X-linked myotubular myopathy (XLMTM; OMIM 300415) is a neuromuscular disorder pathologically categorized as centronuclear myopathy [1]. MTM1 encodes myotubularin, which is implicated in the phosphatidylinositol 3-kinase pathway and is required for muscle cell growth, differentiation, and intracellular trafficking [2-4]. Newborns affected by XLMTM usually present severe hypotonia and typically require mechanical ventilators and nutritional support [5]. Although long-term survivors depend on a wheelchair, ventilator, and tube feeding, the disease course of XLMTM is relatively stable [1]. The critical roles of a multidisciplinary unit include encouragement of exercise training to maximize patients’ motor function and independence as well as safe maintenance of feeding tubes and home ventilators [6,7]. In a cross-sectional study about a natural history of patients with XLMTM, all observed deaths were associated with respiratory failure [1]. Despite a patient surviving respiratory failure, hypoxic brain damage can cause devastating neurodevelopmental outcomes.

New therapeutic strategies have recently been identified for XLMTM in children, with studies investigating gene transfer (Gene Transfer Clinical Study in X-Linked Myotubular Myopathy, ASPIRO, NCT03199469), an antisense oligonucleotide (ASO) strategy (Early Phase Human Drug Trial to Investigate Dynamin 101 (DYN101) in Patients ≥ 16 Years With Centronuclear Myopathies, Unite-CNM, NCT04033159), and tamoxifen therapy (Tamoxifen Therapy for Myotubular Myopathy, TAM4MTM, NCT04915846). To participate in clinical trials, it is essential to understand the volume and their conditions of domestic patients [8-11]. Data regarding patient characteristics must be shared to allow careful monitoring.

This study is the first to review the clinical characteristics and neurological outcomes, including motor milestones, communication skills, and bulbar and respiratory function, in Korean pediatric patients with XLMTM. To evaluate the neurological consequences of hypoxic events, we described the neurological status of patients with XLMTM divided into the following two subgroups: the hypoxic insults (HI) group and the non-HI group.

This study reported the neurodevelopmental outcomes, including motor function, language skills, and swallowing and respiratory function in patients with XLMTM who were followed up at a single center. Similar to our results (age range, 0.4 to 8.9 years) in a prospective study of 45 patients with XLMTM, patients <10 years (age range, 3.5 months to 56.8 years) presented slow improvements in objective muscle functions [2]. However, older patients with ventilation support for >12 hours per day showed accelerated loss of motor function. Because the aforementioned study covered a wide variation in patient ages, the measurement tools for muscle strength and motor function had been designed to accommodate very weak patients. These tools included grip and pinch strength tests, the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale for patients <2 years of age, the Motor Function Measure scale for patients >2 years of age, the MoviPlate device for upper limb motor function testing, and the North Star Ambulatory Assessment scale for ambulant patients. Pulmonary function tests showed results below the normal range, even in patients without ventilator support. In our study, six patients in the non-HI group required ventilator support for >12 hours per day; therefore, a relatively earlier loss of motor function would be expected in those patients than in the two patients without ventilator support (Table 2).

In our cohort, the leading causes of respiratory failure included T-cannula obstruction, T-cannula omission, or aspiration pneumonia. Because patients with XLMTM are at risk for acute respiratory failure, proper education and techniques, such as chest compression, airway clearance by tracheal suction, T-cannula obstruction response, and Ambu bag ventilation, are essential for the management of respiratory emergencies. Emergencies are more likely to occur at a younger age; thus, close attention is required [13]. Repeated training with time intervals might be helpful.

Genotype-phenotype studies have shown that most pathogenic MTM1 variants, regardless of the mutation type, resulted in loss-of-function effects, leading to the classic and severe phenotype [1,14,15]. Our cohort included all reported pathogenic variants, which were identified as three missense mutations and 10 loss-of-function mutations, including deletion, nonsense, frameshift, and splice-site mutations [16,17]. Additionally, a phosphatase domain in exon 11 is critical for maintaining protein function, but our cases did not include a variant located in the phosphatase domain [14]. In the non-HI group, only one patient (no. 2) with a missense mutation (c.679G>A [p.Val227Met]) walked alone without respiratory assistance, consistent with a mild phenotype. Although patient no. 1 had a frameshift mutation, he presented a mild phenotype. Because the frameshift mutation was located at the end of the MTM1 gene (exon 15), it would be expected to produce a relatively stable protein. All patients assisted with BiPAP had loss-of-function mutations, and the duration of BiPAP support differed among patients. Because patients no. 7 and no. 8 were <1 year of age, the serial follow-up will reveal their maximum motor achievement and amount of ventilator support. The HI group had two missense and two splice-site mutations, and the accordance data did not associate survival with these mutation types [1,14].

