X-linked myotubular myopathy: A prospective international natural history study

Abstract

Objectives: Because X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disease caused by mutations in the MTM1 gene with a large phenotypic heterogeneity, to ensure clinical trial readiness, it was mandatory to better quantify disease burden and determine best outcome measures.

Methods: We designed an international prospective and longitudinal natural history study in patients with XLMTM and assessed muscle strength and motor and respiratory functions over the first year of follow-up. The humoral immunity against adeno-associated virus serotype 8 was also monitored.

Results: Forty-five male patients aged 3.5 months to 56.8 years were enrolled between May 2014 and May 2017. Thirteen patients had a mild phenotype (no ventilation support), 7 had an intermediate phenotype (ventilation support less than 12 hours a day), and 25 had a severe phenotype (ventilation support 12 or more hours a day). Most strength and motor function assessments could be performed even in very weak patients. Motor Function Measure 32 total score, grip and pinch strengths, and forced vital capacity, forced expiratory volume in the first second of exhalation, and peak cough flow measures discriminated the 3 groups of patients. Disease history revealed motor milestone loss in several patients. Longitudinal data on 37 patients showed that the Motor Function Measure 32 total score significantly decreased by 2%. Of the 38 patients evaluated, anti-adeno-associated virus type 8 neutralizing activity was detected in 26% with 2 patients having an inhibitory titer >1:10.

Conclusions: Our data confirm that XLMTM is slowly progressive for male survivors regardless of their phenotype and provide outcome validation and natural history data that can support clinical development in this population.

Clinicaltrialsgov identifier: NCT02057705.

Figure 1. Patient flowchart and mutations detected in the MTM1 gene

(A) Patient flowchart. Age is expressed in years. (B) Mutations detected in the MTM1 gene. Mutations written in black, light blue, and dark blue correspond to mild, intermediate, and severe phenotype, respectively. Mutations predicted to be linked to reduction or absence of functional protein are indicated in bold (frameshift, nonsense, splicing, in-frame exon deletion, large deletion, and start codon loss). A protein with residual function may be present for missense mutations and in-frame small deletions. Numbers in parentheses are number of patients with the same mutation and phenotype.

Figure 2. Pulmonary function

Pulmonary function in percentage of predicted value for age at baseline and 12-month visit. FEV₁ = forced expiratory volume in the first second of exhalation; FVC = forced vital capacity; MEP = maximum expiratory pressure; MIP = maximum inspiratory pressure; PCF = peak cough flow.

Figure 3. Muscle strength and motor function

(A) Upper limb muscle strength and (B) motor function at baseline and 12-month visit. CHOP-INTEND = Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; MFM = Motor Function Measure; MHFMS = Modified Hammersmith Functional Motor Scale.

Figure 4. Motor milestones

Median ages of acquisition and loss of motor milestones. Ages are expressed in months.