RESUMEN
Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease (KD), is a rare hereditary neuromuscular disorder demonstrating commonalities with amyotrophic lateral sclerosis (ALS). The current study aimed to define functional and central nervous system abnormalities associated with SBMA pathology, their interaction, and to identify novel clinical markers for quantifying disease activity. 27 study participants (12 SBMA; 8 ALS; 7 Control) were recruited. SBMA patients underwent comprehensive motor and sensory functional assessments, and neurophysiological testing. All participants underwent whole-brain structural and diffusion MRI. SBMA patients demonstrated marked peripheral motor and sensory abnormalities across clinical assessments. Increased abnormalities on neurological examination were significantly associated with increased disease duration in SBMA patients (R2 = 0.85, p < 0.01). Widespread juxtacortical axonal degeneration of corticospinal white matter tracts were detected in SBMA patients (premotor; motor; somatosensory; p < 0.05), relative to controls. Increased axial diffusivity was significantly correlated with total neuropathy score in SBMA patients across left premotor (R2 = 0.59, p < 0.01), motor (R2 = 0.63, p < 0.01), and somatosensory (R2 = 0.61, p < 0.01) tracts. The present series has identified involvement of motor and sensory brain regions in SBMA, associated with disease duration and increasing severity of peripheral neuropathy. Quantification of annualized brain MRI together with Total Neuropathy Score may represent a novel approach for clinical monitoring.
Asunto(s)
Atrofia Bulboespinal Ligada al X , Humanos , Masculino , Persona de Mediana Edad , Femenino , Anciano , Atrofia Bulboespinal Ligada al X/fisiopatología , Atrofia Bulboespinal Ligada al X/patología , Adulto , Esclerosis Amiotrófica Lateral/fisiopatología , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/fisiopatología , Imagen por Resonancia Magnética , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Sustancia Blanca/fisiopatologíaRESUMEN
BACKGROUND: Size index (SI) is a motor unit potential (MUP) parameter in concentric needle electromyography calculated from amplitude and area/amplitude, which can sensitively discriminate between control and neurogenic MUPs. In this study, we investigated the application of SI to myogenic MUPs based on expanded data. METHODS: MUPs were collected from the biceps brachii (BB) and tibialis anterior (TA) muscles. Muscles showing unequivocal neurogenic or myogenic changes by visual inspection were selected for patients. In addition to the original SI, a revised SI (rSI) was defined using the logarithmic scale for area/amplitude. The coefficient for area/amplitude was varied and that achieving the best sensitivity both for BB and TA was selected. RESULTS: Analyzed were 1619, 340, and 498 MUPs from the BB of 26, 10, and 14 subjects (control, neurogenic, and myogenic), respectively, and 1245, 536, and 473 MUPs from the TA of 23, 18, and 13 subjects (control, neurogenic, and myogenic), respectively. For neurogenic MUPs, the original SI and the newly defined rSIn were similarly sensitive (82.1% and 81.8% sensitivity for SI and rSIn, respectively, for BB, and 68.1% and 69.6% for TA), and were more sensitive than area (72.6% for BB and 57.6% for TA), the most sensitive parameter among conventional ones. For myogenic MUPs, the sensitivity of rSIm was 9.0% for BB and 24.5% for TA, which was not significantly different from duration (7.4% for BB and 21.8% for TA), the most sensitive parameter among conventional ones. CONCLUSIONS: SI, rSIn, and rSIm are promising as new MUP parameters.
