Myotubular myopathy (MTM) is one of the most severe neuromuscular disorders of childhood, typically presenting at or around the time of birth with profound hypotonia, severe extremity weakness, progressive ophthalmoparesis, and, often, respiratory failure.  The diagnosis of myotubular myopathy is considered when these features are present in an infant or young boy (it is an X-linked condition) in conjunction with muscle biopsy findings typical of a centronuclear myopathy (small type I fibers, increased central nuclei, and irregular/disorganized appearance of oxidative stains).  Centronuclear myopathies, of which myotubular myopathy is the most common subtype, are a group of congenital myopathies with a range of clinical severity that are united by common biopsy features.  The diagnosis of myotubular myopathy is confirmed by genetic testing of MTM1 (or myotubularin), mutations of which are the only known cause of myotubular myopathy. 90% of cases with typical clinical and biopsy features will be found to have a confirmatory mutation in MTM1

Cases where myotubular myopathy is considered but no MTM1 mutation is detected by conventional sequencing represent a diagnostic dilemma.  There are rare examples where these cases are due to mutations in other CNM genes (RYR1, DNM2, and BIN1). The University of Chicago Genetic Services provides testing of the MTM1, DNM2, BIN1 and RYR1 genes.  The majority of individuals where myotubular myopathy is suspected but no MTM1 mutation is detected are currently genetically unresolved.  This suggests that there are additional genetic causes for myotubular myopathy and/or there are mutations in MTM1 not identified by conventional diagnostic testing.  The potential of other type(s) of MTM1 mutations as a cause of myotubular myopathy is illustrated by the follow case.

The patient had a presumed diagnosis of myoubular myopathy based on clinical and pathologic features.  He had reduced fetal movements, and was born with severe hypotonia and respiratory distress that ultimately required mechanical ventilation.  Birth weight was in the 10th-25th percentile, while length was in the 97th percentile.  Extremity and extraocular muscle weakness was noted, and a gastric tube was placed due to difficulties swallowing and excessive secretions.  At 8 weeks of age, the patient passed away from acute respiratory failure.  There was no family history of neuromuscular diseases.  Muscle biopsy showed features consistent with centronuclear myopathy.  Diagnostic testing for myotonic dystrophy type I, chromosomal microarray analysis, and sequencing of MTM1, DNM2, and RYR1 all proved unrevealing.  Research based whole exome sequencing did not identify mutations in BIN1.  As exonic duplications of the MTM1 gene would not have been identified by traditional sanger sequencing, MTM1 deletion/duplication testing was ultimately performed on the patient and on a maternal DNA sample at UCGS.  UCGS offers an oligonucleotide microarray-based test for the detection of exonic deletions and/or duplications.  This custom designed array by Agilent technologies contains ~50,000 probes present in an 8x60K format with probes more densely spaced in the exons of the genes being tested.  The array has been designed to detect copy number changes as small as 300-400 bp.   

A non-contiguous duplication involving exons 1 and 3-13 was identified in both samples, confirming the diagnosis of myotubular myopathy in the patient and carrier status in the mother.  This case demonstrated the importance of pursuing testing for complex rearrangements in patients when there is a strong clinical suspicion of MTM and conventional sequencing of MTM1 is negative.  It also suggests that at least a fraction of unresolved myotubular myopathy cases are due to MTM1 mutations not detected by gene sequencing.  We therefore recommend MTM1 deletion/duplication testing in all individuals with the clinical/pathologic picture of myotubular myopathy.  This is particularly importance given that (a) more than 50% of mothers will be carriers, (b) there are additional non-muscle features of myotubular myopathy that require clinical monitoring, and (c) therapeutic interventions for this devastating disorder are soon to enter clinical testing.