Faculty Collaboration Database

INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy. J Neuromuscul Dis 2022;9(4):503-516

Date

06/14/2022

Pubmed ID

35694931

Pubmed Central ID

PMC9398079

DOI

10.3233/JND-210781

Scopus ID

2-s2.0-85133659377 (requires institutional sign-in at Scopus site)   16 Citations

Abstract

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.

Author List

Dowling JJ, Müller-Felber W, Smith BK, Bönnemann CG, Kuntz NL, Muntoni F, Servais L, Alfano LN, Beggs AH, Bilder DA, Blaschek A, Duong T, Graham RJ, Jain M, Lawlor MW, Lee J, Coats J, Lilien C, Lowes LP, MacBean V, Neuhaus S, Noursalehi M, Pitts T, Finlay C, Christensen S, Rafferty G, Seferian AM, Tsuchiya E, James ES, Miller W, Sepulveda B, Vila MC, Prasad S, Rico S, Shieh PB, INCEPTUS investigators

Author

Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Child, Preschool
Genetic Therapy
Humans
Longitudinal Studies
Male
Myopathies, Structural, Congenital
Prospective Studies
Quality of Life