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.).

Posttransplant Hodgkin lymphoma preceded by polymorphic posttransplant lymphoproliferative disorder: report of a pediatric case and review of the literature.

Epstein-Barr virus-mediated posttransplant lymphoproliferative disorder (PTLD) is a well-recognized complication of immunosuppression in transplant patients and has broad clinical manifestations and pathologic features ranging from reactive lymphoid proliferation to malignant lymphoma. The category of Hodgkin lymphoma and Hodgkin lymphomalike PTLD is an uncommon variant of PTLD. Development of Hodgkin lymphoma subsequent to other subtypes of PTLD in the same patient is even more unusual, especially in pediatric patients. In this report, we describe a pediatric case of Epstein-Barr virus-associated posttransplant Hodgkin lymphoma developing several years after the patient was diagnosed with polymorphic PTLD and review the literature of the previously reported cases in children to further help characterize the clinical features, histopathologic appearances, biology, and treatment strategies of this uncommon entity.

Videofluoroscopic swallow studies in unilateral cricopharyngeal dysfunction.

OBJECTIVES/HYPOTHESIS: Although the cricopharyngeus muscle is a ring-like structure, unilateral cricopharyngeal dysfunction can produce significant dysphagia. This entity has not been well described in the literature. The aims of the study were to identify the characteristic findings on videofluoroscopic swallow studies in patients with dysphagia secondary to unilateral cricopharyngeal dysfunction, to note the associated vagal nerve injury, and to evaluate patient outcomes following ipsilateral cricopharyngeal myotomy. STUDY DESIGN: Retrospective clinical investigation. METHODS: The clinic charts, electromyographic tests, videostroboscopic examinations, and videofluoroscopic swallow studies were reviewed from a series of patients who presented to our institution from 1993 to 2001 with dysphagia and findings on videofluoroscopic swallow studies suggestive of unilateral cricopharyngeal dysfunction on posterior-anterior view. In patients treated with ipsilateral cricopharyngeal myotomy, postoperative findings on swallow studies and patient outcomes were also reviewed. RESULTS: Eighteen patients demonstrated findings characteristic of unilateral cricopharyngeal muscle dysfunction on videofluoroscopic swallow study. The common feature was a unilateral shelf-like barrier at the cricopharyngeus on the posterior-anterior view with pooling of liquid bolus in the ipsilateral pyriform sinus and episodic shunting to the contralateral side. Eight patients did not have evidence of cricopharyngeal dysfunction (ie, cricopharyngeal bar) on lateral films. Of the 18 patients, 14 had histories consistent with vagal injury secondary to trauma (n = 2), neoplastic involvement (n = 7), iatrogenic injury (n = 2), or central nervous system disease (n = 3). Results of videostroboscopic examinations demonstrated vocal fold motion impairment in 14 patients, and electromyographic test results confirmed unilateral vagal injuries in those who underwent electromyographic testing (n = 6). In the remaining 4 of 18 patients, videostroboscopic examinations demonstrated normal vocal fold abduction but impaired lengthening with a posterior glottic gap, and electromyographic test results (n = 4) indicated unilateral superior laryngeal nerve involvement. Of the 15 patients treated with ipsilateral cricopharyngeal myotomy, 1 patient required postoperative esophageal dilations for an esophageal stricture distal to the cricopharyngeus, whereas the remaining 14 patients had functional resolution of their dysphagia. CONCLUSION: In patients presenting with dysphagia and evidence of unilateral vagal injury, careful assessment of posterior-anterior view on videofluoroscopic swallow study should be included to evaluate for unilateral cricopharyngeal dysfunction.

Morphology of the cricopharyngeal muscle in Zenker and control specimens.

The cricopharyngeal muscle (CPM) is essential for normal deglutition. Pharyngeal dysphagia commonly results from impaired or uncoordinated CPM dilation. Dysfunction of the CPM has also been implicated in the genesis of Zenker's (pharyngoesophageal) diverticulum. Despite the CPM's significance, little is understood about its morphology. We studied CPM biopsy specimens from 20 patients with Zenker's diverticulum and from 5 fresh cadaver patients with detailed histologic techniques to include fiber size and shape and adenosine triphosphatase, reduced nicotinamide adenine dinucleotide, trichrome, succinate dehydrogenase, cytochrome C oxidase, periodic acid-Schiff reaction, oil red O, acid phosphatase, Congo red, crystal violet, and monoadenylate deaminase stains. The normal CPM has unique morphological characteristics, with some myofibers having staining properties that are a hybrid between striated muscle and muscle spindle. The variable orientation of the muscle fibers is also different from that of most other striated musculature. Of the 20 Zenker CPM specimens, 4 specimens did not reveal any significant differences from controls (2 of which had insufficient amounts of tissue for complete analysis). In the remaining 16 specimens, several abnormalities existed, including excessive size variation (16/16), grouping of atrophic fibers (9/16), target or targetoid formations (4/16), cores (2/16), and ragged red fibers (2/16). The final pathological pattern of the 16 specimens was neurogenic in 7, myopathic in 4, and mixed (with neurogenic predominance) in the remaining 5. Two specimens contained significant lymphocytic inflammatory infiltrates. We conclude that the unique neuromuscular function of the CPM in deglutition is likely due to its fiber orientation and the hybrid nature of some of the myofibers. Morphological disturbances of the CPM impair its dilation and may account for the development of Zenker's diverticulum. This disturbance is most often due to progressive denervation of the CPM.