RESUMEN
BACKGROUND: Chronic respiratory insufficiency from progressive muscle weakness causes morbidity and mortality in late-onset Pompe disease (LOPD). Previous Pompe Registry (NCT00231400) analyses for ≤ 5 years' alglucosidase alfa treatment showed a single linear time trend of stable forced vital capacity (FVC) % predicted. METHODS: To assess longer term Pompe Registry data, piecewise linear mixed model regression analyses estimated FVC% predicted trajectories in invasive-ventilator-free patients with LOPD aged ≥ 5 years. We estimated annual FVC change 0-6 months, > 6 months-5 years, and > 5-13 years from treatment initiation, adjusting for baseline age, sex, and non-invasive ventilation. FINDINGS: Among 485 patients (4612 FVC measurements; 8.3 years median follow-up), median ages at symptom onset, diagnosis, and alglucosidase alfa initiation were 34.3, 41.1, and 44.9 years, respectively. FVC% increased during the first 6 months' treatment (slope 1.83%/year; 95% confidence interval: 0.66, 3.01; P = 0.0023), then modestly declined -0.54%/year (-0.79, -0.30; P < 0.0001) during > 6 months-5 years, and -1.00%/year (-1.36, -0.63; P < 0.0001) during > 5-13 years. The latter two periods' slopes were not significantly different from each other (Pdifference = 0.0654) and were less steep than published natural history slopes (-1% to -4.6%/year). Estimated individual slopes were ≥ 0%/year in 96.1%, 30.3%, and 13.2% of patients during the 0-6 month, > 6 month-5 year, and > 5-13 year periods, respectively. CONCLUSION: These real-world data indicate an alglucosidase alfa benefit on FVC trajectory that persists at least 13 years compared with published natural history data. Nevertheless, unmet need remains since most individuals demonstrate lung function decline 5 years after initiating treatment. Whether altered FVC trajectory impacts respiratory failure incidence remains undetermined. TRIAL REGISTRATION: This study was registered (NCT00231400) on ClinicalTrials.gov on September 30, 2005, retrospectively registered.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II , Sistema de Registros , alfa-Glucosidasas , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Masculino , Femenino , alfa-Glucosidasas/uso terapéutico , Adulto , Capacidad Vital/efectos de los fármacos , Capacidad Vital/fisiología , Persona de Mediana Edad , Terapia de Reemplazo Enzimático/métodos , Adulto Joven , Adolescente , Niño , Estudios de Seguimiento , PreescolarRESUMEN
BACKGROUND: Late-onset Pompe disease (LOPD) patients may still need ventilation support at some point of their disease course, despite regular recombinant human alglucosidase alfa treatment. This suggest that other pathophysiological mechanisms than muscle fibre lesion can contribute to the respiratory failure process. We investigate through neurophysiology whether spinal phrenic motor neuron dysfunction could contribute to diaphragm weakness in LOPD patients. MATERIAL AND METHODS: A group of symptomatic LOPD patients were prospectively studied in our centre from January 2022 to April 2023. We collected both demographic and clinical data, as well as neurophysiological parameters. Phrenic nerve conduction studies and needle EMG sampling of the diaphragm were perfomed. RESULTS: Eight treated LOPD patients (3 males, 37.5%) were investigated. Three patients (37.5%) with no respiratory involvement had normal phrenic nerve motor responses [median phrenic compound muscle action potential (CMAP) amplitude of 0.49 mV; 1st-3rd interquartile range (IQR), 0.48-0.65]. Those with respiratory failure (under nocturnal non-invasive ventilation) had abnormal phrenic nerve motor responses (median phrenic CMAP amplitude of 0 mV; 1st-3rd IQR, 0-0.15), and were then investigated with EMG. Diaphragm needle EMG revealed both myopathic and neurogenic changes in 3 (60%) and myopathic potentials in 1 patient. In the last one, no motor unit potentials could be recruited. CONCLUSIONS: Our study provide new insights regarding respiratory mechanisms in LOPD, suggesting a contribution of spinal phrenic motor neuron dysfunction for diaphragm weakness. If confirmed in further studies, our results recommend the need of new drugs crossing the blood-brain barrier.
