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.

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.

Perioral and tongue fasciculations in Kennedy's disease.

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.

[Clinical features of a genetically identified spinal and bulbar muscular atrophy pedigree].

Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked motor neuron disease with significant phenotypic viability. Here, we present a genetically identified SBMA family without bulbar paralysis or androgen insensitivity. All four male patients presented with progressive lower motor neuron paralysis in all limbs, with distal extremities more dominant. None of them had bulbar palsy or androgen insensitivity. A consistently mild elevated blood creatine phosphokinase (CPK) levels were detected in all patients and the EMG showed a chronic neurogenic damage. Muscle biopsy of propositus indicated a typical neurogenic amyotrophy. Genetic testing for SMA of mutation in SMN1 was negative, while for SBMA of androgen receptor showed the increased CAG repeat in exon 1, suggesting that although bulbar symptoms and androgen insensitivity are characteristic symptoms of SBMA, they are not obligatory for the diagnosis. In adult males with a chronic motor neuron syndrome without upper motor neuron signs, even in absence of the classical features of androgen insensitivity or bulbar findings, genetic testing for SBMA should be strongly considered.

Mexiletine in spinal and bulbar muscular atrophy: a randomized controlled trial.

OBJECTIVE: Patients with spinal and bulbar muscular atrophy (SBMA) often experience muscular weakness under cold exposure. METHODS: In our previously conducted observational study, we assessed nerve conduction and grip strength to examine the effect of cold exposure on motor function, based on which we conducted a randomized controlled trial to evaluate the efficacy and safety of mexiletine hydrochloride in SBMA (MEXPRESS). RESULTS: In the observational study, 51 consecutive patients with SBMA and 18 healthy controls (HCs) were enrolled. Of the patients with SBMA, 88.0% experienced cold paresis. Patients with SBMA exhibited greater prolongation of ulnar nerve distal latency under cold (SBMA, 5.6 ± 1.1 msec; HC, 4.3 ± 0.6 msec; p <0.001); the change in the distal latencies between room temperature and cold exposure conditions correlated with the change in grip power. In the MEXPRESS trial, 20 participants took mexiletine or lactose, three times a day for 4 weeks with a crossover design. There was no difference in distal latencies at room temperature and under cold exposure between mexiletine and placebo groups as the primary endpoint. However, tongue pressure and 10-sec grip and release test under cold exposure were improved in the mexiletine group. There were no serious adverse events throughout the study period. INTERPRETATION: Cold paresis is common and associated with prolongation of distal latency in SBMA. The results of the phase II clinical trial revealed that mexiletine showed short-term safety, but it did not restore cold exposure-induced prolongation of distal latency.

[Ending up in a wheelchair in a strange way]. / Op onduidelijke wijze in een rolstoel beland.

In this case-report we present a patient with a genetic disease which was first diagnosed in his eighties. The genetic disease is a rare neurologic disease, Kennedy's disease or spinobulbar muscular atrophy (SBMA). We also discuss the genetics of the disease and developments of future therapies.

Cortical compensation associated with dysphagia caused by selective degeneration of bulbar motor neurons.

According to recent neuroimaging studies, swallowing is processed within multiple regions of the human brain. In contrast to this, little is known about the cortical contribution and compensatory mechanisms produced by impaired swallowing. In the present study, we therefore investigated the cortical topography of volitional swallowing in patients with X-linked bulbospinal neuronopathy (Kennedy disease, KD). Eight dysphagic patients with genetically proven KD and an age-matched healthy control group were studied by means of whole-head magnetoencephalography using a previously established swallowing paradigm. Analysis of data was carried out with synthetic aperture magnetometry (SAM). The group analysis of individual SAM results was performed using a permutation test. KD patients showed significantly larger swallow-related activation of the bilateral primary sensorimotor cortex than healthy controls. In contrast to the control group, in KD patients the maximum activity was located in the right sensorimotor cortex. Furthermore, while in nondysphagic subjects a previously described time-dependent shift from the left to the right hemisphere was found during the one second of most pronounced swallow-related muscle activity, KD patients showed a strong right hemispheric activation in each time segment analyzed. Since the right hemisphere has an established role in the coordination of the pharyngeal phase of swallowing, the stronger right hemispheric activation observed in KD patients indicates cortical compensation of pharyngeal phase dysphagia.

