271st ENMC international workshop: Towards a unifying effort to fight Kennedy's disease. 20-22 October 2023, Hoofddorp, Netherlands.

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.

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.

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.

Development of a functional composite for the evaluation of spinal and bulbar muscular atrophy.

This study aimed to develop a functional measurement that combines quantitative motor evaluation index of various body regions in patients with spinal and bulbar muscular atrophy (SBMA). We assessed subjects with SBMA and healthy controls with quantitative muscle strength measurements and functional scales. We selected tongue pressure, grip power, % peak expiratory flow (%PEF), timed walking test, and % forced vital capacity (%FVC) as components. By combining these values with Z-score, we created a functional composite (SBMA functional composite: SBMAFC). We also calculated the standardized response mean to compare the sensitivity of SBMAFC with that of existing measurements. A total of 97 genetically confirmed patients with SBMA and 36 age- and sex-matched healthy controls were enrolled. In the longitudinal analysis, the standardized response mean of SBMAFC was larger than that of existing rating scales. Receiver operating characteristic (ROC) analysis demonstrated that the SBMAFC is capable of distinguishing between subjects with early-stage SBMA and healthy controls. SBMAFC is more sensitive to disease progression than existing functional rating scales and is a potential outcome measure in clinical trials of SBMA.

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

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

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

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

Genetic Counseling for Adult-Onset Spinal and Bulbar Muscular Atrophy (Kennedy Syndrome): Multiple Cases of Prenatal Testing in a Family.

X-linked spinal and bulbar muscular atrophy (SBMA), also known as Kennedy syndrome, is an adult-onset neurodegenerative disorder characterized by slowly progressive muscle atrophy and other severe symptoms gradually leading to reduced mobility and ultimately to death due to respiratory failure. Two decades ago we reported the first prenatal diagnosis of SBMA worldwide. Here we present a Greek family in which we have performed seven prenatal DNA tests for SBMA mutation after extensive genetic counseling. Since there is not yet a cure for SBMA, prenatal testing may be a good choice for couples at risk for prevention of this neurodegenerative disorder in their offspring. The issues addressed during genetic counseling for such a disabling disorder of adult onset are discussed as a paradigm for other conditions with similar characteristics.

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.

Molecular Mechanisms and Therapeutics for SBMA/Kennedy's Disease.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a polyglutamine (polyQ) expansion in the androgen receptor (AR). Despite the fact that the monogenic cause of SBMA has been known for nearly 3 decades, there is no effective treatment for this disease, underscoring the complexity of the pathogenic mechanisms that lead to a loss of motor neurons and muscle in SBMA patients. In the current review, we provide an overview of the system-wide clinical features of SBMA, summarize the structure and function of the AR, discuss both gain-of-function and loss-of-function mechanisms of toxicity caused by polyQ-expanded AR, and describe the cell and animal models utilized in the study of SBMA. Additionally, we summarize previously conducted clinical trials which, despite being based on positive results from preclinical studies, proved to be largely ineffective in the treatment of SBMA; nonetheless, these studies provide important insights as researchers develop the next generation of therapies.

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

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

Validation of a multiplexed LC-MS/MS clinical assay to quantify insulin-like growth factor-binding proteins in human serum and its application in a clinical study.

Circulating insulin-like growth factor-binding proteins (IGFBPs) continue to gain attention as biomarkers of drug activities on insulin like growth factor (IGF)/IGF receptor signaling pathways. A multiplexed LC-MS/MS method was validated for the absolute quantitation of IGFBPs in human serum. The method was used to measure screening concentrations of IGFBPs in spinal and bulbar muscular atrophy (SBMA) patients in a phase 2 clinical trial. Concentrations of IGFBP 1, 2, 3, and 5 were simultaneously determined based on representative signature peptides derived from an optimized trypsin digestion procedure. Signature peptide levels were absolutely quantitated using a sensitive/specific targeted LC-MS/MS method. Corresponding mass-shifted, stable isotope-labeled peptides were employed as internal standards. A true blank matrix for the quantitation of IGFBPs was not available since they are endogenous proteins in human serum. In this method, calibration standards/curves were prepared using authentic synthetic peptides spiked into a surrogate matrix. The surrogate matrix was generated from human serum treated in the same way as the study samples, but using iodoacetic acid instead of iodoacetamide as the alkylation reagent. This surrogate matrix approach allowed for the direct and sensitive/specific quantification of IGFBP 1, 2, 3, and 5 due to the lack of any endogenous background. Equivalent matrix effect and recovery of analytes was achieved for the authentic and surrogate matrices. The fully validated LC-MS/MS assay will allow further evaluation of the utility of IGFBP biomarkers in clinical trials.