myotubular myopathy ( mtm ) is an x - linked congenital disorder ( xlmtm ) that is caused by mtm1 mutation1 ) . in this condition ,
the small muscle fibers present a central area devoid of myofibrils and mitochondrial aggregates around the centrally located , often large nuclei2 ) . compared with other congenital myopathies ,
the onset of clinical signs is typically at or near birth , and affected infants are areflexic and floppy , exhibiting respiratory difficulty that usually requires ventilatory support4 ) .
the majority of mutations related to xlmtm have been identified in exons 3 , 4 , 8 , 9 , 11 , and 126,7 ) .
several cases have been reported since mtm was first described in 1986 in korea8,9 ) .
however , only one case was reported with regard to the genetic analysis of mtm in the korean population10 ) . here
we report a case of myotubular myopathy in a neonate with a splice site mutation of mtm1 gene at the intron 10 region .
a 2,930 gm male was born at 37 weeks and 5 days gestation age via emergency cesarean section in a local hospital .
polyhydramnios and reduced fetal movements were noted during the antenatal period . during the therapeutic amniocentesis in response to polyhydramnios ,
his apgar scores were 1 - 5 - 5 at 1 , 5 , and 10 minutes ; he required resuscitation and intubation due to poor respiration .
subsequently , he was transferred to pusan national university yangsan hospital and was placed on ventilator support .
his birth weight ( 2,930 g , 50th percentile ) , length ( 51 cm , 75th to 90th percentile ) , and head circumference ( 35 cm , 90th percentile ) were within the normal range .
he had no abnormalities based on the chest radiograph , but findings showed fractures on both his humerus which were splinted for treatment within one month ( fig .
his birth condition presented severe hypotonia , sucking impairment , and the absence of spontaneous movements .
he then required mechanical ventilation from birth throughout his confinement at the hospital due to apnea .
however , magnetic resonance imaging of the brain and electroencephalography showed no evidence of hypoxic ischemic encephalopathy .
postnatal blood gas analysis showed normal levels ; echocardiography and screening blood tests for metabolic disease were also normal .
no neonatal reflexes could be elicited and his posture was extremely floppy - frog like characterized by a long face ( fig .
tests for congenital hypotonic disorders , including spinal muscular atrophy , myotonic dystrophy , pompe disease , prader - willi syndrome , and chromosomal disease were carried out .
muscle biopsy of the left biceps was performed and myotubular myopathy was confirmed based on the findings characterized by large centrally placed nuclei in myofibers ( fig .
peripheral blood samples for the gene study were obtained from the patient and from his mother for x - linked myotubular myopathy . a mutation c.1261 - 1c > a was identified in the intron 10 of the mtm1 gene in this case .
4 ) . he needed tube feeding for nutritional support and a tracheostomy for ventilator support .
he was discharged after six months and was brought home with a mechanical ventilation support .
genomic dna was isolated from peripheral blood using quickgene dna kit ( fujifilm life science , tokyo , japan ) .
to analyze of mtm1 gene mutation , polymerase chain reaction ( pcr ) was performed by use of fourteen sets of primers designed in intronic flanking region containing all exons referred to genbank accession number nt_011726.13 .
after amplification , pcr mixtures were run on 1.2% agarose gel in the presence of ethidium bromide to verify the size and purity of pcr products . after verifying that single specific pcr product
was amplified , dna sequencing was performed using the same primers used in pcr , and bigdye terminatore v3.1 cycle sequencing kit ( applied biosystems , foster city , ca , usa ) according to manufacturer 's instructions .
genomic dna was isolated from peripheral blood using quickgene dna kit ( fujifilm life science , tokyo , japan ) .
to analyze of mtm1 gene mutation , polymerase chain reaction ( pcr ) was performed by use of fourteen sets of primers designed in intronic flanking region containing all exons referred to genbank accession number nt_011726.13 .
after amplification , pcr mixtures were run on 1.2% agarose gel in the presence of ethidium bromide to verify the size and purity of pcr products .
after verifying that single specific pcr product was amplified , dna sequencing was performed using the same primers used in pcr , and bigdye terminatore v3.1 cycle sequencing kit ( applied biosystems , foster city , ca , usa ) according to manufacturer 's instructions .