Asunto(s)
Diafragma , Electromiografía , Enfermedad del Almacenamiento de Glucógeno Tipo II , Neuronas Motoras , Debilidad Muscular , Nervio Frénico , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo II/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Masculino , Diafragma/fisiopatología , Femenino , Persona de Mediana Edad , Debilidad Muscular/etiología , Debilidad Muscular/fisiopatología , Nervio Frénico/fisiopatología , Neuronas Motoras/fisiología , Neuronas Motoras/patología , Adulto , Conducción Nerviosa/fisiología , Fibras Musculares Esqueléticas/patología , Fibras Musculares Esqueléticas/fisiología , Anciano , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/fisiopatología , Estudios Prospectivos , Potenciales de Acción/fisiologíaRESUMEN
BACKGROUND: Late Onset Pompe Disease (LOPD) is a rare myopathy characterized by prevailing weakness of trunk and pelvic girdle muscles that causes motor disabilities. Spinal deformities have been reported unclearly on clinical examination. No study quantitatively assessed upright posture defining specific alterations of LOPD various phenotype. OBJECTIVE: Identify postural abnormalities in a homogeneous group of LOPD patients using 3D Stereophotogrammetry (St) and x-Ray (xR). METHODS: Seven LOPD siblings were recruited. They were assessed by clinical scales and, in upright posture, using xR and 3D-St with a new marker set protocol. Fourteen healthy individuals, age and sex-matched, were used as controls for St-parameters; normative xR-values were found in literature. RESULTS: LOPD patients showed a significant weakness of trunk and tibialis anterior muscles. Statistical analysis of St-parameters showed a larger ankle, knee, elbow, dorsal, S2-C7, heel-S2-C7, heel-S2-nasion angles and a lower sagittal vertical axis (SVA) than controls.xR-analysis highlighted an absence of scoliosis and a lower occipito-cervical, C2-C7 cervical and Cobb dorsal angles, and a trend to lower lumbar lordosis and SVA compared to normal values. Significant correlation was found in dorsal and lumbar angles calculated using xR-markers placed on spiny apophysis, xR-centre of vertebral bodies, Cobb-method and St-markers. CONCLUSION: This is the first quantitative study of postural abnormalities in LOPD patients using 3D-St and xR, highlighting sagittal standing alignment changes, difficult to assess to direct exam.Our new St-protocol showed a high reliability compared to xR. Further studies on larger population of LOPD might confirm the usefulness of these instrumental methods for monitoring disease course.
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Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico por imagen , Fotogrametría/métodos , Postura/fisiología , Radiografía/métodos , Posición de Pie , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Humanos , Lordosis/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
Pompe disease (PD) is a neuromuscular disorder caused by a mutation in the acid alpha-glucosidase (GAA) gene. Patients with late-onset PD retain some GAA activity and present symptoms later in life, with fatality mainly associated with respiratory failure. This case study presents diaphragm electrophysiology and a histological analysis of the brainstem, spinal cord, and diaphragm, from a male PD patient diagnosed with late-onset PD at age 35. The patient was wheelchair dependent by age 38, required nocturnal ventilation at age 40, 24-h noninvasive ventilation by age 43, and passed away from respiratory failure at age 54. Diaphragm electromyography recorded using indwelling "pacing" wires showed asynchronous bursting between the left and right diaphragm during brief periods of independent breathing. The synchrony declined over a 4-yr period preceding respiratory failure. Histological assessment indicated motoneuron atrophy in the medulla and rostral spinal cord. Hypoglossal (soma size: 421 ± 159 µm2) and cervical motoneurons (soma size: 487 ± 189 µm2) had an atrophied, elongated appearance. In contrast, lumbar (soma size: 1,363 ± 677 µm2) and sacral motoneurons (soma size: 1,411 ± 633 µm2) had the ballooned morphology typical of early-onset PD. Diaphragm histology indicated loss of myofibers. These results are consistent with neuromuscular degeneration and the concept that effective PD therapy will need to target the central nervous system, in addition to skeletal and cardiac muscle.NEW & NOTEWORTHY This case study offered a unique opportunity to investigate longitudinal changes in phrenic neurophysiology in an individual with severe, ventilator-dependent, late-onset Pompe disease. Additional diaphragm and neural tissue histology upon autopsy confirmed significant neuromuscular degeneration, and it provided novel insights regarding rostral to caudal variability in the neuropathology. These findings suggest that a successful treatment approach for ventilator-dependent Pompe disease should target the central nervous system, in addition to skeletal muscle.
