Longitudinal changes of swallowing safety and efficiency in infants with spinal muscular atrophy who received disease modifying therapies.

BACKGROUND: Dysphagia is a common feature of the natural history of patients with spinal muscular atrophy (SMA). Literature regarding swallowing safety and efficiency is scarce in patients with SMA, particularly in the era of newborn screening programs and disease-modifying therapies. OBJECTIVE: To describe the longitudinal changes of swallowing safety and efficiency in children with SMA who received one or more disease modifying therapies METHODS: Case series of patients with SMA followed at the University of Florida from 1 May 2019 to 31 December 2022 who had two or more videofluoroscopy swallowing studies (VFSS), with the first being within 30 days of their first treatment. Data extracted from the electronic health record included: neuromotor outcomes, VFSS penetration aspiration scores (PAS), presence of abrnormal oral or pharyngeal residue, clinical history, and timing of disease-modifying therapies administration. RESULTS: Seven subjects were included (five male); three were diagnosed via newborn screen. Median age at diagnosis was 10 days (range: 4-250). Median age at initial VFSS was 29 days (range: 9-246), and age at the last VFSS was 26.1 months (range: 18.2-36.2). All subjects received onasemnogene-abeparvovec (OA); four received additional therapies. PAS at diagnosis was abnormal in four subjects. Six subjects required feeding modifications after VFSS results. Of these, three had silent aspiration (PAS 8) and three of them improved after treatment. CONCLUSIONS: Swallowing safety and efficiency can be impaired in patients with SMA despite early treatment. Larger, prospective studies are needed to define optimal timiing of longitudinal instrumental evaluations.

Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated. METHODS: Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed. FINDINGS: Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants. INTERPRETATION: Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study. FUNDING: Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).

Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial.

BACKGROUND: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1. METHODS: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated. FINDINGS: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure). INTERPRETATION: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing. FUNDING: Astellas Gene Therapies.

Diaphragm pacing and independent breathing in individuals with severe Pompe disease.

Introduction: Pompe disease is an inherited disease characterized by a deficit in acid-α-glucosidase (GAA), an enzyme which degrades lysosomal glycogen. The phrenic-diaphragm motor system is affected preferentially, and respiratory failure often occurs despite GAA enzyme replacement therapy. We hypothesized that the continued use of diaphragm pacing (DP) might improve ventilator-dependent subjects' respiratory outcomes and increase ventilator-free time tolerance. Methods: Six patients (3 pediatric) underwent clinical DP implantation and started diaphragm conditioning, which involved progressively longer periods of daily, low intensity stimulation. Longitudinal respiratory breathing pattern, diaphragm electromyography, and pulmonary function tests were completed when possible, to assess feasibility of use, as well as diaphragm and ventilatory responses to conditioning. Results: All subjects were eventually able to undergo full-time conditioning via DP and increase their maximal tolerated time off-ventilator, when compared to pre-implant function. Over time, 3 of 6 subjects also demonstrated increased or stable minute ventilation throughout the day, without positive-pressure ventilation assistance. Discussion: Respiratory insufficiency is one of the main causes of death in patients with Pompe disease. Our results indicate that DP in Pompe disease was feasible, led to few adverse events and stabilized breathing for up to 7 years.

Intraoperative Hemi-Diaphragm Electrical Stimulation Demonstrates Attenuated Mitochondrial Function without Change in Oxidative Stress in Cardiothoracic Surgery Patients.

