A healthcare claims analysis to identify and characterize patients with suspected X-Linked Myotubular Myopathy (XLMTM) in the Brazilian Healthcare System.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital disease, which is not well-defined. To our knowledge, no studies characterizing the XLMTM disease burden have been conducted in Brazil. We identified and described patients with suspected XLMTM using administrative claims data from the Brazilian public healthcare system. METHODS: Data from 2015 to 2019 were extracted from the DATASUS database. As no XLMTM-specific ICD-10 code was available, a stepwise algorithm was applied to identify patients with suspected XLMTM by selecting male patients with a congenital myopathies code (G71.2), aged < 18 years at index date (first claim of G71.2), with an associated diagnostic procedure (muscle biopsy/genetic test) and without spinal muscular atrophy or Duchenne muscular dystrophy. We attempted to identify patients with suspected severe XLMTM based on use of both respiratory and feeding support, which are nearly universal in the care of XLMTM patients. Analyses were performed for the overall cohort and stratified by age at index date < 5 years old and ≥ 5 years old. RESULTS: Of 173 patients with suspected XLMTM identified, 39% were < 5 years old at index date. Nearly all (N = 166) patients (96%) were diagnosed by muscle biopsy (91% of patients < 5 years old and 99% of patients ≥ 5 years old), six (3.5%) were diagnosed by clinical evaluation (8% of patients < 5 years old and 1% of patients ≥ 5 years old), and one was diagnosed by a genetic test. Most patients lived in Brasilia (n = 55), São Paulo (n = 33) and Minas Gerais (n = 27). More than 85% of patients < 5 years old and approximately 75% of patients ≥ 5 years old had physiotherapy at the index date. In both age groups, nearly 50% of patients required hospitalization at some point and 25% required mobility support. Respiratory and feeding support were required for 3% and 12% of patients, respectively, suggesting that between 5 and 21 patients may have had severe XLMTM. CONCLUSION: In this real-world study, genetic testing for XLMTM appears to be underutilized in Brazil and may contribute to underdiagnosis of the disease. Access to diagnosis and care is limited outside of specific regions with specialized clinics and hospitals. Substantial use of healthcare resources included hospitalization, physiotherapy, mobility support, and, to a lesser extent, feeding support and respiratory support.

Myofibrillar myopathies due to a novel mutation in exon 8 of the LDB3 gene.

Myofibrillar myopathies (MFMs) are a group of genetically heterogeneous diseases affecting the skeletal and cardiac muscles. Myofibrillar myopathies are characterized by focal lysis of myogenic fibers and integration of degraded myogenic fiber products into inclusion bodies, which are typically rich in desmin and many other proteins. Herein, we report a case of a 54-year-old woman who experienced bilateral thigh weakness for over three years. She was diagnosed with MFMs based on muscle biopsy findings and the presence of a novel mutation in exon 8 of the LDB3 gene. Myofibrillar myopathies caused by a mutation in the LDB3 gene are extremely uncommon and often lack distinct clinical characteristics and typically exhibit a slow disease progression. When considering a diagnosis of MFMs, particularly in complex instances of autosomal dominant myopathies where muscle biopsies do not clearly indicate MFMs, it becomes crucial for clinicians to utilize genetic test as a diagnostic tool.

Prognostic Value of Genotype-Phenotype Correlations in X-Linked Myotubular Myopathy and the Use of the Face2Gene Application as an Effective Non-Invasive Diagnostic Tool.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy resulting from dysfunction of the protein myotubularin encoded by the MTM1 gene. XLMTM has a high neonatal and infantile mortality rate due to a severe myopathic phenotype and respiratory failure. However, in a minority of XLMTM cases, patients present with milder phenotypes and achieve ambulation and adulthood. Notable facial dysmorphia is also present. METHODS: We investigated the genotype-phenotype correlations in newly diagnosed XLMTM patients in a patients' cohort (previously published data plus three novel variants, n = 414). Based on the facial gestalt difference between XLMTM patients and unaffected controls, we investigated the use of the Face2Gene application. RESULTS: Significant associations between severe phenotype and truncating variants (p < 0.001), frameshift variants (p < 0.001), nonsense variants (p = 0.006), and in/del variants (p = 0.036) were present. Missense variants were significantly associated with the mild and moderate phenotype (p < 0.001). The Face2Gene application showed a significant difference between XLMTM patients and unaffected controls (p = 0.001). CONCLUSIONS: Using genotype-phenotype correlations could predict the disease course in most XLMTM patients, but still with limitations. The Face2Gene application seems to be a practical, non-invasive diagnostic approach in XLMTM using the correct algorithm.