Asunto(s)
Diafragma/fisiopatología , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Ventilación Pulmonar , Tronco Encefálico/patología , Tronco Encefálico/fisiopatología , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , Humanos , Masculino , Persona de Mediana Edad , Nervio Frénico/patología , Nervio Frénico/fisiopatología , Médula Espinal/patología , Médula Espinal/fisiopatologíaRESUMEN
Late-onset Pompe disease (LOPD) is an inherited autosomal recessive progressive metabolic myopathy that presents in the first year of life to adulthood. Clinical presentation is heterogeneous, differential diagnosis is challenging, and diagnostic delay is common. One challenge to differential diagnosis is the overlap of clinical features with those encountered in other forms of acquired/hereditary myopathy. Tongue weakness and imaging abnormalities are increasingly recognized in LOPD. In order to explore the diagnostic potential of tongue involvement in LOPD, we assessed tongue structure and function in 70 subjects, including 10 with LOPD naive to treatment, 30 with other acquired/hereditary myopathy, and 30 controls with neuropathy. Tongue strength was assessed with both manual and quantitative muscle testing. Ultrasound (US) was used to assess tongue overall appearance, echointensity, and thickness. Differences in tongue strength, qualitative appearance, echointensity, and thickness between LOPD subjects and neuropathic controls were statistically significant. Greater tongue involvement was observed in LOPD subjects compared to those with other acquired/hereditary myopathies, based on statistically significant decreases in quantitative tongue strength and sonographic muscle thickness. These findings provide additional evidence for tongue involvement in LOPD characterized by weakness and sonographic abnormalities suggestive of fibrofatty replacement and atrophy. Findings of quantitative tongue weakness and/or atrophy may aid differentiation of LOPD from other acquired/hereditary myopathies. Additionally, our experiences in this study reveal US to be an effective, efficient imaging modality to allow quantitative assessment of the lingual musculature at the point of care.
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Atrofia/fisiopatología , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Enfermedades de Inicio Tardío/diagnóstico , Enfermedades Musculares/congénito , Enfermedades Musculares/diagnóstico , Lengua/fisiopatología , Adulto , Anciano , Diagnóstico Tardío , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Debilidad Muscular/diagnóstico , Debilidad Muscular/etiología , Lengua/diagnóstico por imagen , Ultrasonografía , Adulto JovenRESUMEN
Late-onset Pompe disease (LOPD) is a rare disease, defined as a progressive accumulation of lysosomal glycogen resulting in muscle weakness and respiratory problems. Anecdotally, individuals often have difficulties walking, yet, there is no three-dimensional data supporting these claims. We aimed to assess walking patterns in individuals with LOPD and compare with healthy individuals. Kinematic, kinetic and spatiotemporal data were compared during walking at a self-selected speed between individuals with LOPD (n = 12) and healthy controls (n = 12). Gait profile scores and movement analysis profiles were also determined to indicate gait quality. In comparison with healthy individuals, the LOPD group demonstrated greater thoracic sway (96%), hip adduction angles (56%) and pelvic range of motion (77%) and reduced hip extensor moments (36%). Greater group variance for the LOPD group were also observed. Individuals with LOPD had a slower (15%) walking speed and reduced cadence (7%). Gait profile scores were 37% greater in the LOPD group compared to the healthy group. Proximal muscular weakness associated with LOPD disease is likely to have resulted in a myopathic gait pattern, slower selected walking speeds and deviations in gait patterns. Although individuals with LOPD presented with some common characteristics, greater variability in gait patterns is likely to be a result of wide variability in phenotype spectrum observed with LOPD. This is the first study to examine walking in individuals with LOPD using instrumented gait analysis and provides an understanding of LOPD on walking function which can help orientate physiotherapy treatment for individuals with LOPD.
Asunto(s)
Marcha , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Velocidad al Caminar , Adolescente , Adulto , Anciano , Fenómenos Biomecánicos , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Humanos , Cinética , Masculino , Persona de Mediana Edad , Movimiento , Fenotipo , Rango del Movimiento Articular , Adulto JovenRESUMEN
To address progressive respiratory muscle weakness in late-onset Pompe disease (LOPD), we developed a 12-week respiratory muscle training (RMT) program. In this exploratory, double-blind, randomized control trial, 22 adults with LOPD were randomized to RMT or sham-RMT. The primary outcome was maximum inspiratory pressure (MIP). Secondary and exploratory outcomes included maximum expiratory pressure (MEP), peak cough flow, diaphragm ultrasound, polysomnography, patient-reported outcomes, and measures of gross motor function. MIP increased 7.6 cmH2O (15.9) in the treatment group and 2.7 cmH2O (7.6) in the control group (Pâ¯=â¯0.4670). MEP increased 14.0 cmH2O (25.9) in the treatment group and 0.0 cmH2O (12.0) in the control group (Pâ¯=â¯0.1854). The only statistically significant differences in secondary/exploratory outcomes were improvements in time to climb 4 steps (Pâ¯=â¯0.0346) and daytime sleepiness (Pâ¯=â¯0.0160). The magnitude of changes in MIP and MEP in the treatment group were consistent with our pilot findings but did not achieve statistical significance in comparison to controls. Explanations for this include inadequate power and baseline differences in subject characteristics between groups. Additionally, control group subjects appeared to exhibit an active response to sham-RMT and therefore sham-RMT may not be an optimal control condition for RMT in LOPD.