Asunto(s)
Electromiografía/métodos , Neuronas Motoras , Fibras Musculares Esqueléticas , Músculo Esquelético/fisiopatología , Enfermedades Neuromusculares/fisiopatología , Adolescente , Adulto , Anciano , Esclerosis Amiotrófica Lateral/fisiopatología , Brazo , Atrofia Bulboespinal Ligada al X/fisiopatología , Estudios de Casos y Controles , Miopatías Distales/fisiopatología , Femenino , Humanos , Pierna , Masculino , Persona de Mediana Edad , Músculo Esquelético/inervación , Distrofia Muscular de Duchenne/fisiopatología , Distrofia Muscular Facioescapulohumeral/fisiopatología , Miositis/fisiopatología , Miositis por Cuerpos de Inclusión/fisiopatología , Distrofia Miotónica/fisiopatología , Enfermedades Neuromusculares/diagnóstico , Síndrome Pospoliomielitis/fisiopatología , Estenosis Espinal/fisiopatología , Adulto JovenRESUMEN
OBJECTIVE: The 'split hand' sign refers to preferential wasting of the thenar and first dorsal interosseous muscles with relatively sparing of the hypothenar muscles in amyotrophic lateral sclerosis (ALS) and both cortical and spinal/peripheral excitotoxic mechanisms have been proposed. We aimed to study split hand and axonal excitability in spinal and bulbar muscular atrophy (SBMA) in which cortical motor neurons are intact. METHODS: In 35 patients with genetically confirmed SBMA, 55 with ALS, 158 with other neuromuscular diseases and 90 normal controls; split hand was strictly determined by amplitudes of compound muscle action potentials. Nerve excitability testing of median motor axons was performed in 35 SBMA and 55 patients with ALS and 45 normal controls. RESULTS: Split hand was as frequently found for patients with SBMA (57%) and ALS (62%), compared with disease (20%) and normal (0%) controls. Excitability testing showed that in both SBMA and ALS, strength-duration time constant was longer, and threshold changes in depolarising threshold electrotonus and superexcitability in the recovery cycle were greater than in normal controls (p<0.01). CONCLUSIONS: Split hand is not specific to ALS and can be caused by the peripheral mechanism alone in SBMA, whereas the effect of upper motor neuron lesion cannot be excluded in ALS. Our results also suggest that SBMA and ALS share common axonal excitability changes; increased nodal persistent sodium and reduced potassium currents that may accelerate motor neuronal death and differently affect axons-innervating different muscles. Ion channel modulators could be a therapeutic option for both SBMA and ALS.
Asunto(s)
Potenciales de Acción , Esclerosis Amiotrófica Lateral/fisiopatología , Atrofia Bulboespinal Ligada al X/fisiopatología , Mano , Nervio Mediano/fisiopatología , Atrofia Muscular/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Axones , Estudios de Casos y Controles , Estimulación Eléctrica , Electrodiagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Enfermedades Neuromusculares/fisiopatologíaRESUMEN
Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets.
Asunto(s)
Atrofia Bulboespinal Ligada al X/metabolismo , Atrofia Bulboespinal Ligada al X/terapia , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Tejido Adiposo/diagnóstico por imagen , Agonistas Adrenérgicos beta/uso terapéutico , Autofagia , Biomarcadores , Atrofia Bulboespinal Ligada al X/diagnóstico por imagen , Atrofia Bulboespinal Ligada al X/fisiopatología , Clenbuterol/uso terapéutico , Creatinina/metabolismo , Dutasterida/uso terapéutico , Glucólisis , Humanos , Factor I del Crecimiento Similar a la Insulina/análogos & derivados , Leuprolida/uso terapéutico , Imagen por Resonancia Magnética , Mitocondrias/metabolismo , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Rápida/patología , Fibras Musculares de Contracción Lenta/metabolismo , Fibras Musculares de Contracción Lenta/patología , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Oligonucleótidos Antisentido/uso terapéutico , Oxidación-Reducción , Tratamiento con ARN de Interferencia , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Expansión de Repetición de TrinucleótidoRESUMEN
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's Disease, is a late-onset X-linked progressive neuromuscular disease, which predominantly affects males. The pathological hallmarks of the disease are selective loss of spinal and bulbar motor neurons, accompanied by weakness, atrophy and fasciculations of bulbar and limb muscles. SBMA is caused by a CAG repeat expansion in the gene that encodes the androgen receptor (AR) protein. Disease manifestation is androgen dependent and results principally from a toxic gain of AR function. There are currently no effective treatments for this debilitating disease. It is important to understand the course of the disease in order to target therapeutics to key pathological stages. This is especially relevant in disorders such as SBMA, for which disease can be identified before symptom onset, through family history and genetic testing. To fully characterise the role of muscle in SBMA, we undertook a longitudinal physiological and histological characterisation of disease progression in the AR100 mouse model of SBMA. Our results show that the disease first manifests in skeletal muscle, before any motor neuron degeneration, which only occurs in late-stage disease. These findings reveal that alterations in muscle function, including reduced muscle force and changes in contractile characteristics, are early pathological events in SBMA mice and suggest that muscle-targeted therapeutics may be effective in SBMA.This article has an associated First Person interview with the first author of the paper.
