关键词: X连锁肌管型肌病, MTM1基因, 基因诊断, 自然史, 新生儿

Abstract:

Objective X-linked myotubular myopathy (XLMTM) caused by MTM1 gene variation is a rare neuromuscular disease. Currently, the systematic summary of the early natural history and diagnostic clinical characteristics of XLMTM patients in China is still incomplete. Methods We retrospectively reviewed clinical data, including perinatal findings, neonatal phenotype, genetic results, and outcomes, of male neonates with genetically confirmed severe XLMTM who were admitted to the neonatal intensive care units (NICUs) in two hospitals, between January 2018 and August 2024. And the early life natural history of this disease was systematically summarized. Results Six male patients were included in this cohort. The average gestational age was (37.5±2.6) weeks. Three cases were indicated with polyhydramnios by prenatal ultrasonography, one case was found with a racquet-shaped placenta at 24 weeks of gestation, and two cases had a family history of multiple early deaths among male infants within the same lineage. Neonatal asphyxia occurred immediately after birth in 6 children, with Apgar scores ranging from 3 to 6 at 1 minute and 4 to 7 at 5 minutes. All the patients presented with severe neonatal respiratory failure and characteristic profound hypotonia/floppy, and required continuous mechanical ventilation, nutritional support and nasogastric feeding throughout the course. All the patients had secondary hole-type atrial septal defect (ASD type II), with defect diameters ranging from 2.0 to 4.5 mm. Associated findings included cryptorchidism, micrognathia and slender limbs. All patients died within 6 months, with a median survival of 32 (3-150) days. The leading causes of death included respiratory failure, infection, and withdrawal of care. Genetic analysis revealed five maternally inherited variants and one de novo mutation in the MTM1 gene; five variants were located in the Rac1-induced recruitment domain (RID), and one in the protein tyrosine phosphatase (PTP) catalytic domain. Conclusions Severe XLMTM neonates exhibit a highly uniform clinical phenotype. The core features of its natural history, including neonatal asphyxia, respiratory failure, characteristic profound hypotonia, specific dysmorphic features and limb anomalies, serve as key diagnostic pointers. This cohort suggests that the natural history of XLMTM neonates in China may differ from international reports, and different types of MTM1 gene variations can all lead to extremely severe phenotypes. Given that most patients show early warning signs such as polyhydramnios during the perinatal period, and the disease progresses rapidly with an extremely poor prognosis, the importance of early genetic screening and diagnosis for high-risk pregnant women and their fetuses is underscored.

Key words: X-linked myotubular myopathy, MTM1 gene, genetic diagnosis, disease natural history, neonate