Mechanical ventilation during cardiothoracic surgery is life-saving but can lead to ventilator-induced diaphragm dysfunction (VIDD) and prolong ventilator weaning and hospital length of stay. Intraoperative phrenic nerve stimulation may preserve diaphragm force production to offset VIDD; we also investigated changes in mitochondrial function after stimulation. During cardiothoracic surgeries (n = 21), supramaximal, unilateral phrenic nerve stimulation was performed every 30 min for 1 min. Diaphragm biopsies were collected after the last stimulation and analyzed for mitochondrial respiration in permeabilized fibers and protein expression and enzymatic activity of biomarkers of oxidative stress and mitophagy. Patients received, on average, 6.2 ± 1.9 stimulation bouts. Stimulated hemidiaphragms showed lower leak respiration, maximum electron transport system (ETS) capacities, oxidative phosphorylation (OXPHOS), and spare capacity compared with unstimulated sides. There were no significant differences between mitochondrial enzyme activities and oxidative stress and mitophagy protein expression levels. Intraoperative phrenic nerve electrical stimulation led to an acute decrease of mitochondrial respiration in the stimulated hemidiaphragm, without differences in biomarkers of mitophagy or oxidative stress. Future studies warrant investigating optimal stimulation doses and testing post-operative chronic stimulation effects on weaning from the ventilator and rehabilitation outcomes.

Respiratory therapies for Amyotrophic Lateral Sclerosis: A state of the art review.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition noteworthy for upper and lower motor neuron death. Involvement of respiratory motor neuron pools leads to progressive pathology. These impairments include decreases in neural activation and muscle coordination, progressive airway obstruction, weakened airway defenses, restrictive lung disease, increased risk of pulmonary infections, and weakness and atrophy of respiratory muscles. These neural, airway, pulmonary, and neuromuscular changes deteriorate integrated respiratory-related functions including sleep, cough, swallowing, and breathing. Ultimately, respiratory complications account for a large portion of morbidity and mortality in ALS. This state-of-the-art review highlights applications of respiratory therapies for ALS, including lung volume recruitment, mechanical insufflation-exsufflation, non-invasive ventilation, and respiratory strength training. Therapeutic acute intermittent hypoxia, an emerging therapeutic tool for inducing respiratory plasticity will also be introduced. A focus on emerging evidence and future work underscores the common goal to continue to improve survival for patients living with ALS.

Polysomnography findings in children with spinal muscular atrophy after onasemnogene-abeparvovec.

BACKGROUND: Sleep disordered breathing (SDB) is common in patients with neuromuscular diseases, including spinal muscular atrophy (SMA). While polysomnography (PSG) findings have been described in natural history studies of patients with SMA, reports regarding PSG in treated children are limited to nusinersen. We aim to describe the sleep characteristics in a cohort of children treated with Onasemnogene-abeparvovec. METHODS: We conducted a cross-sectional cohort study of children with SMA followed at the University of Florida Center for neuromuscular and rare diseases and had a diagnostic or split night PSG after SMA treatment. RESULTS: Eight children were included in the cohort (four female), aged 5-250 days at diagnosis. Five children had two survival motor neuron 2 (SMN2) copies, two had three SMN2 copies and one subject had four SMN2 copies. Median age at the time of treatment was 46.5 days (range 20-257). All children received onasemnogene-abeparvovec (OA) before their PSG; in addition to OA, one received nusinersen and one received risdiplam. Apnea hypopnea index (AHI) ranged from 3.6 to 24.1/h. REM AHI was higher than NREM AHI. Median Children's Hospital of Philadelphia Infant test of neuromuscular disorders (CHOP-Intend) score at the time of PSG was 55 (range 33-64). There was no correlation between age at treatment, CHOP-Intend score and AHI. CONCLUSION: SDB is common in treated children with SMA, regardless of age at diagnosis, treatment and neuromotor scores. While AHI may not be the only indicator of SDB in this population, indications, timing of PSG in this cohort remain unknown.

Predictors of Peak Expiratory Cough Flow in Individuals with Amyotrophic Lateral Sclerosis.