Whole exome sequencing discloses a pathogenic MTM1 gene mutation in a continuous polyhydramnios family in China: Case report and literature review.

Polyhydramnios can be caused by genetic defects at times. However, to establish an accurate diagnosis and provide a precise prenatal consultation in a given case is still a great challenge toward obstetricians. To uncover the genetic cause of polyhydramnios in the two consecutive pregnancies, we performed whole-exome sequencing of DNA for the second suffering fetuses, their parents, and targeted sanger sequencing of other members of this family. We discovered a hemizygous truncating variant in MTM1 gene, c.438_439 del (p. H146Q fs*10) in this Chinese family. In the light of the molecular discoveries, the fetus's clinical phenotype was considered to be a good fit for X-linked myotubular myopathy (XLMTM). There is no related research to the prenatal manifestations of MTM1-related XLMTM among Chinese population, and this is the first one to present. Though the etiology of polyhydramnios is complicated, WES may provide us with a creative avenue in prenatal diagnosis.

Congenital myopathies.

The congenital myopathies are inherited muscle disorders characterized clinically by hypotonia and weakness, usually from birth, with a static or slowly progressive clinical course. Historically, the congenital myopathies have been classified according to major morphological features seen on muscle biopsy as nemaline myopathy, central core disease, centronuclear or myotubular myopathy, and congenital fiber type disproportion. However, in the past two decades, the genetic basis of these different forms of congenital myopathy has been further elucidated with the result being improved correlation with histological and genetic characteristics. However, these notions have been challenged for three reasons. First, many of the congenital myopathies can be caused by mutations in more than one gene that suggests an impact of genetic heterogeneity. Second, mutations in the same gene can cause different muscle pathologies. Third, the same genetic mutation may lead to different pathological features in members of the same family or in the same individual at different ages. This chapter provides a clinical overview of the congenital myopathies and a clinically useful guide to its genetic basis recognizing the increasing reliance of exome, subexome, and genome sequencing studies as first-line analysis in many patients.

Real-world analysis of healthcare resource utilization by patients with X-linked myotubular myopathy (XLMTM) in the United States.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy with multisystem involvement, often requiring invasive ventilator support, gastrostomy tube feeding, and wheelchair use. Understanding healthcare resource utilization in patients with XLMTM is important for development of targeted therapies but data are limited. METHODS: We analyzed individual medical codes as governed by Healthcare Common Procedure Coding System, Current Procedural Terminology, and International Classification of Diseases, 10th Revision (ICD-10) for a defined cohort of XLMTM patients within a US medical claims database. Using third-party tokenization software, we defined a cohort of XLMTM patient tokens from a de-identified dataset in a research registry of diagnostically confirmed XLMTM patients and de-identified data from a genetic testing company. After approval of an ICD-10 diagnosis code for XLMTM (G71.220) in October 2020, we identified additional patients. RESULTS: A total of 192 males with a diagnosis of XLMTM were included: 80 patient tokens and 112 patients with the new ICD-10 code. From 2016 to 2020, the annual number of patients with claims increased from 120 to 154 and the average number of claims per patient per year increased from 93 to 134. Of 146 patients coded with hospitalization claims, 80 patients (55%) were first hospitalized between 0 and 4 years of age. Across all patients, 31% were hospitalized 1-2 times, 32% 3-9 times, and 14% ≥ 10 times. Patients received care from multiple specialty practices: pulmonology (53%), pediatrics (47%), neurology (34%), and critical care medicine (31%). The most common conditions and procedures related to XLMTM were respiratory events (82%), ventilation management (82%), feeding difficulties (81%), feeding support (72%), gastrostomy (69%), and tracheostomy (64%). Nearly all patients with respiratory events had chronic respiratory claims (96%). The most frequent diagnostic codes were those investigating hepatobiliary abnormalities. CONCLUSIONS: This innovative medical claims analysis shows substantial healthcare resource use in XLMTM patients that increased over the last 5 years. Most patients required respiratory and feeding support and experienced multiple hospitalizations throughout childhood and beyond for those that survived. This pattern delineation will inform outcome assessments with the emergence of novel therapies and supportive care measures.