Asunto(s)
Atrofia Bulboespinal Ligada al X/patología , Atrofia Bulboespinal Ligada al X/fisiopatología , Contracción Muscular , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Animales , Fenómenos Biomecánicos , Peso Corporal , Supervivencia Celular , Progresión de la Enfermedad , Miembro Posterior/inervación , Miembro Posterior/fisiopatología , Ratones , Actividad Motora/fisiología , Neuronas Motoras/patología , Fatiga Muscular , Músculo Esquelético/inervación , Atrofia Muscular/patología , Atrofia Muscular/fisiopatología , Oxidación-ReducciónRESUMEN
Spinal and bulbar muscular atrophy or Kennedy disease (KD) is an X-linked recessive disorder caused by a pathogenic CAG expansion in the first exon of the androgen receptor. Proximal muscle atrophy, weakness, contraction fasciculations, bulbar involvement, and sensory disturbances are part of the clinical picture of KD. We report the unusual genetic and phenotypic expression in 2 monozygotic twins. Genetic analysis has shown abnormal expansion of CAG repeat in the first exon of the androgen receptor gene on chromosome X different between the twin brothers (44, respectively, 46) but with large phenotypical differences including onset age, evolution, and clinical features. Disease began at age 31 for the first brother, respectively, and at 56 years for the second one and consisted of muscle wasting and progressive impairment of walking. In addition, the second brother did not manifest bulbar involvement 3 years after clinical onset and has more sensory features. Besides classical EMG testing, we evaluate sensory participation in spinal and bulbar muscular atrophy with sudoscan device and confirmed the sensory deficit. We discussed epigenetic factors potentially involved in KD that could play a role in the phenotypical differences. To the best of our knowledge, this is the first case describing CAG trinucleotide repeats in monozygotic twins and also the first sudoscan diagnostic of sensory disturbances in Kennedy syndrome.
Asunto(s)
Atrofia Bulboespinal Ligada al X/genética , Edad de Inicio , Atrofia Bulboespinal Ligada al X/fisiopatología , Progresión de la Enfermedad , Electromiografía , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Receptores Androgénicos/genética , Repeticiones de Trinucleótidos/genética , Gemelos MonocigóticosAsunto(s)
Investigación Biomédica , Atrofia Bulboespinal Ligada al X , Sistema de Registros , Atrofia Bulboespinal Ligada al X/genética , Atrofia Bulboespinal Ligada al X/metabolismo , Atrofia Bulboespinal Ligada al X/fisiopatología , Atrofia Bulboespinal Ligada al X/terapia , Europa (Continente) , Unión Europea , Humanos , Péptidos/genética , Receptores Androgénicos/genéticaRESUMEN
Spinal and bulbar muscular atrophy (Kennedy's disease) has been associated with balance dysfunction and falls. However, postural control has not been studied quantitatively. Here, we quantified upright stance and aimed to disentangle the role of vestibular, proprioceptive and oculomotor deficits. Static balance was assessed in Kennedy patients (n = 7) during quiet stance on a force platform under different visual and proprioceptive feedback conditions. Vestibular function was assessed with the video head impulse test. Sural nerve neurography was employed to evaluate the severity of peripheral neuropathy. Also, horizontal saccades were recorded and quantified by the main sequence relationship. Posturographic analyses revealed significantly increased body sway, more pronounced in conditions with closed eyes, which was also reflected in the calculated Romberg indices. Horizontal vestibulo-ocular reflex gains were normal, i.e. > 0.75. In contrast, compound sensory nerve action potentials were markedly decreased in all patients (mean = 2.4 µV). Two patients showed slow saccades with increased exponential main sequence constants. We conclude that Kennedy patients exhibit severe deficits in quiet stance. Postural instability is greatest in conditions of absent vision with reduced proprioception being the main determinant of unsteadiness. Some patients show slowed saccadic eye movements suggesting a nuclear abducens neuronopathy.