Asunto(s)
Ejercicios Respiratorios/métodos , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Músculos Respiratorios/fisiopatología , Adulto , Anciano , Diafragma/fisiopatología , Método Doble Ciego , Femenino , Humanos , Inhalación/fisiología , Masculino , Persona de Mediana Edad , Debilidad Muscular/fisiopatología , Pruebas de Función Respiratoria , UltrasonografíaRESUMEN
The aim of this study was to assess whether different cut-offs of maximum inspiratory and/or expiratory pressure (MIP/MEP) are valuable screening parameters to detect restrictive respiratory insufficiency. Spirometry, MIP, MEP and capillary blood gas analysis were obtained from patients with confirmed neuromuscular disorders. We calculated regression analysis, sensitivity, specificity and predictive values. We enrolled 29 patients with myotonic dystrophy type 1 (DM1), 19 with late-onset Pompe disease (LOPD), and 24 with spinal muscular atrophy type 3. Moderate to high reduction in manometry was exclusively found in LOPD and DM1 patients. Significant associations were found between manometry and spirometry. Highest adjusted r2 was found for MIP % predicted and forced vital capacity (FVC) % predicted. Manometry predicted abnormal FVC and forced expiratory volume 1 s (FEV1). MEP > 80 cmH2O predicted normal FVC and FEV1, regardless of cut-off values. MIP and MEP did not positively predict alterations in capillary blood gas analysis. Disease-specific cut-offs of manometry did not increase the prediction rate of patients with abnormal FVC and FEV1. Predicted values should be calculated for a more comprehensive interpretation of manometry results. MIP and MEP can serve as a screening parameter for patients with neuromuscular disorders, but parallel testing of both MIP and MEP needs to be performed to increase the positive prediction probability across disease groups.
Asunto(s)
Presiones Respiratorias Máximas , Enfermedades Neuromusculares/fisiopatología , Insuficiencia Respiratoria/diagnóstico , Adulto , Análisis de los Gases de la Sangre , Estudios Transversales , Femenino , Alemania , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Distrofia Miotónica/fisiopatología , Estudios Prospectivos , Pruebas de Función Respiratoria , Músculos Respiratorios/fisiopatología , Espirometría , Adulto JovenRESUMEN
Muscle disorders are characterized by differential involvement of various muscle groups. Among these, weakness predominantly affecting finger flexors is an uncommon pattern, most frequently found in sporadic inclusion-body myositis. This finding is particularly significant when the full range of histopathological findings of inclusion-body myositis is not found on muscle biopsy. Prominent finger flexor weakness, however, is also observed in other myopathies. It occurs commonly in myotonic dystrophy types 1 and 2. In addition, individual reports and small case series have documented finger flexor weakness in sarcoid and amyloid myopathy, and in inherited myopathies caused by ACTA1, CRYAB, DMD, DYSF, FLNC, GAA, GNE, HNRNPDL, LAMA2, MYH7, and VCP mutations. Therefore, the finding of finger flexor weakness requires consideration of clinical, myopathological, genetic, electrodiagnostic, and sometimes muscle imaging findings to establish a diagnosis.
