Androgen receptor post-translational modifications and their implications for pathology.

A major mechanism to modulate the biological activities of the androgen receptor (AR) involves a growing number of post-translational modifications (PTMs). In this review we summarise the current knowledge on the structural and functional impact of PTMs that affect this major transcription factor. Next, we discuss the cross-talk between these different PTMs and the presence of clusters of modified residues in the AR protein. Finally, we discuss the implications of these covalent modifications for the aetiology of diseases such as spinal and bulbar muscular atrophy (Kennedy's disease) and prostate cancer, and the perspectives for pharmacological intervention.

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.

Kennedy's disease.

A 57-year-old man developed worsening early morning headaches, muscle cramps and falls over 12 months. He had widespread fasciculation and was diagnosed with motor neurone disease, and treated with nocturnal hypoventilation. Based on this diagnosis, he made significant personal and financial decisions including retiring and selling his house. He subsequently developed a lump in his right breast and was found to have gynaecomastia. This triggered genetic testing for Kennedy's disease leading to the correct diagnosis. This case highlights an unusual presentation of a rare disease leading to misdiagnosis and major repercussions for the patient. Recent genetic analysis from the 100 000 genome project suggests Kennedy's disease may be four times more prevalent in the population than previously thought, highlighting the need to consider genetic testing, especially if there is a suggestion of multisystem disease.

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.

Exercise attenuates polyglutamine-mediated neuromuscular degeneration in a mouse model of spinal and bulbar muscular atrophy.

BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by the expansion of trinucleotide cytosine-adenine-guanine (CAG) repeats, which encodes a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. Recent evidence suggests that, in addition to motor neuron degeneration, defective skeletal muscles are also the primary contributors to the pathogenesis in SBMA. While benefits of physical exercise have been suggested in SBMA, underlying mechanism remains elusive. METHODS: We investigated the effect of running exercise in a transgenic mouse model of SBMA carrying human AR with 97 expanded CAGs (AR97Q). We assigned AR97Q mice to exercise and sedentary control groups, and mice in the exercise group received 1-h forced running wheel (5 m/min) 5 days a week for 4 weeks during the early stage of the disease. Motor function (grip strength and rotarod performance) and survival of each group were analysed, and histopathological and biological features in skeletal muscles and motor neurons were evaluated. RESULTS: AR97Q mice in the exercise group showed improvement in motor function (~40% and ~50% increase in grip strength and rotarod performance, respectively, P < 0.05) and survival (median survival 23.6 vs. 16.7 weeks, P < 0.05) with amelioration of neuronal and muscular histopathology (~1.4-fold and ~2.8-fold increase in motor neuron and muscle fibre size, respectively, P < 0.001) compared to those in the sedentary group. Nuclear accumulation of polyQ-expanded AR in skeletal muscles and motor neurons was suppressed in the mice with exercise compared to the sedentary mice (~50% and ~30% reduction in 1C2-positive cells in skeletal muscles and motor neurons, respectively, P < 0.05). We found that the exercise activated 5'-adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibited mammalian target of rapamycin pathway that regulates protein synthesis in skeletal muscles of SBMA mice. Pharmacological activation of AMPK inhibited protein synthesis and reduced polyQ-expanded AR proteins in C2C12 muscle cells. CONCLUSIONS: Our findings suggest the therapeutic potential of exercise-induced effect via AMPK activation in SBMA.

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

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

Genotype and clinical phenotype analysis of a Family with Kennedy disease.

To investigate the clinical phenotype-genotype correlations of a family with Kennedy disease (KD) and improve our understanding of the disease. KD was confirmed after clinical phenotypic analyses, laboratory tests, polymerase chain reaction assays for cytosine-adenine-guanine (CAG) repeats, and neuro-electrophysiological tests. The disease was assessed using the KD1234 scale and the spinal and bulbar muscular atrophy functional rating scale. The average age of disease onset was 30.8 ± 2.85 years. Clinically diagnosed members had 48 CAG repeats (≥35 is abnormal) in the androgen receptor gene. The patients exhibited gynecomastia and testicular dysfunction. The lesions mainly involved the medulla oblongata and spinal cord. Progesterone and serum creatine kinase levels were significantly high. Electromyography showed chronic neurogenic damage and abnormal sensory and motor conduction in family members who did not participate in sports, exercise, or physical hobbies. Our study showed that this family had a stable inheritance of CAG repeats, and the genotype was consistent with the clinical phenotype. Gynecomastia was the first symptom, with progressive androgen resistance resulting in testicular atrophy, infertility, and sexual dysfunction. Changes in serum creatine kinase may indicate the progression or relief of symptoms, and rehabilitation may delay the progression of muscle atrophy.

Clinical Features of Female Carriers and Prodromal Male Patients With Spinal and Bulbar Muscular Atrophy.

