distinguishing features of DDs in ALS. [Copyright &y& Elsevier]

Abstract: Dysphagia in X-linked bulbospinal muscular atrophy (Kennedy disease) has never been characterized in detail by objective swallowing studies. We assessed the nature of swallowing impairment in Kennedy disease by undertaking fiberoptic endoscopic evaluation of swallowing examinations of 10 genetically confirmed patients with Kennedy disease who were scored according to an ordinal rating scale including 25 different items. The results were compared to an age-matched control group of 10 healthy volunteers. Swallowing dysfunction was found in 80% of patients with Kennedy disease. The main pattern of dysphagia was an incomplete food bolus clearance through the pharynx with residues left in the valleculae overflowing into the laryngeal vestibule after the swallow. Total duration of the pharyngeal swallow was significantly shorter in patients with Kennedy disease compared to the control group. These findings suggest that dysphagia in Kennedy disease is predominantly characterized by an impairment of the pharyngeal phase of swallowing resulting from reduced base-of-tongue movement and bilateral paresis of pharyngeal and laryngeal muscles. [Copyright &y& Elsevier]

Two years prior to diagnosis of Kennedy's disease (KD), a 53-year-old man began experiencing neurological symptoms, including nasal speech, postural tremor, tremor in the upper extremities, and muscle weakness. Genetic analysis revealed 46 CAG repeats in the androgen receptor gene. The patient's altered social conduct and complaints of forgetfulness led to a neuropsychological assessment. A mild impairment in visuospatial and visuoconstructive abilities, visual short-term memory, and a personality disorder were detected. Although cognition and behaviour in KD are typically normal, our findings suggest that the disease may cause mild cognitive and behavioural changes as part of the disease's clinical manifestation. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to investigate the metabolic abnormalities in Kennedy disease (KD) patients using proton magnetic resonance spectroscopy. Five patients with KD showing typical phenotype were compared with eight age-matched, healthy control subjects. Relative metabolite concentrations for N-acetyl-aspartate (NAA), choline (Cho) and phosphocreatine (Cr) and lactate (Lac) were measured in the motor cortex and the brainstem area. In the motor cortex, NAA/Cr ratio was significantly reduced in KD patients (P =0.04). In the brainstem area, metabolic ratios including NAA/Cho, NAA/Cr and Cho/Cr failed to show significant difference between KD patients and normal controls. No pathologic Lac signal was noted in patients and controls. These findings corroborate a previous study indicating an involvement of the motor cortices in patients with KD. [Copyright &y& Elsevier]

The androgen receptor (AR) is a ligand-activated transcription factor that is central to androgen-dependent development and diseases. Activity of the receptor is influenced by the length of a CAG/glutamine tract in its N-terminal transactivating domain. Expansions of this tract cause Kennedy disease, a protein aggregation degenerative disorder of motor neurons that occurs only in men, and shorter length tracts have been linked to increased risk of prostate cancer. Here we review recent data from mouse models in which gene targeting was used to humanize the mouse Ar gene and introduce CAG/glutamine tracts of varying lengths. Insertion of an expanded tract encoded by 113 CAG repeats modeled Kennedy disease and revealed an important myopathic contribution to the disease phenotype. Variations in CAG tract length within the range of normal human alleles influenced the onset and progression of prostate cancer when targeted Ar mice were crossed to a transgenic prostate cancer model. This series of mice with different Ar alleles has provided insights into the mechanisms by which variations in the CAG/glutamine tract length influence the occurrence of human disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: Expansions of triplet repeats are found in a number of neurodegenerative conditions, and different tissues in the same person can have varying repeat lengths. In Kennedy disease, motor neuron loss is due to expansion of the CAG repeat length in the androgen receptor gene (AR). We hypothesised that patients with other sporadic motor neuron diseases could have AR expansions that were restricted to CNS tissue. Methods: We measured the AR triplet repeat length in DNA extracted from the brains of 23 patients with sporadic amyotrophic lateral sclerosis (SALS) and 3 with sporadic progressive muscular atrophy (SPMA). Paired blood samples were available in 15 patients to look for blood–brain differences in CAG repeat length. Results: No CAG expansions in the Kennedy disease range were found in the SALS or SPMA brains. Furthermore, no brain–blood differences were found in the lengths of AR triplet repeats. Brain AR repeat length was not associated with the duration, or age or site of onset, of disease. Conclusions: The findings indicate that a brain-specific expansion of AR triplet repeats is unlikely to underlie motor neuron loss in SALS or SPMA. [Copyright &y& Elsevier]