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Dedos/fisiopatología , Debilidad Muscular/fisiopatología , Músculo Esquelético/fisiopatología , Enfermedades Musculares/fisiopatología , Amiloidosis/patología , Amiloidosis/fisiopatología , Miopatías Distales/patología , Miopatías Distales/fisiopatología , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Humanos , Músculo Esquelético/patología , Enfermedades Musculares/patología , Distrofias Musculares/patología , Distrofias Musculares/fisiopatología , Distrofia Muscular de Cinturas/patología , Distrofia Muscular de Cinturas/fisiopatología , Distrofia Muscular de Duchenne/patología , Distrofia Muscular de Duchenne/fisiopatología , Miositis por Cuerpos de Inclusión/patología , Miositis por Cuerpos de Inclusión/fisiopatología , Distrofia Miotónica/patología , Distrofia Miotónica/fisiopatología , Sarcoidosis/patología , Sarcoidosis/fisiopatologíaRESUMEN
Despite a wide clinical spectrum, the adult form of Pompe disease is the most common one, and represents more than 90% of diagnosed patients in France. Since the marketing of enzyme replacement therapy (alglucosidase alfa, Myozyme), all reports to date in adults demonstrated an improvement of the walking distance, and a trend toward stabilization of respiratory function, but the majority of these studies were less than 5 years of duration. We report here the findings from 158 treated patients included in the French Pompe Registry, who underwent regular clinical assessments based on commonly used standardized tests (6-minute walking test, MFM scale, sitting vital capacity, MIP and MEP). For longitudinal analyses, the linear mixed effects models were used to assess trends in primary endpoints over time under ERT. A two-phase model better described the changes in distance traveled in the 6-minute walk test and MFM. 6MWT showed an initial significant increase (1.4% ± 0.5/year) followed by a progressive decline (-2.3%/year), with a cut-off point at 2.2 years. A similar pattern was observed in total MFM score (6.6% ± 2.3/year followed by a - 1.1%/year decline after 0.5 years). A single-phase decline with a slope of -0.9 ± 0.1%/year (P < .001) was observed for FVC, and MEP remained stable over the all duration of follow-up. This study provides further evidence that ERT improves walking abilities and likely stabilizes respiratory function in adult patients with Pompe disease, with a ceiling effect for the 6MWT in the first 3 years of treatment.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , alfa-Glucosidasas/uso terapéutico , Adolescente , Adulto , Anciano , Niño , Terapia de Reemplazo Enzimático , Femenino , Francia , Enfermedad del Almacenamiento de Glucógeno Tipo II/mortalidad , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sistema de Registros , Pruebas de Función Respiratoria , Resultado del Tratamiento , Prueba de Paso , Adulto JovenRESUMEN
AIMS: In late-onset Pompe disease (LOPD), a lysosomal storage disorder with glycogen accumulation in several tissues, patients suffer from progressive skeletal muscle weakness. Lower urinary tract symptoms (LUTS) have rarely been reported. The aim of this study is to objectively assess LUTS in patients with LOPD for the first time using urodynamic studies and to determine differences between LOPD patients with and without LUTS. METHODS: Eighteen patients with LOPD were recruited, of whom seven patients (38.9%) reported LUTS (both voiding and storage symptoms). Six of these patients underwent urodynamic studies. Medical histories and motor function tests were compared between the 7 patients with LUTS and the 11 patients without LUTS. The Student t test was used to determine an association between the two cohorts. RESULTS: In the seven LOPD patients with LUTS urodynamics revealed neurogenic dysfunction, underactive detrusor, and bladder outlet obstruction. These patients had suffered from clinical symptoms for a longer period of time before starting enzyme replacement therapy (P = .017) than patients without LUTS. They also scored more poorly on muscle function tests. Urodynamic results point to neurogenic causes for LUTS in LOPD, that is, neurogenic reflex bladder or impaired filling sensation. This could be due to glycogen accumulation in the urothelium and central nervous system. Patients with LUTS also seem to be more severely affected by LOPD than patients without LUTS. CONCLUSION: LUTS in LOPD requires early and specific treatment to limit the development of severe health problems. Urodynamic studies should be considered in assessing LUTS.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Síntomas del Sistema Urinario Inferior/fisiopatología , Anciano , Estudios de Cohortes , Terapia de Reemplazo Enzimático/métodos , Femenino , Glucógeno/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo II/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Humanos , Síntomas del Sistema Urinario Inferior/complicaciones , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Examen Neurológico , Encuestas y Cuestionarios , Vejiga Urinaria Neurogénica/complicaciones , Vejiga Urinaria Neurogénica/fisiopatología , Vejiga Urinaria de Baja Actividad/complicaciones , Vejiga Urinaria de Baja Actividad/fisiopatología , Urodinámica , Urotelio/metabolismoRESUMEN
Pompe disease is a glycogen storage disease caused by a deficiency in acid α-glucosidase (GAA), a hydrolase necessary for the degradation of lysosomal glycogen. This deficiency in GAA results in muscle and neuronal glycogen accumulation, which causes respiratory insufficiency. Pompe disease mouse models provide a means of assessing respiratory pathology and are important for pre-clinical studies of novel therapies that aim to treat respiratory dysfunction and improve quality of life. This review aims to compile and summarize existing manuscripts that characterize the respiratory phenotype of Pompe mouse models. Manuscripts included in this review were selected utilizing specific search terms and exclusion criteria. Analysis of these findings demonstrate that Pompe disease mouse models have respiratory physiological defects as well as pathologies in the diaphragm, tongue, higher-order respiratory control centers, phrenic and hypoglossal motor nuclei, phrenic and hypoglossal nerves, neuromuscular junctions, and airway smooth muscle. Overall, the culmination of these pathologies contributes to severe respiratory dysfunction, underscoring the importance of characterizing the respiratory phenotype while developing effective therapies for patients.
