X-linked myotubular myopathy (XLMTM) is a rare condition of centronuclear myopathy caused by myotubularin 1 (
Patients diagnosed with centronuclear myopathy by muscle pathology and
All 13 patients were severely affected by neonatal hypotonia and required respiratory support and a feeding tube during the neonatal period. The follow-up duration was 4.4 years (range, 0.3 to 8.9). In the non-HI group, developmental milestones were delayed but were slowly achieved. Some patients underwent training in oral feeding with thickened foods and weaning from ventilation. Patients with HI showed poor motor function catch-up and communication skills. Three deaths were associated with acute respiratory failure.
Patients with XLMTM without HI can survive long-term with the slow achievement of motor milestones and bulbar and respiratory function. However, hypoxic brain damage following acute respiratory failure negatively influences their developmental potential or even lead to death. Therefore, parental education for proper respiratory management is necessary, especially for young children.
X-linked myotubular myopathy (XLMTM; OMIM 300415) is a neuromuscular disorder pathologically categorized as centronuclear myopathy [
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 [
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.
Male patients with a confirmed muscle biopsy result consistent with centronuclear myopathy and an
The median age of the 13 patients was 4.4 years (range, 0.3 to 8.9). Muscle biopsies were performed at a median age of 3.7 months (range, 0.9 to 11.3). All patients presented with neonatal hypotonia (
Among the 13 patients,
Eight patients (61.5%) in the non-HI group and five (38.5%) in the HI group had different neurodevelopmental outcomes in terms of maximum performance of motor and language function (
All patients received nutritional support through a nasogastric tube after birth. Percutaneous endoscopic gastrostomy (PEG) was performed on five patients (38.5%) at a median age of 2.4 years (range, 0.3 to 4.6). According to a videofluoroscopic swallow study, some patients underwent a challenge with oral feeding with thickened food. Two patients in the non-HI group were able to switch to full oral feeding. Both survivors in the HI group underwent PEG after revealing hypoxic brain insults.
Eight patients (61.5%) underwent tracheostomy at a median age of 3.8 months (range, 1.6 to 11.5) and in them prolonged intubation was maintained due to failure of ventilator weaning and airway protection from respiratory emergencies was required [
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 [
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 [
Genotype-phenotype studies have shown that most pathogenic
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 [
There have been recent moves towards therapeutic strategies [
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.
Anna Cho, Ki Joong Kim and Jong-Hee Chae are the editorial board members of the journal, but They was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Conceptualization: WJK, SYK, AC, and JHC. Data curation: HW, SL, and JYH. Formal analysis: HW. Methodology: WJK, MJK, MWS, and JHC. Project administration: HW and JHC. Visualization: HW, SYK, and AC. Writing-original draft: HW. Writing-review & editing: BCL, KJK, and JHC.
Clinical features of patients with XLMTM (n=13)
Variable | Value |
---|---|
Prenatal and postnatal features | |
Polyhydramnios or poor fetal movement | 5 (38.5) |
Preterm birth | 9 (69.2) |
Birth asphyxia | 5 (38.5) |
Physical examination at the first admission | |
Hypotonia after birth | 13 (100) |
Myopathic face | 7 (53.8) |
Facial weakness or ophthalmoplegia | 5 (38.5) |
Early bulbar weakness | 13 (100) |
High-arched palate | 5 (38.5) |
Club foot/joint contracture | 3(23.1) |
Pigeon/funnel chest | 5 (38.5) |
Undescended testis | 10 (76.9) |
Creatine kinase (IU/L) | 58.7 (25–88) |
Bulbar/respiratory support after birth | |
Initial tube feeding | 13 (100) |
Initial respiratory support | 13 (100) |
IPPV/SIMV | 7 (53.8) |
CPAP/BiPAP | 3 (23.1) |
Oxygen supply | 2 (15.4) |
Unknown | 1 (7.7) |
Values are presented as number (%) or median (range).