Are cognitive and behavioural deficits a part of the clinical picture in Kennedy's disease? A case study.

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.

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

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disease affecting only males characterized by progressive muscular atrophy and weakness in bulbar and limb muscles. The present study aimed to evaluate the features of velopharyngeal dysfunction (VPD) in SBMA subjects by an acoustic analysis of speech. Twenty-three genetically confirmed patients with SBMA were enrolled and assessed their speech by measuring the nasalance score with a Nasometer II. The nasalance scores of the SBMA group was higher than that of healthy controls (p = .035) and significantly correlated with the total score of the revised amyotrophic lateral sclerosis functional rating scale (rs = -0.520, p = .011). On the basis of the results of the VPD study, the efficacy of a palatal lift prosthesis (PLP) was assessed in two patients with SBMA to treat their VPD. The PLP improved dysarthria in both cases, although the impact of the prosthesis on dysphagia was not consistent. The present study suggested that the nasalance score is a useful quantitative measurement to evaluate VPD in patients with SBMA. A PLP may improve dysarthria in SBMA patients by reducing VPD, but the clinical application of this procedure should be considered carefully in view of its possible negative effect on dysphagia.

Rare association of antisynthetase syndrome and Kennedy's disease.

Antisynthetase syndrome is a type of Idiopathic Inflammatory Myopathy (IIM) associated with anti-Jo1 antibody. Kennedy's disease or X-linked spinal and bulbar muscular atrophy (SBMA) is a rare neuromuscular disease. We describe the case report of a 53-year-old man who presented with proximal muscle weakness and a history of bilateral hand tremor. Initial physical examination demonstrated "mechanic's hands", Raynaud's phenomenon, having elevated creatine kinase and lactate dehydrogenase levels and anti-Jo1 antibody positivity. His muscle biopsy demonstrated inflammatory infiltrate characteristic of IIM. Considering these findings, we reached the diagnosis of antisynthetase syndrome and commenced immunosuppressive therapy. On follow-up examination, he had developed dysphagia, and his tremor had worsened. His electroneurogram result was characteristic of Kennedy's disease, and the genetic test result showed an allele with 44 CAG repeat expansion in the androgen receptor gene of the X chromosome. This confirmed that in addition to antisynthetase syndrome, he also had Kennedy's disease. This patient now receives immunology and neurology follow-up. His symptoms have improved with low dose corticosteroids, propranolol for tremor, vitamin B supplementation, and physiotherapy. This article presents a rare case report of a patient with concurrent antisynthetase syndrome and Kennedy's disease, both of which lead to elevated creatine kinase levels and muscle weakness, thus, underpinning the importance of careful follow-up of patients with IIM and maintaining an open mind to other diagnoses when faced with refractory and/or new symptoms.

Study protocol for the MEXiletine hydrochloride administration trial: a placebo-controlled, randomised, double-blind, multicentre, crossover study of its efficacy and safety in spinal and bulbar muscular atrophy (MEXPRESS).

INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive neuromuscular disease. Cold exposure often leads to worsening of motor symptoms including paresis. Although mexiletine hydrochloride administration has been shown to be effective for the treatment of several muscular diseases, its effectiveness in SBMA has not been validated to date. The trial will test it as a symptomatic drug for cold paresis. This study is the first trial to evaluate the efficacy and safety of mexiletine hydrochloride administration in patients with SBMA. METHODS AND ANALYSIS: A placebo-controlled, randomised, double-blind, multicentre, crossover clinical trial will be conducted to assess the safety and efficacy of mexiletine hydrochloride in patients with SBMA. The eligible patients will be assigned randomly in a 1:1 ratio to two groups in a double-blind manner. Participants will take mexiletine hydrochloride (300 mg/day) or a placebo orally three times a day for 4 weeks (period 1). After a 1-week washout period, participants will take the other drug for 4 weeks (period 2). The primary endpoint is the difference in distal latencies between room temperature and cold exposure conditions. ETHICS AND DISSEMINATION: This study will be conducted in compliance with the Helsinki Declaration and the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Japanese government and has been approved by the ethics committee of Nagoya University Graduate School of Medicine, as a central institutional review board, and by each facility. The results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: UMIN000026150; Pre-results.