Asunto(s)
Atrofia Bulboespinal Ligada al X/fisiopatología , Equilibrio Postural/fisiología , Propiocepción/fisiología , Movimientos Sacádicos/fisiología , Enfermedades Vestibulares/fisiopatología , Potenciales de Acción/fisiología , Adulto , Estudios de Casos y Controles , Humanos , Masculino , Persona de Mediana Edad , Células Receptoras Sensoriales/fisiología , Nervio Sural/fisiologíaRESUMEN
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.
Asunto(s)
Atrofia Bulboespinal Ligada al X/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Atrofia Bulboespinal Ligada al X/genética , Atrofia Bulboespinal Ligada al X/fisiopatología , Nervios Craneales/fisiopatología , Análisis Factorial , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Variaciones Dependientes del Observador , Reproducibilidad de los ResultadosRESUMEN
Spinobulbar muscular atrophy (SBMA) is caused by a trinucleotide repeat expansion in the androgen receptor gene on the X chromosome. There is a toxic effect of the mutant receptor on muscle and neurons resulting in muscle weakness and atrophy. The weakness can be explained by wasting due to loss of muscle cells, but it is unknown whether weakness also relates to poor muscle contractility of the remaining musculature. In this study, we investigated the muscle contractility in SBMA. We used stationary dynamometry and quantitative MRI to assess muscle strength and absolute and fat-free, cross-sectional areas. Specific muscle force (strength per cross-sectional area) and contractility (strength per fat-free cross-sectional area) were compared with healthy controls and their relation to walking distance and disease severity was investigated. Specific force was reduced by 14-49% in SBMA patients compared to healthy controls. Contractility was reduced by 22-39% in elbow flexion, knee extension, ankle dorsi- and plantarflexion in SBMA patients. The contractility decreased with increasing muscle fat content in muscles with affected contractility in SBMA. The decreased muscle contractility in SBMA may relate to motor neuron degeneration and changed fibre type distribution and muscle architecture.
Asunto(s)
Atrofia Bulboespinal Ligada al X/fisiopatología , Neuronas Motoras/fisiología , Contracción Muscular/fisiología , Fuerza Muscular/fisiología , Músculos/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Atrofia Bulboespinal Ligada al X/genética , Cromosomas Humanos X/genética , Estudios Transversales , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Dinamómetro de Fuerza Muscular , Debilidad Muscular/genética , Degeneración Nerviosa , Receptores Androgénicos/genética , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
A 64-year-old man was diagnosed with spinal and bulbar muscular atrophy (SBMA) in 2014, and began gait training with the hybrid assistive limb (HAL) in 2017. We conducted 2 courses of HAL-based gait training and temporary improvement was confirmed both before and after intervention based on evaluation of the 2-minute walking distance, walking speed, and the Timed Up and Go test. HAL-based gait training may be effective for improving and maintaining walking ability in SBMA. However, long-term observation of this patient will be performed.