In the non-HI group, swallowing and self-respiratory function gradually improved. In two patients, the transition to a complete oral diet was made relatively early, at 5 and 9 months. Some patients gradually tried oral intake in small amounts in childhood. Similarly, except for two patients discharged without a ventilator in the neonatal period, other patients were stable only for a few hours on room air without respiratory support. Complete recovery of swallowing and self-respiratory function was particularly difficult. Nevertheless, even a small amount of oral challenge and attempt at short spontaneous breathing without a ventilator yielded positive effects. The challenges were aimed not at achieving complete normal function but at improving the patients’ quality of life by being able to tasting food and broadening the scope of daily activity. Therefore, it is crucial to encourage rehabilitation for patients.

Multidisciplinary therapeutic approaches are emphasized, including those related to neurology, neonatology, pulmonology, gastroenterology, rehabilitation medicine, and orthopedic surgery [6,7,18,19]. The decision to conduct a diagnostic workup involving a muscle biopsy for infants with hypotonia is sometimes difficult owing to a few factors, including the general anesthesia required for invasive procedures, the risk of respiratory complications, and occasional non-specific results. Except in cases of spinal muscular atrophy, which is routinely diagnosed through genetic investigations without the need for histopathological results, the roles of a muscle biopsy are to classify the specific disease category, help clinicians choose a genetic test, and/or modify a previous diagnosis [20]. Patients with congenital myopathy present a higher concordance rate between biopsy and genetic findings than those with congenital muscular dystrophies and metabolic myopathies. Although the genetic era of neuromuscular diseases has conspicuously developed, muscle biopsy remains a valuable tool guided by rational diagnostic algorithms. Regarding treatment, clinicians should provide proper management during serial follow-up, including routine assessments of skeletal and respiratory muscle function, speech therapy for pronunciation, and the application of devices for independent walking and scoliosis depending on the patients’ ages.

There have been recent moves towards therapeutic strategies [14]. Medical approaches suggested from Mtm1 mull mouce models include phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta (PIK3C2b) inhibition and mammalian target of rapamycin (mTOR) modulation [21,22]. Moreover, in light of proven efficacy in animal models, several clinical trials of gene therapy have been initiated, including gene replacement therapy (ASPIRO, NCT03199469) and ASO-based gene knockdown (Unite-CNM, NCT04033159). The gene transfer study (ASPIRO, NCT03199469) included 26 patients <6 years of age who required mechanical ventilator support. A clinical study of the ASO-based RNA knockdown (Unite-CNM, NCT04033159) is recruiting patients >15 years of age with identified MTM1 or dynamin 2 (DNM2) mutations. The study also has an upcoming plan for children 2 to 16 years of age. Another study, focused on tamoxifen therapy for XLMTM patients (TAM4MTM, NCT04915846), is recruiting patients >1 year of age. Tamoxifen is expected to reduce DNM2 expression, resulting in changes in the triad structure and improvement of muscle contractility [23,24]. To facilitate enrollment in upcoming clinical trials, it is important to collect patients in Korea and evaluate their conditions.

However, this study had several limitations. First, it did not have a substantial degree of variation in age distribution due to the small size of the cohort. Second, data on developmental milestones were retrospectively collected from the descriptive medical records. Third, for an accurate evaluation of motor function improvement and deterioration, it is necessary to adopt measurement scales suitable for each patient’s age.

Patients with XLMTM without HI can be long-term survivors with the slow achievement of motor milestones and bulbar and respiratory function. However, hypoxic brain insults following acute respiratory failure are significant events that negatively influence the developmental potential or even lead to death. Therefore, parental education for proper respiratory management is necessary, especially when children are at a young age.