We created transgenic mice that overexpress WI androgen receptor (AR) exclusively in their skeletal muscle fibers. Unexpectedly, these mice display androgen-dependent muscle weakness and early death, show changes in muscle morphology and gene ex- pression consistent with neurogenic atrophy, and exhibit a loss of motor axons. These features reproduce those seen in models of Kennedy disease, a polyglutamine expansion disorder caused by a CAG repeat expansion in the AR gene. These findings demonstrate that toxicity in skeletal muscles is sufficient to cause motoneuron disease and indicate that overexpression of the WT AR can exert toxicity comparable with the polyglutamine expanded protein. This model has two clear implications for Kennedy disease: (i) mechanisms affecting AR gene expression may cause neuromuscular symptoms similar to those of Kennedy disease and (ii) therapeutic approaches targeting skeletal muscle may provide effective treatments for this disease. [ABSTRACT FROM AUTHOR]

Background  Spinal and bulbar muscular atrophy or Kennedy disease (KD) is an X-linked neurodegenerative disease caused by an expansion of a polymorphic tandem CAG repeat within the androgen receptor (AR) gene on chromosomal locus Xq11-q12. The CAG repeat region encodes a polyglutamine tract that, when expanded to above 40 in number, results in KD, a neurodegenerative disease primarily targeting lower motor neurones. KD is also associated with partial androgen insensitivity due to loss of receptor function. Degree of expansion of this repeat region, located in the first exon, is correlated with age at onset and disease severity. Androgenetic alopecia (AGA) is a polygenic trait also associated with functional polymorphism of the AR gene. Objectives  To test whether partial loss of function in the AR gene associated with CAG polymorphism reduces the risk of AGA in affected men. Methods  Members of the Kennedy’s Disease Association, an American-based support group, were invited to participate in an online survey to determine the age-related prevalence of AGA among men affected by KD. Data from 115 respondents with KD were compared with data from 654 white men of European descent in Maryborough, Australia. Results  The mean AGA score for men with KD was 1·64 (95% confidence interval, CI 1·41–1·87). The mean score for men in Maryborough was 2·82 (95% CI 2·71–2·93). The difference between the means was highly significant ( P < 0·001), indicating thicker hair among the KD cohort. Treating AGA score as a continuous variable we found age to be highly significantly related to AGA score in men from Maryborough ( P < 0·001) but not among men affected by KD ( P = 0·90). Conclusions  Men with KD have a reduced risk of AGA, likely to be due to a functional alteration in the AR caused by the polyglutamine expansion. [ABSTRACT FROM AUTHOR]

Abstract: Polyglutamine (polyQ) diseases, including Huntington’s disease (HD), are caused by expansion of polyQ-encoding repeats within otherwise unrelated gene products. The aggregation mechanism of polyQ diseases, the inhibition mechanism of Congo red, and the alleviation mechanism of trehalose were proposed here based on quantum chemical calculations and molecular dynamics simulations. The calculations and simulations revealed the following. The effective molecular bonding is between glutamine (Gln) and Gln (Gln+Gln), between Gln and Congo red (Gln+Congo red), and between Gln and trehalose (Gln+trehalose). The bonding strength is −13.1kcal/mol for Gln+Gln, −24.4kcal/mol for Gln+Congo red, and −12.0kcal/mol for Gln+trehalose. In the polyQ region, both the number of intermolecular Gln+Gln formations and the total calories generated by the Gln+Gln formation are proportional to the number of repetitions of Gln. We propose an aggregation mechanism whose heat generated by the intermolecular Gln+Gln formation causes the pathogeny of polyQ disease. In our aggregation mechanism, this generated heat collapses the host protein and promotes fibrillogenesis. Without contradiction, our mechanism can explain all the experimental results reported to date. Our mechanism can also explain the inhibition mechanism by Congo red as an inhibitor of polyglutamine-induced protein aggregation and the alleviation mechanism by trehalose as an alleviator of that aggregation. The inhibition mechanism by Congo red is explained by the strong interaction with Gln and by the characteristic structure of Congo red. [Copyright &y& Elsevier]

Summary: Since the identification of the polyglutamine repeat expansion responsible for Kennedy disease (KD) more than a decade ago, several laboratories have created animal models for KD. The slowly progressive nature of KD, its X-linked dominant mode of inheritance, and its recently elucidated hormone dependence have made the modeling of this lower motor neuron disease uniquely challenging. Several models have been generated in which variations in specificity, age of onset, and rate of progression have been achieved. Animal models that precisely reproduce the motor neuron specificity, delayed onset, and slow progression of disease may not support preclinical therapeutics testing, whereas models with rapidly progressing symptoms may preclude the ability to fully elucidate pathogenic pathways. Drosophila models of KD provide unique opportunities to use the power of genetics to identify pathogenic pathways at work in KD. This paper reviews the new wealth of transgenic mouse and Drosophila models for KD. Whereas differences, primarily in neuropathological findings, exist in these models, these differences may be exploited to begin to elucidate the most relevant pathological features of KD. [Copyright &y& Elsevier]