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial.

BACKGROUND: Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. METHODS: In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a confirmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0·06 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932. FINDINGS: 31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in five patients. TMV decreased from baseline to day 85 in the placebo group (-3·4% [-110 cm3]) but not in the BVS857 group (0% [2 cm3]). A significant difference in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1·04 [90% CI 1·01-1·07]; p=0·02). There were no differences between groups in measures of muscle strength and function. INTERPRETATION: TMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. FUNDING: Novartis Pharmaceuticals and the US National Institutes of Health.

Quantitative Assessment of Swallowing Dysfunction in Patients with Spinal and Bulbar Muscular Atrophy.

Objective This study aimed to evaluate swallowing dysfunction in patients with spinal and bulbar muscular atrophy and to identify the most appropriate method of assessing swallowing dysfunction using a videofluoroscopic swallowing study. Methods In the videofluoroscopic swallowing study, patients were instructed to swallow 3 mL of 40% weight/volume barium sulfate twice, and the pharyngeal residue was measured. We used three different methods to quantify the pharyngeal barium residue and an eight-point scale to evaluate the laryngeal penetration leading to aspiration pneumoniae. Patients We assessed 111 patients with spinal and bulbar muscular atrophy who weren't undergoing disease-specific treatment. Results Our results showed that the pharyngeal barium residue after initial swallowing correlated better with the bulbar-related functional rating scales than that after multiple deglutition. This correlation was vague when the data from patients whose barium residue was >50% were eliminated. In addition, evaluating the pharyngeal residue after initial swallowing proved to be the most sensitive method with regard to laryngeal penetration. Conclusion This study showed that the pharyngeal barium residue after initial swallowing was the most appropriate parameter for quantitatively assessing the degree of dysphagia using a videofluoroscopic swallowing study and suggests that this method may predict laryngeal penetration and aspiration in patients with spinal and bulbar muscular atrophy.

Minor cognitive disturbances in X-linked spinal and bulbar muscular atrophy, Kennedy's disease.

Spinal and bulbar muscular atrophy (SBMA), Kennedy's disease, is an adult-onset hereditary neurodegenerative disorder, associated predominantly with a lower motor neuron syndrome and eventually endocrine and sensory disturbances. In contrast to other motor neuron diseases such as amyotrophic lateral sclerosis (ALS), the impairment of cognition in SBMA is not well documented. We conducted a systematic cross-sectional neuropsychological study in order to investigate cognition in SBMA patients more thoroughly. We investigated 20 genetically proven SBMA patients compared to 20 age- and education-matched control subjects using a comprehensive neuropsychological test battery, measuring executive functioning, attention, memory and visuospatial abilities. The SBMA patients performed significantly worse than healthy controls in three sub-tests in the executive and attention domains. This low performance was in the working memory (digit span backward task), verbal fluency category (single letter fluency task) and memory storage capacity (digit span forward task). No disturbances were detected in other cognitive domains. The impairments were subclinical and not relevant to the patients' everyday functioning. In addition, no correlations were found between cognitive scores and the CAG repeat length. In conclusion, we found minor cognitive disturbances in patients with SBMA, which could indicate subtle frontal lobe dysfunction. These findings extend our neurobiological understanding of SBMA.

Postural leg tremor in X-linked spinal and bulbar muscular atrophy.

X-linked spinal and bulbar muscular atrophy (SBMA) is an adult-onset neuromuscular disorder caused by a CAG repeat expansion in the androgen receptor gene. Postural hand tremor is well known as a non-motor neuron sign, but to our knowledge postural leg tremor has not been reported. We studied the occurrence and physiological features of postural leg tremor in 12 male patients (38-64 years old) with genetically proven SBMA. Three patients had postural leg tremor with a frequency of 4-7Hz. In these patients, sensory nerve action potential (SNAP) was not detected in the lower limbs. There were significant differences between the patients with postural leg tremor and those without postural leg tremor in both the SNAP of the sural nerve and the length of the CAG repeat. Phenotypical differences between shorter CAG repeats, which indicate a sensory-dominant phenotype, and longer CAG repeats, which indicate a motor-dominant phenotype, have been previously reported. In the present study, 60% of patients with shorter CAG repeats (<47) showed leg tremor and none of the patients with longer CAG repeats (≥47) did. Postural leg tremor could be a clinical feature that predicts shorter CAG repeats of the androgen receptor gene.