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Modelos Animales de Enfermedad , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Fenotipo , Respiración , Animales , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , RatonesRESUMEN
BACKGROUND: Respiratory muscle weakness is a primary cause of morbidity and mortality in patients with Pompe disease. We previously described the effects of our 12-week respiratory muscle training (RMT) regimen in 8 adults with late-onset Pompe disease [1] and 2 children with infantile-onset Pompe disease [2]. CASE REPORT: Here we describe repeat enrollment by one of the pediatric participants who completed a second 12-week RMT regimen after 7 months of detraining. We investigated the effects of two 12-week RMT regimens (RMT #1, RMT #2) using a single-participant A-B-A experimental design. Primary outcome measures were maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP). Effect sizes for changes in MIP and MEP were determined using Cohen's d statistic. Exploratory outcomes targeted motor function. RELEVANCE: From pretest to posttest, RMT #2 was associated with a 25% increase in MIP and a 22% increase in MEP, corresponding with very large effect sizes (d= 2.92 and d= 2.65, respectively). Following two 12-week RMT regimens over 16 months, MIP increased by 69% and MEP increased by 97%, corresponding with very large effect sizes (d= 3.57 and d= 5.10, respectively). MIP and MEP were largely stable over 7 months of detraining between regimens. Magnitude of change was greater for RMT #1 relative to RMT #2.
Asunto(s)
Ejercicios Respiratorios/métodos , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Enfermedad del Almacenamiento de Glucógeno Tipo II/rehabilitación , Insuficiencia Respiratoria/fisiopatología , Insuficiencia Respiratoria/rehabilitación , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/complicaciones , Humanos , Lactante , Fuerza Muscular/fisiología , Insuficiencia Respiratoria/complicaciones , Músculos Respiratorios/fisiopatología , Retratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: Interpretation of genetic variants detected by sequencing of genomic DNA, which may cause splicing defects, regularly requires mRNA analysis. Usually, only bioinformatic testing is provided, because simple and non-invasive assay protocols are lacking. Furthermore, the detection of mis-splicing is often hampered by nonsense mediated mRNA decay (NMD). METHODS: Starting from a case of Pompe disease with two potential splicing variants an assay for the analysis of splice defects in general was developed. We analyzed the transcripts from the gene of interest by standard methods after short-term culture of the patient's lymphocytes in the presence and absence of a NMD inhibitor. Variant and wild type transcript expression were quantified by allele specific PCR in the patient and both parents and the expression ratio with/without NMD inhibition was calculated for each transcript. RESULTS: NMD detection in lymphocytes was optimized and evaluated by analyzing a naturally occurring NMD transcript. Several compounds inhibited NMD successfully, including potential therapeutic agents. Sample storage for up to 4â¯days at room temperature prior to lymphocyte isolation did not affect results. In a proof of concept we identified two candidate variants as severe splicing variants in a patient with Pompe disease, but the strategy can also be used to screen for any mis-spliced transcripts prone to NMD. CONCLUSIONS: We developed a simple, non-invasive assay for the detection and characterization of potential splicing variants. This is essential, because early and near-term diagnosis and disease classification is required to facilitate therapy in many genetic diseases.