mutations in the mtm1 gene encoding myotubularin cause xlmtm , a well - defined subtype of human centronuclear myopathy4 ) .
xlmtm is characterized by the early onset and presence of uniformly small muscle fibers with centrally placed nuclei3,4 ) .
although centrally located nuclei can be found in many myopathies , clinical , genetic , and pathological factors can help distinguish these myopathies from xlmtm4 ) .
clinical characterization of xlmtm has been comprehensive and the disorder has been found to give rise to a severe phenotype in males .
it is present at birth with marked weakness and hypotonia , external ophthalmoplegia and respiratory failure due to the weakness of the muscles responsible for respiration11 ) .
signs of antenatal onset include reduced fetal movements , polyhydramnios and thinning of ribs as seen on chest radiographs11 ) ; however , these manifestations are rarely observed in other congenital myopathies .
the diagnosis of xlmtm has traditionally relied upon the identification of characteristic histopathologic changes in muscle samples from affected males . because of the time required for molecular analysis of mtm1 , the clinical diagnosis of xlmtm continues to rely upon muscle biopsy13 ) .
hematoxylin and eosin - stained cross sections of xlmtm muscle show increased variability in fiber size , but this is generally not as extreme as what is seen in the dystrophic processes .
the cardinal histopathologic feature of xlmtm is the presence of hypotrophic myofibers with relatively large , centrally placed nuclei3 ) .
the x - linked nature of this disorder facilitated genetic analysis , with linkage studies assigning the gene to xq28 in 199011 ) .
laporte et al.1 ) isolated the mtm1 gene by positional cloning and named the gene product , ' myotubularin ' . in 1997 ,
de gouyon et al.14 ) and laporte et al.15 ) carried out a complete gene sequencing of 15 coding exons and flanking intron .
in several series , mutations were detected in 60% to 90% of individuals with xlmtm14,15 ) .
the majority of mutations were identified in exons 3 , 4 , 8 , 9 , 11 , and 126,7 ) .
the first report concerning an xlmtm family with two affected infants diagnosed by muscle biopsy and gene analysis was released in korea8 ) .
a nonsense mutation arg486stop was identified in exon 7 of the mtm1 gene in that family .
moreover , we detected another splice site mutation of mtm1 gene c.1261 - 1c > a at the intron 10 region in a present neonate with xlmtm .
although , the diagnosis is confirmed by muscle biopsy , mtm1 mutation analysis is critical in consulting with the mother about prenatal family planning and antenatal genetic screening .
prenatal testing should still be offered to all women who might give birth to affected male infants3 ) .
the management is essentially supportive and/or rehabilitative , requiring a multidisciplinary approach11,17 ) . in the majority of cases , the course is fatal within the initial months of life , but a proportion of affected males infants may survive into their teens or beyond 11,18,19 ) .
therefore , physicians who care for the newborn should consider the possibility that a neuromuscular disorder might be present in a hypotonic infant .
when a floppy infant is regarded to have hypoxic ischemic encephalopathy based on a perinatal circumstantial evidence , an accurate diagnosis should be established by carrying out appropriate clinical procedures . if a neuromuscular disorder is suspected , a muscle biopsy should be done .
we report that a neonate initially misdiagnosed with hypoxic ischemic encephalopathy was diagnosed with a xlmtm with a splice site mutation of mtm1 gene at the intron 10 region .
 x - linked recessive myotubular myopathy ( xlmtm ) is a severe congenital muscle disorder caused by mutations in the mtm1 gene and characterized by severe hypotonia and generalized muscle weakness in affected males . 
 it is generally a fatal disorder during the neonatal period and early infancy . 
 the diagnosis is based on typical histopathological findings on muscle biopsy , combined with suggestive clinical features . 
 we experienced a case of a newborn who required intubation and ventilator care because of profound hypotonia and respiratory difficulty . 
 the preliminary diagnosis at the time of request for retrieval was hypoxic ischemic encephalopathy , but the infant was clinically reevaluated for generalized weakness and muscle atrophy . 
 muscle biopsies showed variability in fiber size and centrally located nuclei in nearly all the fibers . 
 we detected an mtm1 gene mutation of c.1261 - 1c > a in the intron 10 region , and diagnosed the neonate with myotubular myopathy . 
 the same mutation was detected in his mother . 