A natural history study of X-linked myotubular myopathy

Abstract

Objective: To define the natural history of X-linked myotubular myopathy (MTM).

Methods: We performed a cross-sectional study that included an online survey (n = 35) and a prospective, 1-year longitudinal investigation using a phone survey (n = 33).

Results: We ascertained data from 50 male patients with MTM and performed longitudinal assessments on 33 affected individuals. Consistent with existing knowledge, we found that MTM is a disorder associated with extensive morbidities, including wheelchair (86.7% nonambulant) and ventilator (75% requiring >16 hours of support) dependence. However, unlike previous reports and despite the high burden of disease, mortality was lower than anticipated (approximate rate 10%/y). Seventy-six percent of patients with MTM enrolled (mean age 10 years 11 months) were alive at the end of the study. Nearly all deaths in the study were associated with respiratory failure. In addition, the disease course was more stable than expected, with few adverse events reported during the prospective survey. Few non-muscle-related morbidities were identified, although an unexpectedly high incidence of learning disability (43%) was noted. Conversely, MTM was associated with substantial burdens on patient and caregiver daily living, reflected by missed days of school and lost workdays.

Conclusions: MTM is one of the most severe neuromuscular disorders, with affected individuals requiring extensive mechanical interventions for survival. However, among study participants, the disease course was more stable than predicted, with more individuals surviving infancy and early childhood. These data reflect the disease burden of MTM but offer hope in terms of future therapeutic intervention.

Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Survival and burden of disease in an MTM cohort

(A) Survival of participants over the course of the study. For those who died, age and cause of death are summarized in the table to the right of the graph. Twelve of 50 patients in our cohort were deceased, and the average age at death was 6 years 10 months. Note that 3 died during the longitudinal study, including 1 individual who died 2 months after survey completion. (B) Burden of disease (respiratory, feeding, and ambulation support requirements). Breakdown of technology support required, including wheelchair dependence, feeding tube, and ventilation. Forty-eight of 50 patients with MTM had some technology dependence, and 37 of 48 were wheelchair, ventilator, and tube feed dependent. (C) Change in respiratory status during the 1-year longitudinal survey (listed as percent of the total cohort, n = 33). The majority of individuals had either no change or small fluctuations in support. Small fluctuations were defined as 1 or 2 increases or decreases in time on ventilation that lasted

Figure 2. Perinatal evaluation score (PES) and neonatal respiratory support in relation to patient outcome

(A) Breakdown of PES and patient outcome. PES was defined by McEntagart et al. Individuals with scores for at least 4 of the 6 PES factors were included. Most individuals in our cohort were in the severe or moderate categories for PES (PES

Figure 3. Genotype–phenotype correlations

Genetic testing results were available for 35 individuals. Twenty-seven unique mutations were identified. For genotype–phenotype assessment, mutations were categorized as nonsense (n = 17), missense (n = 10), or splice site (n = 8). Of note, 1 recurrent missense mutation (R69C in the PH-GRAM domain) has been shown to alter splicing (Pierson et al.). (A) Mutation type and location. Mutations in MTM1 were found throughout the gene, and there was no obvious clustering in sections of the MTM1 gene coding for the known functional domains. Protein domain locations were defined by Laporte et al. (B) Mutation type and location in relationship to respiratory requirement. Because nearly all individuals required ventilatory support, there was no clear correlation between ventilation and mutation type, although a higher proportion of individuals with missense mutations did not need invasive support (4 of 10 missense on noninvasive support vs 0 of 17 nonsense and 1 of 8 splice site). (C) Mutation location and motor function. Other than 1 individual with a nonsense mutation, only individuals with missense mutations achieved the ability to ambulate independently (3 of 10).

Figure 4. Hospitalizations and surgeries during a 1-year prospective study of myotubular myopathy

We tracked hospital visits (ER and admissions) and surgeries during our 1-year prospective analysis. Twenty-four of 33 individuals in the study required at least 1 of these services (pie chart, top left). There were 38 ER visits (pie chart, top right, listed by chief complaint), with fever and infection the most common reasons. Infections included pneumonia, pseudomonas, enterovirus, and rhinovirus. aRespiratory issues included respiratory distress, lung collapse, and high CO2 levels. bEquipment issues included ventilator malfunction, mucous plugs, and leaky gastrostomy tubes. cOther reasons for ER visits included drug allergy, power chair accident, postsurgical hip pain, and inability to urinate. There were 13 emergent hospitalizations (i.e., not scheduled or elective admissions), with infection the overwhelmingly most common reason for admission (pie chart, bottom right). There were 27 elective surgical procedures reported, with ear tube placement (i.e., myringotomy tube placement) the most common surgery. ER = emergency room.