Asunto(s)
Empalme Alternativo/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Linfocitos/metabolismo , Degradación de ARNm Mediada por Codón sin Sentido/efectos de los fármacos , ARN Mensajero/genética , Alelos , Empalme Alternativo/efectos de los fármacos , Anisomicina/farmacología , Células Cultivadas , Preescolar , Cromatografía Liquida , Codón sin Sentido , Exones , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Heterocigoto , Humanos , Lactante , Linfocitos/efectos de los fármacos , Masculino , Mutación , Degradación de ARNm Mediada por Codón sin Sentido/genética , Inhibidores de la Síntesis de la Proteína/farmacología , ARN Mensajero/efectos de los fármacos , Espectrometría de Masas en Tándem , alfa-Glucosidasas/sangre , alfa-Glucosidasas/genéticaRESUMEN
OBJECTIVES: To report the respiratory function of school-aged children with infantile Pompe disease (IPD) who started enzyme replacement therapy (ERT) in infancy and early childhood. STUDY DESIGN: This is a retrospective chart review of pulmonary function tests of: (a) patients with IPD 5 to 18 years of age, (b) who were not ventilator dependent, and (c) were able to perform upright and supine spirometry. Subjects were divided into a younger (5-9 years) and older cohort (10-18 years) for the analysis. Upright and supine forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were analyzed. RESULTS: Fourteen patients, all cross-reactive immunologic material (CRIM)-positive, met the inclusion criteria and were included in this study. Mean upright and supine FVC were 70.3% and 64.9% predicted, respectively, in the 5- to 9-year-old cohort; and 61.5% and 52.5% predicted, respectively, in the 10- to 18-year-old group. Individual patient trends showed stability in FVC overtime in six of the 14 patients. MIPs and MEPs were consistent with inspiratory and expiratory muscle weakness in the younger and older age group but did not decline with age. CONCLUSION: Data from this cohort of CRIM-positive patients with IPD showed that ERT is able to maintain respiratory function in a subgroup of patients whereas others had a steady decline. There was a statistically significant decline in FVC from the upright to a supine position in both the younger and older age groups of CRIM-positive ERT-treated patients. Before ERT, patients with IPD were unable to maintain independent ventilation beyond the first few years of life.
Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Adolescente , Adulto , Niño , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Humanos , Masculino , Pruebas de Función Respiratoria , Sobrevivientes , Resultado del Tratamiento , Adulto JovenRESUMEN
Pompe disease is an autosomal recessive lysosomal glycogen storage disorder caused by the deficiency of acid alpha-glucosidase and subsequent progressive glycogen accumulation due to mutations in the GAA gene. Pompe disease manifests with a broad spectrum of disease severity, ranging from severe infantile-onset diseases such as hypotonia and hypertrophic cardiomyopathy to late-onset diseases such as myopathy and respiratory compromise. The diagnosis requires demonstration of deficiency of the lysosomal acid alpha-glucosidase enzyme, which can be assayed in dried blood spot or liquid blood samples, together with supportive biomarker tests, and confirmed with molecular genetic analysis. Targeted screening of at-risk populations and universal newborn screening can result in earlier diagnosis and enable earlier treatment initiation, which result in the potential improvement of clinical outcomes. Disease-modifying treatment with enzyme replacement therapy has partially altered the natural history of the disease, but more efficacious novel therapies are under evaluation including second-generation enzyme replacement therapies, molecular chaperones and gene therapy approaches. Long-term survivors with Pompe disease are now manifesting novel aspects of the disease including widespread vascular disease, smooth muscle and central nervous system involvement, and these emerging phenotypes will require additional specific therapeutic approaches.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Enfermedad del Almacenamiento de Glucógeno Tipo II/terapia , alfa-Glucosidasas/deficiencia , alfa-Glucosidasas/genética , alfa-Glucosidasas/uso terapéutico , Terapia de Reemplazo Enzimático/métodos , Terapia Genética/métodos , HumanosRESUMEN
Whole-body magnetic resonance imaging (WBMRI) has clinical utility in measuring the amount of fatty infiltration in late-onset Pompe disease (LOPD). Muscle strength and function testing also provide valuable insight to the progression of myopathy seen in these patients. The main purpose of this study was to determine how closely muscle strength and functional testing correlate to the amount of fatty infiltration seen on WBMRI. LOPD patients were followed longitudinally and WBMRI, muscle strength testing using the modified Medical Research Council (mMRC) scale, muscle function testing using the Gait, Stairs, Gowers, Chair (GSGC) score, and labs including urinary glucose tetrasaccharide (Glc4) were performed at each visit. The amount of fat seen on WBMRI was quantified using proton density fat fraction (PDFF) and correlated to appropriate muscle strength and functional tests. Nineteen patients with LOPD aged 10 to 67 years were followed for a 1 to 2 year duration. There was a small increase of 1.26% (±2.57%) in overall PDFF per year in patients on ERT. Muscle strength (mMRC) and functional testing (GSGC) correlated highly with PDFF (r = -.7596, P < .0001 and r = .8267, P < .0001, respectively). Time to carry out individual tasks of the GSGC also correlated highly with PDFF of the muscles involved. Glc4 levels were normal on most visits (27/39) despite varying severity of muscle weakness in patients. Muscle strength and GSGC scores correlate highly with PDFF values from WBMRI. They may be used in assessing severity of muscle disease and to follow LOPD patients over time.