Extremely thinning ribs in severe congenital myopathy.

A full-term boy born with global hypotonia, weakness, and respiratory insufficiency was finally diagnosed as X-linked centronuclear myopathy by whole exome sequencing, with a mutation in the MTM1 gene encoding myotubularin. In addition to the typical phenotypes, the infant had a distinctive feature in his chest x-ray, extremely thinning ribs. This was presumably due to scarcely antepartum work of breathing and may be an important suggestive indicator for skeletal muscle conditions.

A Possible Case of Centronuclear Myopathy: A Case Report.

Congenital myopathies (CMs) are a group of diseases that primarily affect the muscle fiber, especially the contractile apparatus and the different components that condition its normal functioning. They present as muscle weakness and hypotonia at birth or during the first year of life. Centronuclear CM is characterized by a high incidence of nuclei located centrally and internally in muscle fibers. Clinical case: a 22-year-old male patient with symptoms of muscle weakness since early childhood, with difficulty in performing physical activity according to his age, with the presence of a long face, a waddling gait, and a global decrease in muscle mass. Electromyography was performed, showing a neurogenic pattern and not the expected myopathic one, neuroconduction with reduced amplitude of the motor potential of the peroneal nerve and axonal and myelin damage of the posterior tibial nerves. The microscopic study of the studied striated muscle fragments stained with hematoxylin-eosin and Masson's trichrome showed the presence of fibers with central nuclei, diagnosing CM. The patient meets most of the description for CM, with involvement of all striated muscles, although it is important to note the neurogenic pattern present in this case, due to the denervation of damaged muscle fibers, which contain terminal axonal segments. Neuroconduction shows the involvement of motor nerves, but with normal sensory studies, axonal polyneuropathy is unlikely, due to normal sensory potentials. Different pathological findings have been described depending on the mutated gene in this disease, but all coincide with the presence of fibers with central nuclei for diagnosis by this means, which is so important in institutions where it is not possible to carry out genetic studies, and allowing early specific treatment, according to the stage through which the patient passes.

Respiratory features of centronuclear myopathy in the Netherlands.

Centronuclear myopathy (CNM) is a heterogeneous group of muscle disorders primarily characterized by muscle weakness and variable degrees of respiratory dysfunction caused by mutations in MTM1, DNM2, RYR1, TTN and BIN1. X-linked myotubular myopathy has been the focus of recent natural history studies and clinical trials. Data on respiratory function for other genotypes is limited. To better understand the respiratory properties of the CNM spectrum, we performed a retrospective study in a non-selective Dutch CNM cohort. Respiratory dysfunction was defined as an FVC below 70% of predicted and/or a daytime pCO2 higher than 6 kPa. We collected results of other pulmonary function values (FEV1/FVC ratio) and treatment data from the home mechanical ventilation centres. Sixty-one CNM patients were included. Symptoms of respiratory weakness were reported by 15/47 (32%) patients. Thirty-three individuals (54%) with different genotypes except autosomal dominant (AD)-BIN1-related CNM showed respiratory dysfunction. Spirometry showed decreased FVC, FEV1 & PEF values in all but two patients. Sixteen patients were using HMV (26%), thirteen of them only during night-time. In conclusion, this study provides insight into the prevalence of respiratory symptoms in four genetic forms of CNM in the Netherlands and offers the basis for future natural history studies.

X-linked myotubular myopathy: a clinical report and a review of the mild phenotype. / Miopatía miotubular ligada al cromosoma X: informe clínico y revisión del fenotipo leve.