BACKGROUND AND OBJECTIVES: To assess the clinical and electrophysiologic features of female carriers and early-stage male patients with spinal and bulbar muscular atrophy (SBMA) to elucidate the early pathophysiologic changes of the disease. METHODS: Female carriers, early-stage male patients with SBMA, and age-matched male and female healthy controls were recruited. The results of motor functional scales, motor unit number estimation, dual-energy X-ray absorptiometry, and peripheral blood tests were compared between female carriers and healthy female controls and between patients with SBMA and healthy male controls. EMG was also investigated in female carriers. RESULTS: We enrolled 21 female carriers and 11 early-stage male patients. Seventeen female and 14 male age-matched healthy controls were also enrolled. Female carriers experienced early-stage symptoms such as muscle cramps more frequently than healthy female controls. Decreased motor unit number estimation and EMG abnormalities including high amplitude or polyphasic potentials were observed in female carriers together with mild muscle weakness in neck flexion and a slow walking speed. Changes of muscle-related markers, including serum creatine kinase and dual-energy X-ray absorptiometry, were clearly detected in early-stage male patients with SBMA, but not in female carriers. DISCUSSION: The present study revealed that female carriers of SBMA manifest mild muscular weakness associated with changes in neurogenic biomarkers. Conversely, male patients showed neurogenic and myopathic changes even at the early stage. These results suggest a testosterone-independent neurodegenerative pathophysiology in female SBMA carriers.

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.

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.

J wave syndromes in patients with spinal and bulbar muscular atrophy.

BACKGROUND: Males with X-linked recessive spinobulbar muscular atrophy (SBMA) are reported to die suddenly and a Brugada electrocardiography (ECG) pattern may be present. A hallmark of this pattern is the presence of ST segment elevations in right precordial leads associated with an increased risk of sudden cardiac death. OBJECTIVE: We aimed to detect subtle myocardial abnormalities using ECG and cardiovascular magnetic resonance imaging (CMR) in patients with SBMA. METHODS: 30 SBMA patients (55.7 ± 11.9 years) and 11 healthy male controls underwent 12-lead ECGs were recorded using conventional and modified chest leads. CMR included feature-tracking strain analysis, late gadolinium enhancement and native T1 and T2 mapping. RESULTS: Testosterone levels were increased in 6/29 patients. Abnormal ECGs were recorded in 70%, consisting of a Brugada ECG pattern, early repolarization or fragmented QRS. Despite normal left ventricular ejection fraction (66 ± 5%), SBMA patients exhibited more often left ventricular hypertrophy as compared to controls (34.5% vs 20%). End-diastolic volumes were smaller in SBMA patients (left ventricular volume index 61.7 ± 14.7 ml/m2 vs. 79.1 ± 15.5 ml/m2; right ventricular volume index 64.4 ± 16.4 ml/m2 vs. 75.3 ± 17.5 ml/m2). Tissue characterization with T1-mapping revealed diffuse myocardial fibrosis in SBMA patients (73.9% vs. 9.1%, device-specific threshold for T1: 1030 ms). CONCLUSION: SBMA patients show abnormal ECGs and structural abnormalities, which may explain an increased risk of sudden death. These findings underline the importance of ECG screening, measurement of testosterone levels and potentially CMR imaging to assess cardiac risk factors.

Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activity.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset neuromuscular condition caused by an abnormal polyglutamine (polyQ) tract expansion in androgen receptor (AR) protein. SBMA is a disease with high unmet clinical need. Recent studies have shown that mutant AR-altered transcriptional activity is key to disease pathogenesis. Restoring the transcriptional dysregulation without affecting other AR critical functions holds great promise for the treatment of SBMA and other AR-related conditions; however, how this targeted approach can be achieved and translated into a clinical application remains to be understood. Here, we characterized the role of AR isoform 2, a naturally occurring variant encoding a truncated AR lacking the polyQ-harboring domain, as a regulatory switch of AR genomic functions in androgen-responsive tissues. Delivery of this isoform using a recombinant adeno-associated virus vector type 9 resulted in amelioration of the disease phenotype in SBMA mice by restoring polyQ AR-dysregulated transcriptional activity.

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.

Effect of leuprorelin in bulbar function of spinal and bulbar muscular atrophy patients: observational study for 1 year.