Kennedy disease misdiagnosed as polymyositis: a case report.

BACKGROUND: Polymyositis is an immune-mediated myopathy with clinical features of proximal muscle weakness. Dysphagia and neck flexor weakness can develop along with respiratory muscle weakness as the disease progresses. Kennedy disease or X-linked spinobulbar muscular atrophy is a rare X-linked recessive disorder with clinical features of slowly progressive atrophy and weakness of limb and bulbar muscles. These two disorders may have overlapping clinical manifestations. CASE PRESENTATION: We present the case of a 52-year-old Filipino man with chronic weakness involving his proximal muscle groups who carried the diagnosis of polymyositis and was refractory to multiple immunomodulatory therapies. Further neurologic examination and history taking along with selective serologic and electrodiagnostic studies instead confirmed the diagnosis of Kennedy disease. CONCLUSIONS: Distinction between polymyositis and Kennedy disease may be difficult given the potential overlapping clinical manifestations. However, with careful neurological history taking, examination, and selective serologic plus electrodiagnostic investigations the correct diagnosis may be made, thus sparing the patient ineffective therapy. One must always be sure of the diagnosis of polymyositis before it's classified as refractory.

Complications after cardiovascular surgery in a case of undiagnosed spinal-bulbar muscular atrophy (Kennedy disease).

Neurodegenerative diseases are often associated with life-threatening declines in respiratory and swallowing mechanisms. We report the case of a 70-year-old man who had postoperative dysphagia and respiratory failure that required reintubation after coronary artery bypass surgery. Impairment of the patient's speech, swallowing, and respiratory mechanisms identified during postoperative clinical and instrumental examinations was suggestive of a neurodegenerative disease. Genetic testing confirmed a diagnosis of spinal-bulbar muscular atrophy (Kennedy disease). This case report aims to highlight increased morbidity in patients with undiagnosed neuromuscular disorders in the critical care setting and the benefits of vigilant postoperative monitoring and multidisciplinary involvement throughout the care of complex patients.

Enfermedad de Kennedy y resistencia parcial androgénica. Descripción de 4 casos y revisión de la literatura / Kennedy's disease and partial androgen insensitivity syndrome. Report of 4 cases and literature review

La enfermedad de Kennedy o atrofia muscular espino-bulbar es un trastorno neurodegenerativo raro de herencia recesiva ligada al cromosoma X que afecta a varones en la edad adulta. Está causado por la expansión repetida de la secuencia citosina-adenosina-guanina en el exón 1 del gen del receptor androgénico localizado en el cromosoma Xq11-12, y se caracteriza por la degeneración progresiva de las neuronas motoras espinales. Desde el punto de vista endocrinológico es común encontrar en estos pacientes datos de hipogonadismo englobados en el síndrome de resistencia androgénica, particularmente la forma parcial. Se describen 4 casos con presentación clínica neurológica típica de la enfermedad, con debilidad muscular generalizada lentamente progresiva con atrofia y afectación de musculatura bulbar; entre las manifestaciones endocrinológicas observadas la ginecomastia fue la más frecuente. El estudio molecular mostró una expansión anormal del triplete citosina-adenosina-guanina en el gen del receptor androgénico en todos los casos

Kennedy's disease, also known as bulbospinal muscular atrophy, is a rare, X -linked recessive neurodegenerative disorder affecting adult males. It is caused by expansion of an unstable cytosine-adenine-guanine tandem-repeat in exon 1 of the androgen-receptor gene on chromosome Xq11-12, and is characterized by spinal motor neuron progressive degeneration. Endocrinologically, these patients often have the features of hypogonadism associated to the androgen insensitivity syndrome, particularly its partial forms. We report 4 cases with the typical neurological presentation, consisting of slowly progressing generalized muscle weakness with atrophy and bulbar muscle involvement; these patients also had several endocrine manifestations; the most common non-neurological manifestation was gynecomastia. In all cases reported, molecular analysis showed an abnormal cytosine-adenine-guanine triplet repeat expansion in the androgen receptor gene