INTRODUCTION: X-linked myotubular myopathy is a rare centronuclear myopathy that affects approximately 1 in 50,000 male newborns caused by pathogenic variants in the myotubularin 1 gene (MTM1). The clinical severity varies, however the need for ventilatory support occurs almost invariably. CASE REPORT: We report the case of a 4-year-old boy presenting mild muscle hypotonia at 12 months-old, expressive language disorder, global developmental delay, and a sensory processing disorder. Clinical exome sequencing identified the hemizygous variant c.722G>A p.(Arg241His) in exon 9 of the myotubularin 1 gene (NM_000252.2). The mother is a heterozygous carrier of the same variant. A diagnosis of a mild form of maternal inherited X-linked myotubular myopathy was established. The child presented significant improvement with speech, occupational, and physical therapies, with no respiratory intercurrences or ventilator dependency. CONCLUSION: The presentation of a mild form of this myotubular myopathy, being less commonly reported, added challenge to the diagnosis. The combination of mild hypotonia, feeding difficulties and expressive language disorder should raise suspicion of a neuromuscular disease. There is a lack of verified motor or developmental scores specific to this myopathy to further determine prognosis and need of other therapies. While currently the severity myotubular myopathy is classified according to ventilator dependency, this may be insufficient and unapplicable to milder cases. There is an evident need for a grading system for mild and moderate cases assessing muscle weakness and fatigue, daily life limitations, motor developmental delay, early phenotypical scores, or recurrent respiratory infections.

TITLE: Miopatía miotubular ligada al cromosoma X: informe clínico y revisión del fenotipo leve.Introducción. La miopatía miotubular ligada al X es una miopatía centronuclear rara que afecta aproximadamente a 1 de cada 50.000 recién nacidos varones causada por variantes patógenas en el gen de la miotubularina 1 (MTM1). La gravedad clínica varía; sin embargo, la necesidad de soporte ventilatorio ocurre casi invariablemente. Caso clínico. Presentamos el caso de un niño de 4 años que presentaba hipotonía muscular leve a los 12 meses, trastorno del lenguaje expresivo, retraso global del desarrollo y trastorno del procesamiento sensorial. La secuenciación clínica del exoma identificó la variante hemicigótica c.722G>A p.(Arg241His) en el exón 9 del gen de la miotubularina 1 (NM_000252.2). La madre es portadora heterocigota de la misma variante. Se estableció el diagnóstico de una forma leve de miopatía miotubular ligada al cromosoma X de herencia materna. El niño presentó una mejoría significativa con terapias del habla, ocupacional y física, sin intercurrencias respiratorias ni dependencia de ventilador. Conclusión. La presentación de una forma leve de esta miopatía miotubular, al notificarse más raramente, añadió desafío al diagnóstico. La combinación de hipotonía leve, dificultades de alimentación y trastorno del lenguaje expresivo debe hacer sospechar una enfermedad neuromuscular. Se carece de puntuaciones motoras o de desarrollo verificadas específicas de esta miopatía para determinar el pronóstico y la necesidad de otras terapias. Aunque actualmente la gravedad de la miopatía miotubular se clasifica según la dependencia del ventilador, esto puede ser insuficiente e inaplicable a los casos más leves. Es evidente la necesidad de un sistema de clasificación para los casos leves y moderados que evalúe la debilidad muscular y la fatiga, las limitaciones de la vida diaria, el retraso del desarrollo motor, las puntuaciones fenotípicas tempranas o las infecciones respiratorias recurrentes.

X-linked myotubular myopathy associated with an MTM1 variant in a Maine coon cat.

OBJECTIVE: Describe the clinical course and diagnostic and genetic findings in a cat with X-linked myotubular myopathy. CASE SUMMARY: A 7-month-old male Maine coon was evaluated for progressively worsening gait abnormalities and generalized weakness. Neurolocalization was to the neuromuscular system. Genetic testing for spinal muscular atrophy (LIX1) was negative. Given the progressive nature and suspected poor long-term prognosis, the owners elected euthanasia. Histopathology of skeletal muscle obtained post-mortem disclosed numerous rounded atrophic or hypotrophic fibers with internal nuclei or central basophilic staining. Using oxidative reactions mediated by cytochrome C oxidase and succinic dehydrogenase, scattered myofibers were observed to have central dark staining structures and a "ring-like" appearance. Given the cat's age and clinical history, a congenital myopathy was considered most likely, with the central nuclei and "ring-like" changes consistent with either centronuclear or myotubular myopathy. Whole genome sequencing identified an underlying missense variant in myotubularin 1 (MTM1), a known candidate gene for X-linked myotubular myopathy. NEW OR UNIQUE INFORMATION PROVIDED: This case is the first report of X-linked myotubular myopathy in a cat with an MTM1 missense mutation. Maine coon cat breeders may consider screening for this variant to prevent production of affected cats and to eradicate the variant from the breeding population.