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

ClC-2-like Chloride Current Alterations in a Cell Model of Spinal and Bulbar Muscular Atrophy, a Polyglutamine Disease.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by expansions of a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. SBMA is associated with the progressive loss of lower motor neurons, together with muscle weakness and atrophy. PolyQ-AR is converted to a toxic species upon binding to its natural ligands, testosterone, and dihydrotestosterone (DHT). Our previous patch-clamp studies on a motor neuron-derived cell model of SBMA showed alterations in voltage-gated ion currents. Here, we identified and characterized chloride currents most likely belonging to the chloride channel-2 (ClC-2) subfamily, which showed significantly increased amplitudes in the SBMA cells. The treatment with the pituitary adenylyl cyclase-activating polypeptide (PACAP), a neuropeptide with a proven protective effect in a mouse model of SBMA, recovered chloride channel current alterations in SBMA cells. These observations suggest that the CIC-2 currents are affected in SBMA, an alteration that may contribute and potentially determine the pathophysiology of the disease.

Deubiquitinase USP7 contributes to the pathogenicity of spinal and bulbar muscular atrophy.

Polyglutamine (polyQ) diseases are devastating, slowly progressing neurodegenerative conditions caused by expansion of polyQ-encoding CAG repeats within the coding regions of distinct, unrelated genes. In spinal and bulbar muscular atrophy (SBMA), polyQ expansion within the androgen receptor (AR) causes progressive neuromuscular toxicity, the molecular basis of which is unclear. Using quantitative proteomics, we identified changes in the AR interactome caused by polyQ expansion. We found that the deubiquitinase USP7 preferentially interacts with polyQ-expanded AR and that lowering USP7 levels reduced mutant AR aggregation and cytotoxicity in cell models of SBMA. Moreover, USP7 knockdown suppressed disease phenotypes in SBMA and spinocerebellar ataxia type 3 (SCA3) fly models, and monoallelic knockout of Usp7 ameliorated several motor deficiencies in transgenic SBMA mice. USP7 overexpression resulted in reduced AR ubiquitination, indicating the direct action of USP7 on AR. Using quantitative proteomics, we identified the ubiquitinated lysine residues on mutant AR that are regulated by USP7. Finally, we found that USP7 also differentially interacts with mutant Huntingtin (HTT) protein in striatum and frontal cortex of a knockin mouse model of Huntington's disease. Taken together, our findings reveal a critical role for USP7 in the pathophysiology of SBMA and suggest a similar role in SCA3 and Huntington's disease.

[Fatherhood achieved in a case of nonobstructive azoospermia with Kennedy's disease via microdissection testicular sperm extraction and ICSI: A case report and literature review].

OBJECTIVE: To explore the feasibility of biological fatherhood in nonobstructive azoospermia patient with Kennedy's disease and review the relevant literature. METHODS: A twenty-eight man complaining of weakness in the lower extremities for a year underwent physical and laboratory examinations and was found with azoospermia. At the request of the patient for assisted reproduction, we performed microdissection testicular sperm extraction (micro-TESE). RESULTS: Physical examination showed grade-4 and grade-4+ muscular strength in the proximal and distal lower extremities, respectively. The levels of Creatine kinase (CK), serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) of the patient were 432 U/L,18.1IU/L,10.4 IU/L and 8.6 nmo/L, respectively. The peroneal motor nerve conduction velocity was significantly decreased. Examination of the androgen receptor (AR) gene revealed 56 CAG repeats in exon 1, which confirmed Kennedy's disease. The patient was found with testicular atrophy and mild gynecomastia but normal seminal plasma biochemical parameters and peripheral karyotype and no Y chromosome microdeletion. Some sperm were found in micro-TESE though none in the previous testicular biopsy. Immunoradiometric assay showed a serum ß-HCG level of 873 IU/L at 2 weeks and ultrasonography manifested clinical pregnancy at 4 weeks after in vitro fertilization-embryo transfer following intracytoplasmic sperm injection (ICSI). At 38 weeks and 2 days of gestation, a healthy boy was born by caesarean in a local hospital. CONCLUSIONS: Nonobstructive azoospermia patients with Kennedy's disease can achieve biological fatherhood via micro-TESE and ICSI.

Autophagy and Polyglutamine Disease.

Polyglutamine (polyQ) disease is a type of fatal neurodegenerative disease caused by an expansion of CAG repeats in a specific gene, resulting in a protein with an abnormal polyQ fragment. The age of onset and the degree of pathological deterioration are related to the length of the polyQ fragment. At least 9 kinds of polyglutamine diseases have been discovered, including Huntington disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinobulbar muscular atrophy (SBMA) and six spinocerebellar ataxia (SCA) such as SCA1, 2, 3, 6, 7 and 17 subtypes (Table 9.1). Previous studies suggest that autophagy plays a major role in the quality control of disease proteins in polyQ diseases. In this chapter, we majorly focused on three representative polyQ diseases, including spinocerebellar Ataxia type 3 (SCA3), spinocerebellar ataxia type 7 (SCA7) and Huntington's disease (HD). The relationship of the ubiquitin-proteasome system and autophagy involved in disease protein accumulation were summarized.

The French national protocol for Kennedy's disease (SBMA): consensus diagnostic and management recommendations.

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.