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Atrofia Bulboespinal Ligada al X/rehabilitación , Terapia por Ejercicio/instrumentación , Dispositivo Exoesqueleto , Marcha/fisiología , Rehabilitación Neurológica/instrumentación , Acondicionamiento Físico Humano/instrumentación , Modalidades de Fisioterapia/instrumentación , Caminata/fisiología , Atrofia Bulboespinal Ligada al X/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
OBJECTIVE: To determine whether blood biomarkers of neuronal damage (neurofilament light chain [NfL]), muscle damage (creatine kinase [CK]), and muscle mass (creatinine) are altered in spinal and bulbar muscular atrophy (SBMA) and can be used as biomarkers for disease severity. METHODS: In this multicenter longitudinal prospective study, plasma and serum were collected from 2 cohorts of patients with SBMA in London, United Kingdom (n = 50), and Padova, Italy (n = 43), along with disease (amyotrophic lateral sclerosis [ALS]) and healthy controls, and levels of plasma and serum NfL, CK, and creatinine were measured. Disease severity was assessed by the SBMA Functional Rating Scale and the Adult Myopathy Assessment Tool at baseline and 12 and 24 months. RESULTS: Blood NfL concentrations were increased in ALS samples, but were unchanged in both SBMA cohorts, were stable after 12 and 24 months, and were not correlated with clinical severity. Normal NfL levels were also found in a well-established mouse model of SBMA. Conversely, CK concentrations were significantly raised in SBMA compared with ALS samples, and were not correlated to the clinical measures. Creatinine concentrations were significantly reduced in SBMA, and strongly and significantly correlated with disease severity. CONCLUSIONS: While muscle damage and muscle mass biomarkers are abnormal in SBMA, axonal damage markers are unchanged, highlighting the relevant primary role of skeletal muscle in disease pathogenesis. Creatinine, but not CK, correlated with disease severity, confirming its role as a valuable biomarker in SBMA.
Asunto(s)
Atrofia Bulboespinal Ligada al X/sangre , Creatina Quinasa/sangre , Creatinina/sangre , Proteínas de Neurofilamentos/sangre , Anciano , Esclerosis Amiotrófica Lateral/sangre , Animales , Biomarcadores/sangre , Atrofia Bulboespinal Ligada al X/fisiopatología , Modelos Animales de Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Ratones , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To investigate the phenotypic features, with emphasis on muscle, in 40 patients with spinobulbar muscular atrophy (SBMA) using quantitative MRI, stationary dynamometry, questionnaires, and functional tests. METHODS: Patients with genetically confirmed SBMA were included. MRI was used to describe muscle involvement and quantify muscle fat fractions of arm, back, and leg muscles. Muscle strength was assessed with a stationary dynamometer. All patients were evaluated with the SBMA functional rating scale and the 6-minute walk test among others. MRI and muscle strength results were compared with healthy controls. RESULTS: Forty patients with SBMA were included. The muscle fat content was significantly higher in patients with SBMA than in controls: paraspinal fat fraction was 45% vs 33% in controls, thigh fat fraction 36% vs 14%, calf fat fraction 37% vs 15%, upper arm fat fraction 20% vs 8%, and forearm fat fraction was 20% vs 9%. Muscle strength in patients was reduced to approximately half of that in controls in all muscles. Muscle fat content correlated with muscle strength, SBMA functional rating scale score, and 6-minute walk test distance. CONCLUSIONS: Our results show that there is a diffuse muscle involvement pattern in SBMA. Leg muscles are more vulnerable than arm muscles, especially the posterior flexor muscles. The muscle fat content correlates with muscle function and disease severity.