XLMTL, X-linked myotubular myopathy; IPPV, intermittent positive-pressure ventilation; SIMV, synchronized intermittent mechanical ventilator; CPAP, continuous positive airway pressure; BiPAP, bilevel positive airway pressure.
Neurodevelopmental outcomes in patients with XLMTM
Variable | Variant | Inheritance | Current age (yr) | Maximum motor performance | Maximum language/cognitive functions | Nutritional support (oral feeding trial, amount) | Respiratory support (ventilation weaning trial, amount) | ARF (yr) | HIE (yr) | Death (yr) |
---|---|---|---|---|---|---|---|---|---|---|
Non-hypoxic insult group (n=8) | ||||||||||
A. Walking alone without respiratory assistance (n=2) | ||||||||||
1 | c.1786_1795del (p.Met596Cysfs) | 4.4 | Walking alone | Sentences | PEG since 3 yr (yes, 10%) | Room air | No | No | No | |
2 | c.679G>A (p.Val227Met) | Maternal | 5.5 | Walking alone | Sentences | Full oral feeding since 5 mo | Room air | No | No | No |
B. Sitting up with BiPAP (n=4) | ||||||||||
3 | exon 3 and 4 deletion | Maternal | 4.4 | Sitting with assistance | Sentences, reading characters, doing a puzzle | NG tube (yes, spoon) | BiPAP via T-can since 6 mo (yes, 5 hr) | No | No | No |
4 | c.1558C>T (p.Arg520Ter) | Maternal | 5.8 | Sitting with assistance | A few words, obeying simple commends | Full oral feeding since 9 mo | BiPAP via T-can since 2 mo (yes, 4 hr) | No | No | No |
5 | c.1353+2T>G | Maternal | 8.2 | Sitting with assistance | Counting number | PEG since 5yr (no) | BiPAP via T-can since 2 mo (yes, 2 hr) | 0.5 | No | No |
6 | c.678+1G>C | Maternal | 8.9 | Sitting with assistance | Reading characters | PEG since 4mo (yes, spoon) | BiPAP via T-can since 9 mo (yes, 0.5 hr) | No | No | No |
C. Unable to control head with BiPAP (n=2) | ||||||||||
7 | c.342_342+4del | 0.4 | Eye contact | - | NG tube (no) | Nasal CPAP (no) | No | No | No | |
8 | c.1353+1G>A | Maternal | 0.7 | Eye contact | Social smile | NG tube (no) | BiPAP via T-can since 5 mo (no) | No | No | No |
Hypoxic insults group (n=5) | ||||||||||
9 | c.342_342+4del | 0.3 | Eye contact | - | NG tube (no) | Nasal CPAP (no) | 0.3 | 0.3 | 0.3 | |
10 | c.1261-10A>G | Maternal | 1.1 | Head control | Speech imitation | NG tube (no) | Mask BiPAP (yes, 1 hr before ARF) | 1.1 | 1.1 | 1.1 |
11 | c.342_342+4del | Maternal | 1.1 | Eye contact > bedridden | Unknown | NG tube (no) | BiPAP via T-can since 2 mo (no) | 0.5, 1 | 0.5 | 1.1 |
12 | c.1262G>A (p.Arg421Gln) | 3.3 | Eye contact, hand use | Non-verbal (preference) | PEG since 1 yr (yes) | BiPAP via T-can since 1 yr (no) | No | Unknown | No | |
13 | c.566A>G (p.Asn189Ser) | Maternal | 4.5 | Sitting with assistance > incomplete head control | Non-verbal > none | PEG since 2 yr (no) | BiPAP via T-can since 2 mo (yes, 1 hr → no after ARF) | 2 | 2 | No |
NMBI accession numbers: NM_000252.3 and NP_000243.1.
XLMTM, X-linked myotubular myopathy; ARF, acute respiratory failure; HIE, hypoxic-ischemic encephalopathy; PEG, percutaneous endoscopic gastrostomy; BiPAP, bilevel positive airway pressure; NG, nasogastric; T-can, T-cannula; CPAP, continuous positive airway pressure.