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Imagen por Resonancia Magnética/métodos , Debilidad Muscular/fisiopatología , Imagen de Cuerpo Entero/métodos , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fuerza Muscular/fisiología , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Examen Físico , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
OBJECTIVES: To evaluate the clinical and molecular spectrum, and factors affecting clinical outcome of patients in India diagnosed with infantile-onset Pompe disease (IOPD). STUDY DESIGN: In this multicenter, cross-sectional study, we evaluated the records of 77 patients with IOPD to analyze their clinical course, outcomes, and factors influencing the outcomes. RESULTS: Of the 77 patients with IOPD, phenotype data were available in 59; 46 (78%) had the classic phenotype. Overall, 58 of 77 (75%) and 19 of 77 (25%) patients were symptomatic before and after age 6 months, respectively. Alpha-glucosidase gene variant analysis available for 48 patients (96 alleles) showed missense variants in 49 alleles. Cross-reactive immunologic material (CRIM) status could be determined or predicted in 44 of 48 patients. In total, 32 of 44 patients (72%) were CRIM-positive, and 12 of 44 patients (27%) were CRIM-negative. Thirty-nine cases received enzyme-replacement therapy (ERT), alglucosidase alfa, and 38 patients never received ERT. Median age at initiation of ERT was 6.5 months. Response to ERT was better in babies who had CRIM-positive, non-classic IOPD. CONCLUSIONS: This study highlights the clinical spectrum of IOPD in India and provides an insight on various factors, such as undernutrition, feeding difficulties, and recurrent respiratory infection, as possible factors influencing clinical outcomes in these patients. The study also reiterates the importance of raising awareness among clinicians about the need for early diagnosis and timely treatment of IOPD.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Edad de Inicio , Estudios Transversales , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/mortalidad , Enfermedad del Almacenamiento de Glucógeno Tipo II/terapia , Humanos , India/epidemiología , Lactante , Recién Nacido , Masculino , Fenotipo , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Maximal inspiratory pressure (PIMAX) reflects inspiratory weakness in late-onset Pompe disease (LOPD). However, static pressure tests may not reveal specific respiratory muscle adaptations to disruptions in breathing. We hypothesized that dynamic respiratory muscle functional tests reflect distinct ventilatory compensations in LOPD. We evaluated LOPD (n = 7) and healthy controls (CON, n = 7) during pulmonary function tests, inspiratory endurance testing, dynamic kinematic MRI of the thorax, and ventilatory adjustments to single-breath inspiratory loads (inspiratory load compensation, ILC). We observed significantly lower static and dynamic respiratory function in LOPD. PIMAX, spirometry, endurance time, and maximal diaphragm descent were significantly correlated. During single-breath inspiratory loads, inspiratory time and airflow acceleration increased to preserve volume, and in LOPD, the response magnitudes correlated to maximal chest wall kinematics. The results indicate that changes in diaphragmatic motor function and strength among LOPD subjects could be detected through dynamic respiratory testing. We concluded that neuromuscular function significantly influenced breathing endurance, timing and loading compensations.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Músculos Respiratorios/fisiopatología , Adulto , Edad de Inicio , Fenómenos Biomecánicos , Estudios de Casos y Controles , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico por imagen , Humanos , Inhalación , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculos Respiratorios/diagnóstico por imagen , Tórax/diagnóstico por imagen , Factores de Tiempo , Adulto JovenRESUMEN
Pathological studies on rodent models and patients with Pompe disease have demonstrated the accumulation of glycogen in spinal motor neurons; however, this finding has rarely been evaluated clinically in patients with Pompe disease. In this study, we analyzed seven patients (age, 7-11 years) with Pompe disease who received long-term enzyme replacement therapy. In addition to traditional myopathy-related clinical and electrophysiological features, these patients often developed bilateral foot drop, distal predominant weakness of four limbs, and hypo- or areflexia with preserved sensory function. Electrophysiological studies showed not only reduced amplitudes of compound muscle action potential, but also absent or impersistent F waves and mixed small and large/giant polyphasic motor unit action potentials with normal sensory study. Muscle biopsy usually showed the existence of angular fingers, fiber type grouping or group atrophy. Taken together, these features support the co-existence of motor neuronopathy additionally to myopathy.