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Myotubular myopathy: morphological, immunohistochemical and clinical variation
T R Helliwell1, I H Ellis, R E Appleton
1Department of Pathology, University of Liverpool, UK.
Abstract:
Myotubular myopathy frequently presents in male infants with severe generalised muscular hypotonia and weakness associated with ventilatory insufficiency, and is diagnosed on biopsy by the presence of many fibres with central nuclei and mitochondrial aggregation. In a 6-year period, we have investigated five unrelated patients with clinical and pathological features suggesting an X-linked myotubular myopathy, including one female patient. In one male infant, a biopsy of vastus lateralis showed less than 2% centrally-nucleated fibres, while biceps brachii showed up to 15% centrally-nucleated fibres. Immunohistochemical expression of the neural cell adhesion molecule (CD56) was more intense in the biceps muscle than in vastus lateralis, while expression of desmin and vimentin was similar. Morphometric evaluation of tissue from each of the patients revealed a wide spread of values for the number of centrally-nucleated fibres per microscopic field, and variation in the extent of immunohistochemical expression of NCAM, utrophin, laminin alpha 5 chain, vimentin and HLA1 antigen. These variations in the manifestations of myotubular myopathy have not been previously described, and will need to be correlated with the increasing knowledge of the mutations in the MTM1 gene coding for myotubularin.
Insights
This study reveals significant variability in the pathological features of X-linked myotubular myopathy (MTM), even within the same patient. These findings highlight the need for further research into MTM1 gene mutations and their impact on disease presentation.
Area of Science:
- Neurology
- Genetics
- Pathology
Background:
- Myotubular myopathy (MTM) is a severe congenital muscle disorder typically affecting male infants.
- Diagnosis relies on identifying numerous centrally nucleated muscle fibers and mitochondrial aggregation on biopsy.
- Previous understanding suggested a consistent pathological presentation.
Purpose of the Study:
- To investigate clinical and pathological variations in patients with suspected X-linked myotubular myopathy.
- To explore the spectrum of disease manifestations beyond typical presentations.
- To correlate observed variations with potential MTM1 gene mutations.
Main Methods:
- Investigated five unrelated patients over six years, including one female.
- Performed muscle biopsies (vastus lateralis, biceps brachii) for histological and immunohistochemical analysis.
- Utilized morphometric evaluation to quantify centrally nucleated fibers and assess protein expression (CD56, desmin, vimentin, NCAM, utrophin, laminin alpha 5 chain, HLA1).
Main Results:
- Observed significant variation in the percentage of centrally nucleated fibers between different muscles in the same patient (e.g., <2% in vastus lateralis vs. up to 15% in biceps brachii).
- Detected differential expression of neural cell adhesion molecule (CD56) between muscles.
- Morphometric analysis revealed a wide spread of values for centrally nucleated fibers and varying immunohistochemical expression of multiple markers.
Conclusions:
- The study identified previously undescribed variations in the pathological manifestations of X-linked myotubular myopathy.
- These findings underscore the heterogeneity of the disease.
- Further correlation with MTM1 gene mutations is necessary to understand these variable presentations.