Asunto(s)
Tejido Adiposo/diagnóstico por imagen , Atrofia Bulboespinal Ligada al X/diagnóstico por imagen , Fuerza Muscular , Músculo Esquelético/diagnóstico por imagen , Adulto , Anciano , Brazo , Músculos de la Espalda/diagnóstico por imagen , Músculos de la Espalda/fisiopatología , Atrofia Bulboespinal Ligada al X/fisiopatología , Estudios de Casos y Controles , Antebrazo , Humanos , Pierna , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Fenotipo , Muslo , Prueba de PasoRESUMEN
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a rare, X-linked hereditary lower motor neuron disease, characterized by progressive muscular weakness. An expanded trinucleotide repeat (CAG > 37) in the androgen receptor gene (AR), encoding glutamine, is the mutation responsible for Kennedy's disease. Toxicity of this mutant protein affects both motor neurons and muscles. In this review, we provide a comprehensive, clinically oriented overview of the current literature regarding Kennedy's disease, highlighting gaps in our knowledge that remain to be addressed in further research. Kennedy's disease mimics are also discussed, as are ongoing and recently completed therapeutic endeavours.
Asunto(s)
Atrofia Bulboespinal Ligada al X , Atrofia Bulboespinal Ligada al X/genética , Atrofia Bulboespinal Ligada al X/fisiopatología , Atrofia Bulboespinal Ligada al X/terapia , Humanos , Receptores Androgénicos/genética , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
Peculiar cognitive profile of patients with SBMA has been described by fragmented literature. Our retrospective study reports the neuropsychological evaluations of a large cohort of patients in order to contribute towards the understanding of this field. We consider 64 neuropsychological evaluations assessing mnesic, linguistic and executive functions collected from 2013 to 2015 in patients attending at Motor Neuron Disease Centre of University of Padova. The battery consisted in: Digit Span forwards and backwards, Prose Memory test, Phonemic Verbal fluency and Trail making tests. ANCOVA statistics were employed to compare tests scores results with those obtained from a sample of healthy control subjects. Multiple linear regressions were used to study the effect on cognitive performance of CAG-repeat expansion, the degree of androgen insensitivity and their interaction to cognitive performance. Statistical analyses did not reveal altered scores in any neuropsychological tests among those adopted. Interestingly, patients performed significantly better in the Prose Memory test's score. No relevant associations were found with genetic, hormonal or clinical patients' profile. Results inconsistent with previous studies have been interpreted according to the phenomenon of somatic mosaicism. We suggest a testosterone-related and the mood state-dependant perspectives as two possible interpretations of the enhanced performances in the Prose Memory test. Further studies employing more datailed tests batteries are encouraged.
Asunto(s)
Atrofia Bulboespinal Ligada al X/fisiopatología , Trastornos del Conocimiento/fisiopatología , Cognición/fisiología , Memoria/fisiología , Adulto , Atrofia Bulboespinal Ligada al X/diagnóstico , Trastornos del Conocimiento/diagnóstico , Función Ejecutiva/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Neuropsicología/métodos , Estudios RetrospectivosRESUMEN
A distinguishing aspect of spinal and bulbar muscular atrophy (SBMA) is its androgen-dependence, possibly explaining why only males are clinically affected. This disease, which impairs neuromuscular function, is linked to a polyglutamine expansion mutation in the androgen receptor (AR). In mouse models of SBMA, motor dysfunction is associated with pronounced defects in neuromuscular transmission, including defects in evoked transmitter release (quantal content, QC) and fiber membrane excitability (based on the resting membrane potential, RMP). However, whether such defects are androgen-dependent is unknown. Thus, we recorded synaptic potentials intracellularly from adult muscle fibers of transgenic (Tg) AR97Q male mice castrated pre-symptomatically. Although castration largely protects both QC and the RMP of fibers, correlating with the protective effect of castration on motor function, significant deficits in QC and RMP remained. Surprisingly, comparable defects in QC and RMP were also observed in pre-symptomatic AR97Q males, indicating that such defects emerge early and are pre-clinical. Exposing asymptomatic Tg females to androgens also induces both motor dysfunction and comparable defects in QC and RMP. Notably, asymptomatic Tg females also showed significant deficits in QC and RMP, albeit less severe, supporting their pre-clinical nature, but also raising questions about the androgen-dependence of pre-clinical symptoms. In summary, current evidence indicates that disease progression depends on androgens, but early pathogenic events may be triggered by the mutant AR allele independent of androgens. Such early, androgen-independent disease mechanisms may also be relevant to females carrying the SBMA allele.