Dystussia is prevalent in individuals with amyotrophic lateral sclerosis (ALS), leading to a diminished physiologic capacity to effectively defend the airway. We aimed to identify predictors of peak expiratory cough flow rate in individuals with ALS. One hundred and thirty-four individuals with a confirmed diagnosis of ALS (El-Escorial criteria revised) completed the ALS Functional Rating Scale-Revised (ALSFRS-R) and underwent pulmonary function and cough spirometry testing. Pearson's correlation coefficients and hierarchical multiple regression modeling were conducted to determine predictors of voluntary cough peak expiratory flow rate (p < 0.05). The full model including age, bulbar disease, cough spirometry metrics, and respiratory parameters had a marginal R2 = 0.635, F (7, 126) = 30.241, p < 0.0005, adjusted R2 = 0.61. Maximum expiratory pressure, compression phase, and vital capacity did not contribute and were therefore removed (p < 0.05). The most parsimonious predictive model included age, bulbar disease, peak inspiratory flow rate and duration, peak expiratory rise time, and inspiratory pressure generation with a marginal R2 = 0.543. Although expiratory pressure generation has historically served as the therapeutic target to improve dystussia in ALS, the current dataset highlighted that the inability to quickly and forcefully inspire during the inspiratory phase of voluntary cough places patients at a mechanical disadvantage to generate subsequent high-velocity expiratory airflow to clear the airway. Thus, therapeutic training programs that include both inspiratory and expiratory strength targets may optimize airway clearance capacity in this challenging patient population.

Effect of Test Interface on Respiratory Muscle Activity and Pulmonary Function During Respiratory Testing in Healthy Adults: A Pilot Study.

Purpose: The mouthpiece is the standard interface for spirometry tests. Although the use of a mouthpiece can be challenging for patients with orofacial weakness, maintaining a proper seal with a facemask can be an issue for healthy individuals during forceful efforts. We compared respiratory muscle activity and tests using a mouthpiece and facemask in healthy adults to investigate whether they can be used interchangeably. Methods: In this observational study, subjects (n=12) completed forced vital capacity, maximal respiratory pressure, and peak cough flow with a mouthpiece and facemask. Root mean square values of the genioglossus, diaphragm, scalene, and sternocleidomastoid were compared between conditions. Results: When switching from a mouthpiece to a facemask, significantly higher values were seen for peak cough flow (average bias= -54.36 L/min, p<0.05) and the difference seen with MEP and MIP were clinically significant (average bias: MEP=27.33, MIP=-5.2). Additionally, submental activity was significantly greater when MIP was conducted with a mouthpiece. No significant differences were seen in respiratory muscle activity during resting breathing or spirometry. Conclusion: There are clinically significant differences with cough and MEP tests and neck muscles are activated differently based on interface. Considering the small sample size, our findings suggest a facemask may be used to complete some PFTs.

Exploring inspiratory occlusion metrics to assess respiratory drive in patients under acute intermittent hypoxia.

Patients living with Amyotrophic Lateral Sclerosis (ALS) experience respiratory weakness and, eventually, failure due to inspiratory motor neuron degeneration. Routine pulmonary function tests (e.g., maximum inspiratory pressure (MIP)) are used to assess disease progression and ventilatory compromise. However, these tests are poor discriminators between respiratory drive and voluntary respiratory function at rest. To better understand ALS disease progression, we can look into compensatory strategies and how patients consciously react to the occlusion and the effort produced to meet the ventilatory challenge of the occlusion. This ventilatory challenge, especially beyond the P0.1 (200 ms and 300 ms), provides information regarding the patient's ability to recruit additional respiratory muscles as a compensatory strategy. Utilizing a standard P0.1 protocol to assess respiratory drive, we extend the occlusion time analysis to 200 ms and 300 ms (Detected Occlusion Response (DOR)) in order to capture compensatory respiratory mechanics. Furthermore, we followed an Acute Intermittent Hypoxia (AIH) protocol known to increase phrenic nerve discharge to evaluate the compensatory strategies. Inspiratory pressure, the rate of change in pressure, and pressure generation normalized to MIP were measured at 100 ms, 200 ms, and 300 ms after an occlusion. Airway occlusions were performed three times during the experiment (i.e., baseline, 30 and 60 minutes post-AIH). Results indicated that while AIH did not elicit change in the P0.1 or MIP, the DOR increased for ALS patients. These results support the expected therapeutic role of AIH and indicate the potential of the DOR as a metric to detect compensatory changes.

INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death. OBJECTIVE: We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study. METHODS: Thirty-four participants < 4 years old with XLMTM and receiving ventilator support enrolled in INCEPTUS, a prospective, multicenter, non-interventional study. Disease-related adverse events, respiratory and motor function, feeding, secretions, and quality of life were assessed. RESULTS: During median (range) follow-up of 13.0 (0.5, 32.9) months, there were 3 deaths (aspiration pneumonia; cardiopulmonary failure; hepatic hemorrhage with peliosis) and 61 serious disease-related events in 20 (59%) participants, mostly respiratory (52 events, 18 participants). Most participants (80%) required permanent invasive ventilation (>16 hours/day); 20% required non-invasive support (6-16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19-52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort. CONCLUSIONS: INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.

Acute intermittent hypoxia and respiratory muscle recruitment in people with amyotrophic lateral sclerosis: A preliminary study.

Respiratory failure is the main cause of death in amyotrophic lateral sclerosis (ALS). Since no effective treatments to preserve independent breathing are available, there is a critical need for new therapies to preserve or restore breathing ability. Since acute intermittent hypoxia (AIH) elicits spinal respiratory motor plasticity in rodent ALS models, and may restore breathing ability in people with ALS, we performed a proof-of-principle study to investigate this possibility in ALS patients. Quiet breathing, sniff nasal inspiratory pressure (SNIP) and maximal inspiratory pressure (MIP) were tested in 13 persons with ALS and 10 age-matched controls, before and 60 min post-AIH (15, 1 min episodes of 10% O2, 2 min normoxic intervals) or sham AIH (continuous normoxia). The root mean square (RMS) of the right and left diaphragm, 2nd parasternal, scalene and sternocleidomastoid muscles were monitored. A vector analysis was used to calculate summated vector magnitude (Mag) and similarity index (SI) of collective EMG activity during quiet breathing, SNIP and MIP maneuvers. AIH facilitated tidal volume and minute ventilation (treatment main effects: p < 0.05), and Mag (ie. collective respiratory muscle activity; p < 0.001) during quiet breathing in ALS and control subjects, but there was no effect on SI during quiet breathing. SNIP SI decreased in both groups post-AIH (p < 0.005), whereas Mag was unchanged (p = 0.09). No differences were observed in SNIP or MIP post AIH in either group. Discomfort was not reported during AIH by any subject, nor were adverse events observed. Thus, AIH may be a safe way to increase collective inspiratory muscle activity during quiet breathing in ALS patients, although a single AIH presentation was not sufficient to significantly increase peak inspiratory pressure generation. These preliminary results provide evidence that AIH may improve breathing function in people with ALS, and that future studies of prolonged, repetitive AIH protocols are warranted.

Characterizing Expiratory Respiratory Muscle Degeneration in Duchenne Muscular Dystrophy Using MRI.

BACKGROUND: Expiratory muscle weakness and impaired airway clearance are early signs of respiratory dysfunction in Duchenne muscular dystrophy (DMD), a degenerative muscle disorder in which muscle cells are damaged and replaced by fibrofatty tissue. Little is known about expiratory muscle pathology and its relationship to cough and airway clearance capacity; however, the level of muscle replacement by fat can be estimated using MRI and expressed as a fat fraction (FF). RESEARCH QUESTION: How does abdominal expiratory muscle fatty infiltration change over time in DMD and relate to clinical expiratory function? STUDY DESIGN AND METHODS: Individuals with DMD underwent longitudinal MRI of the abdomen to determine FF in the internal oblique, external oblique, and rectus abdominis expiratory muscles. FF data were used to estimate a model of expiratory muscle degeneration by using nonlinear mixed effects and a cumulative distribution function. FVC, maximal inspiratory and expiratory pressures, and peak cough flow were collected as clinical correlates to MRI. RESULTS: Forty individuals with DMD (aged 6-18 years at baseline) participated in up to five visits over 36 months. Modeling estimated the internal oblique progresses most quickly and reached 50% replacement by fat at a mean patient age of 13.0 years (external oblique, 14.0 years; rectus abdominis, 16.2 years). Corticosteroid-untreated individuals (n = 4) reached 50% muscle replacement by fat 3 to 4 years prior to treated individuals. Individuals with mild clinical dystrophic phenotypes (n = 3) reached 50% muscle replacement by fat 4 to 5 years later than corticosteroid-treated individuals. Internal and external oblique FFs near 50% were associated with maximal expiratory pressures < 60 cm H2O and peak cough flows < 270 L/min. INTERPRETATION: These data improve understanding of the early phase of respiratory compromise in DMD, which typically presents as airway clearance dysfunction prior to the onset of hypoventilation, and links expiratory muscle fatty infiltration to pulmonary function measures.