Pulmonary lymphangiectasia in myotubular myopathy: a novel unrecognized association?

Chylothorax has been reported in rare cases of X-linked myotubular myopathy, but the pathophysiology of this association is not fully understood. We report a case of a neonate presenting prenatally with hydrops and chylothorax. The patient died at 17 days of life due to respiratory failure secondary to severe pulmonary hypertension. Comprehensive genetic testing identified a de novo hemizygous frameshift mutation in the MTM1 gene (c.142-143del, p.Glu48Serfs*12) with subsequent autopsy confirming the diagnosis of X-linked myotubular myopathy. Lung microscopy demonstrated primary pulmonary lymphangiectasia as the cause for the massive chylothorax. To the best of our knowledge, this is the first reported case of molecularly confirmed X-linked myotubular myopathy with pulmonary lymphangiectasia with prenatal findings of hydrops, chylothorax and postnatal severe pulmonary hypertension.

Neonatal myofibrillar myopathy type II associated with biallelic UNC-45B gene novel mutation and perinatal myasthenia as the core phenotype: A case report.

Myofibrillar myopathy (MFM) is characterized by phenotypic heterogeneity; decreased function of the myosin-directed chaperone, UNC-45B protein, leads to MFM II, which is characterized by slow progressive proximal myasthenia. Currently, only two studies have reported 11 cases worldwide. This study aimed to conduct genetic research and etiological analysis of a neonatal case of perinatal myasthenia who eventually died due to autonomic dyspnea. The case involved a newborn female admitted for weak cries and groaning. Physical examination revealed shallow and irregular spontaneous breathing, difficulty feeding, hip flexion and knee flexion in both lower limbs, hypotonia (level 1), less translation action, and inability to resist gravity. The child died at 23 days after birth. Gene testing, mutation analysis, and crystal structure analysis were conducted. Cell culture and plasmid construction were conducted, followed by western blot analysis. Pathological changes, including Z-line breakage, were observed in the muscle biopsies of different tissues. Gene testing showed that UNC-45B had a novel compound heterozygous mutation (c.2357T>A/p.Met786Lys, c.2591A>C/p.His864Pro), and in vitro functional experiments showed that the variants could lead to a decrease in protein expression. This study expands the UNC-45B mutation and phenotype spectrum by reporting an MFM II case in a Chinese patient for the first time.

Patient perspective: my rare disease journey.

My underlying diagnosis since birth was congenital muscular dystrophy not otherwise specified Being born in 1970 meant that there were no genetic testing, no standards of care, and no true understanding of the pathology that separates one congenital-onset neuromuscular disorder from the next. Two muscle biopsies described histological abnormalities of small type 1 fibers and were among the first of M.H. Brooke's cases described as congenital fiber-type disproportion (Brooke, Experta Medica 295: 147 [1973]).

Mutational and clinical spectrum of centronuclear myopathy in 9 cases and a literature review of Chinese patients.

Centronuclear myopathy (CNM) is a group of congenital myopathies with the histopathological findings of centralized nuclei in muscle fibres. In this study, we summarized the mutational spectrum and phenotypic features of nine Chinese patients with CNM and reanalysed the existing data on 32 CNM patients reported in China. In a cohort comprising nine patients, 14 variants were found in three CNM-related genes, including DNM2, RYR1, and TTN, in 4, 3, and 2 patients, respectively. Of the total 14 variants identified, nine were reported, and 5 were novel including one pathogenic, one likely pathogenic, and 3 of undetermined significance (VUS). Pathologically, we identified the percentage of muscle fibres with central nuclei was much higher in the DNM2-related CNM patients than that in other genetic type of CNM. Of the 32 genetic-diagnosed CNM patients previously reported from China, DNM2, MTM1, SPEG, RYR1, and MYH7 mutations accounted for 59.4%, 25.0%, 9.4%, 3.1%, and 3.1%, respectively. Notably, all of the 20 variants of DNM2 were missense mutations, and the missense mutations in exon 8 were found in 60.0% of DNM2 variants. The c.1106G > A/ p.R369Q (NM_001005360) occurred in 26.3% patients of this Chinese cohort with DNM2-CNM. In conclusion, CNM showed a highly variable genetic spectrum, with DNM2 as the most common causative gene in Chinese CNM patients.

