Mortality and respiratory support in X-linked myotubular myopathy: a RECENSUS retrospective analysis

Abstract

Purpose Individuals with X-linked myotubular myopathy (XLMTM) who survive infancy require extensive supportive care, including ventilator assistance, wheelchairs and feeding tubes. Half die before 18 months of age. We explored respiratory support and associated mortality risk in RECENSUS, particularly among patients ≤5 years old who received respiratory support at birth; this subgroup closely matches patients in the ASPIRO trial of gene therapy for XLMTM. Design RECENSUS is an international, retrospective study of patients with XLMTM. Descriptive and timeto-event analyses examined survival on the basis of age, respiratory support, tracheostomy use, predicted mutational effects and life-sustaining care. Results Outcomes for 145 patients were evaluated. Among 126 patients with respiratory support at birth, mortality was 47% overall and 59% among those ≤5 years old. Median survival time was shorter for patients ≤5 years old than for those >5 years old (2.2 years (IQR 0.7-5.6) vs 30.2 years (IQR 19.4-30.2)). The most common cause of death was respiratory failure (66.7%). Median survival time was longer for patients with a tracheostomy than for those without (22.8 years (IQR 8.7-30.2) vs 1.8 years (IQR 0.2-not estimable)). The proportion of patients living without a tracheostomy was 50% at age 6 months and 28% at age 2 years. Median survival time was longer with provision of life-sustaining care than without (19.4 years (IQR 3.1-not estimable) vs 0.2 years (IQR 0.1-2.1)). Conclusions High mortality, principally due to respiratory failure, among patients with XLMTM ≤5 years old despite respiratory support underscores the need for early diagnosis, informed decision-making and diseasemodifying therapies. Trial registration number NCT02231697

Hierarchical Bayesian modelling of disease progression to inform clinical trial design in centronuclear myopathy

“…Patients who survive beyond the neonatal period live with a high disease burden: a majority require the use of a wheelchair, feeding tube, and ventilation support. Additionally, respiratory function is also altered in patients who do not need ventilator support and respiratory complications are the most frequent cause of death [ 29 , 30 ]. Despite their rarity and their heterogeneous genotype and phenotype, CNMs are currently the targets of several clinical and pre-clinical development efforts that make them a paradigm for the need of alternative statistical strategies in clinical trials [ 31 ].…”

Current Genetic Survey and Potential Gene-Targeting Therapeutics for Neuromuscular Diseases

“…A member of centronuclear myopathy, XLMTM is a rare form of NMD that presents with myopathy, hypotonia [ 77 ], respiratory distress [ 78 ] and when involving the respiratory muscles is accompanied by high mortality (around 47%) [ 79 ]. Mutation in the active site of tyrosine phosphatase myotubularin-encoding gene (MTM1 ) results in pathological features such as a smallness of myofibers, centrally nucleated myofibers mislocation organelles [ 80 ], and ultimately the phenotype of muscle fiber disorganization [ 81 ].…”

“…Mutation in the active site of tyrosine phosphatase myotubularin-encoding gene (MTM1 ) results in pathological features such as a smallness of myofibers, centrally nucleated myofibers mislocation organelles [ 80 ], and ultimately the phenotype of muscle fiber disorganization [ 81 ]. XLMTM predominantly affects males with 25% of boys dying in their first year [ 77 ] and others who survive often requiring extensive supportive care such as a ventilator [ 79 ].…”

The genetic crystal ball: new answers and new questions for infants with neuromuscular disorders and respiratory failure

“…The RECENSUS Study, a portion of which is published in this journal, provides extremely valuable data that will help clinicians and parents answer some of the important questions that they are likely to face following diagnosis of XLMTM 3. This multicentre, international study, reports retrospectively gathered data on mortality and respiratory support for the largest ever published cohort of infants with XLMTM (n=145) from eight different sites in USA, Europe, Canada, South America and Australia.…”

“…There are multiple different agents and strategies currently being developed or in the early stages of evaluation. Preliminary reports from the first nine patients treated with an adenovirus vector-based gene therapy for XLMTM apparently indicate improvements in muscle strength and respiratory function—including some patients being weaned off respiratory support 3. These reports (which have been publicised, but not yet published in a peer-reviewed journal) raise the tantalising prospect that the outcome for new patients with XLMTM will be much better than in historical cohorts like RECENSUS.…”