Asunto(s)
Andrógenos/genética , Atrofia Bulboespinal Ligada al X/fisiopatología , Neuronas Motoras/patología , Receptores Androgénicos/genética , Andrógenos/metabolismo , Animales , Atrofia Bulboespinal Ligada al X/genética , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Neuronas Motoras/metabolismo , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/patologíaRESUMEN
BACKGROUND: Excitability studies on normal and diseased human axons in vivo have been greatly enhanced by fast non-invasive threshold-tracking techniques, using surface stimulation and recording. Although sensory axons are often more affected in disease, most studies to date have focussed on motor axons, because of technical difficulties in resolving pathologically small nerve volleys in the presence of noise and stimulus artefact. NEW METHODS: This paper describes techniques for tracking low-amplitude compound action potentials, using a battery-powered, isolated preamplifier of simple construction with high common mode rejection (>125â¯dB [balanced inputs]) and low noise (<0.4⯵V referred to inputs [shorted]). RESULTS: We demonstrate the preamplifier's capability by tracking targets as small as 2 µV for a full range of excitability measurements without the usual distortion due to residual stimulus artefact and without the need for clamping, additional filtering or ensemble averaging. COMPARISON WITH EXISTING METHODS: In practice, threshold-tracking studies have been unable to study sensory axons when the maximal compound sensory action potential was less than about 15⯵V. The techniques and amplifier in the present study allow measurements to be made from nerve with maximal responses less than half that size, and we present three recordings in patients with pathologically small nerve action potentials ≤7⯵V. CONCLUSIONS: Based on measurements of stimulus artefact distortion, noise and the performance in experiments, we conclude that the techniques described here will facilitate the study of diseased axons for which the sensory potentials have high thresholds and may be only a few microvolts in amplitude.
Asunto(s)
Potenciales de Acción , Axones/fisiología , Electrodiagnóstico/instrumentación , Células Receptoras Sensoriales/fisiología , Neuropatías Amiloides/diagnóstico , Neuropatías Amiloides/fisiopatología , Artefactos , Atrofia Bulboespinal Ligada al X/diagnóstico , Atrofia Bulboespinal Ligada al X/fisiopatología , Tamaño de la Célula , Impedancia Eléctrica , Suministros de Energía Eléctrica , Estimulación Eléctrica/instrumentación , Estimulación Eléctrica/métodos , Diseño de Equipo , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/fisiopatología , Reproducibilidad de los Resultados , Fenómenos Fisiológicos de la Piel , Programas Informáticos , Extremidad SuperiorAsunto(s)
Atrofia Bulboespinal Ligada al X/genética , Receptores Androgénicos/genética , Expansión de Repetición de Trinucleótido/genética , Atrofia Bulboespinal Ligada al X/fisiopatología , Exones/genética , Hormonas/metabolismo , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) is caused by the expansion of a CAG repeat in the androgen receptor gene. The relationship between the CAG repeat size and electrophysiological findings is not completely understood. METHODS: We retrospectively analyzed 62 SBMA patients to assess the correlation between their CAG repeat size and electrophysiological findings. RESULTS: In multiple regression analysis including age at examination and disease duration, we identified a negative correlation between the CAG repeat size and the compound muscle action potential (CMAP) amplitude. No significant correlation was found between the CAG repeat size and sensory nerve action potential (SNAP) amplitude. DISCUSSION: Contrary to previous reports of motor- and sensory-dominant phenotypes correlating with CAG repeat sizes, the CAG repeat size was negatively correlated only with CMAP amplitude, and not with SNAP amplitude. Muscle Nerve 57: 683-686, 2018.