An autopsy case of recurrent pneumothorax and peliosis-like intrapulmonary hematoma with X-linked myotubular myopathy.

BACKGROUND: The typical non-muscle complications of long-surviving X-linked myotubular myopathy (XLMTM) include scoliosis, head deformity, macrocephaly, gastroesophageal reflux disease and peliosis hepatis. Recently, pulmonary blebs and recurrent pneumothorax have also been reported as uncommon complications, whereas no reports on autopsy cases have focused on lung lesions. CASE PRESENTATION: An 8-year-old boy with XLMTM presented recurrent pneumothorax requiring bleb resection and pleurodesis. He subsequently developed multiple pulmonary mass lesions. He died of hemorrhagic shock due to peliosis hepatis. Autopsy showed multiple peliosis-like hematomas in the blebs of the lung. The histopathological examination of the hematomas revealed pooled blood without a pathway to bronchus. No apparent increase in desmin- or α-smooth muscle actin (α-SMA)-positive cells, namely myofibroblasts, was observed around hematomas, suggesting that the mutation in the myotubularin gene was involved in the defective repair process in the liver and lung tissues. CONCLUSION: Recurrent pneumothorax should be considered as a non-muscle complication of XLMTM. Peliosis-like intrapulmonary hematoma may also be a critical complication caused by poor proliferation of myofibroblasts in the tissue repair process.

X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) is a severe congenital muscle disease caused by mutation in the MTM1 gene. MTM1 encodes myotubularin (MTM1), an endosomal phosphatase that acts to dephosphorylate key second messenger lipids PI3P and PI3,5P2. XLMTM is clinically characterized by profound muscle weakness and associated with multiple disabilities (including ventilator and wheelchair dependence) and early death in most affected individuals. The disease is classically defined by characteristic changes observed on muscle biopsy, including centrally located nuclei, myofiber hypotrophy, and organelle disorganization. In this review, we highlight the clinical and pathologic features of the disease, present concepts related to disease pathomechanisms, and present recent advances in therapy development.

Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands.

Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype-genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0-80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.

Clinical and genetic analysis of a case with centronuclear myopathy caused by SPEG gene mutation: a case report and literature review.

BACKGROUND: Centronuclear myopathy (CNM), a subtype of congenital myopathy (CM), is a group of clinical and genetically heterogeneous muscle disorders. Since the discovery of the SPEG gene and disease-causing variants, only a few additional patients have been reported. CASE PRESENTATION: The child, a 13-year-old female, had delayed motor development since childhood, weakness of both lower extremities for 10 years, gait swinging, and a positive Gower sign. Her distal muscle strength of both lower extremities was grade IV. The electromyography showed myogenic damage and electromyographic changes. Her 11-year-old sister had a similar muscle weakness phenotype. Gene sequencing revealed that both sisters had SPEG compound heterozygous mutations, and the mutation sites were c.3715 + 4C > T and c.3588delC, which were derived from their parents. These variant sites have not been reported before. The muscle biopsy showed the nucleic (> 20% of fibers) were located in the center of the cell, the average diameter of type I myofibers was slightly smaller than that of type II myofibers, and the pathology of type I myofibers was dominant, which agreed with the pathological changes of centronuclear myopathy. CONCLUSIONS: The clinical phenotypes of CNM patients caused by mutations at different sites of the SPEG gene are also different. In this case, there was no cardiomyopathy. This study expanded the number of CNM cases and the mutation spectrum of the SPEG gene to provide references for prenatal diagnosis and genetic counseling.