Case Studies in Neuroscience: Neuropathology and diaphragm dysfunction in ventilatory failure from late-onset Pompe disease.

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.

Dynamic respiratory muscle function in late-onset Pompe disease.

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.

Pompe disease gene therapy: neural manifestations require consideration of CNS directed therapy.

Pompe disease is a neuromuscular disease caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase leading to lysosomal and cytoplasmic glycogen accumulation in neurons and striated muscle. In the decade since availability of first-generation enzyme replacement therapy (ERT) a better understanding of the clinical spectrum of disease has emerged. The most severe form of early onset disease is typically identified with symptoms in the first year of life, known as infantile-onset Pompe disease (IOPD). Infants are described at floppy babies with cardiac hypertrophy in the first few months of life. A milder form with late onset (LOPD) of symptoms is mostly free of cardiac involvement with slower rate of progression. Glycogen accumulation in the CNS and skeletal muscle is observed in both IOPD and LOPD. In both circumstances, multi-system disease (principally motoneuron and myopathy) leads to progressive weakness with associated respiratory and feeding difficulty. In IOPD the untreated natural history leads to cardiorespiratory failure and death in the first year of life. In the current era of ERT clinical outcomes are improved, yet, many patients have an incomplete response and a substantial unmet need remains. Since the neurological manifestations of the disease are not amenable to peripheral enzyme replacement, we set out to better understand the pathophysiology and potential for treatment of disease manifestations using adeno-associated virus (AAV)-mediated gene transfer, with the first clinical gene therapy studies initiated by our group in 2006. This review focuses on the preclinical studies and clinical study findings which are pertinent to the development of a comprehensive gene therapy strategy for both IOPD and LOPD. Given the advent of newborn screening, a significant focus of our recent work has been to establish the basis for repeat administration of AAV vectors to enhance neuromuscular therapeutic efficacy over the life span.

Imaging respiratory muscle quality and function in Duchenne muscular dystrophy.

OBJECTIVE: Duchenne muscular dystrophy (DMD) is characterized by damage to muscles including the muscles involved in respiration. Dystrophic muscles become weak and infiltrated with fatty tissue, resulting in progressive respiratory impairment. The objective of this study was to assess respiratory muscle quality and function in DMD using magnetic resonance imaging and to determine the relationship to clinical respiratory function. METHODS: Individuals with DMD (n = 36) and unaffected controls (n = 12) participated in this cross sectional magnetic resonance imaging study. Participants underwent dynamic imaging of the thorax to assess diaphragm and chest wall mobility and chemical shift-encoded imaging of the chest and abdomen to determine fatty infiltration of the accessory respiratory muscles. Additionally, clinical pulmonary function measures were obtained. RESULTS: Thoracic cavity area was decreased in individuals with DMD compared to controls during tidal and maximal breathing. Individuals with DMD had reduced chest wall movement in the anterior-posterior direction during maximal inspirations and expirations, but diaphragm descent during maximal inspirations (normalized to height) was only decreased in a subset of individuals with maximal inspiratory pressures less than 60% predicted. Muscle fat fraction was elevated in all three expiratory muscles assessed (p < 0.001), and the degree of fatty infiltration correlated with percent predicted maximal expiratory pressures (r = - 0.70, p < 0.001). The intercostal muscles demonstrated minimal visible fatty infiltration; however, this analysis was qualitative and resolution limited. INTERPRETATION: This magnetic resonance imaging investigation of diaphragm movement, chest wall movement, and accessory respiratory muscle fatty infiltration provides new insights into the relationship between disease progression and clinical respiratory function.