Research Overview


An Overview of Myotubular and Centronuclear Myopathy by Dr Meriel McEntegart

Dr Meriel McEntagart is a consultant clinical geneticist at St George's Hospital in London and has a special interest in inherited neuromuscular disorders.

Dr McEntagart developed an interest in congential myopathies while training with Professor Peter Harper and Professor Angus Clarke at the Institute of Medical Genetics in Cardiff, Wales. She took up her post in their department shortly after the MTM1 gene that causes X linked myotubular myopathy was identified and was given the opportunity to carry out a large study to evaluate the relationship between the specific mutation in the gene and the severity of the disease. In the process Dr McEntagart met many families affected by this condition as well as the scientists who are working to identify a treatment for this disorder and continues to be interested in helping families affected by all forms of myotubular myopathy.
We are grateful to Dr McEntagart for providing us with a summary of the progress of research to date into the myotubular and centronuclear myopathies.

  

The myotubular and centronuclear myopathies belong to a group of conditions known as the Congenital Myopathies. These are inherited muscle disorders distinguished by specific structural changes seen within the muscle on histopathological (microscopic) examination. The characteristic feature in the case of the myotubular/centronculear myopathies is the presence of the nucleus in the centre of the muscle fibre instead of the usual position at the edge. In the first description of a family with this condition by Spiro and colleagues in 1966 the term myotubular myopathy was proposed. They considered that the disease resulted from maturational arrest in the fetal stage of muscle development as the histological findings were thought to resemble developing fetal muscle when fetal myotubes are present. Sher and colleagues described a further family with the condition the following year but preferred the term centronculear myopathy. With further clinical descriptions it has become clear that there are 3 forms of the condition distinguished by inheritance pattern and variation in the severity of symptons. They are

1) Congenital X-linked Recessive (OMIM 310400)
2) Congenital Autosomal Recessive (OMIM 255200)
3) Autosomal Dominant (OMIM 160150)

The term Myotubular Myopathy has been retained for the x linked recessive form while centronuclear myopathy is generally used to refer to the autosomal forms. The genes causing all three forms have now been identified following genetic linkage analysis studies in affected families. The gene for the x linked recessive form, which is the most common form, was identified first (1996) and the genes for the autosomal forms which are rarer, were identified approximately 10 years later. The function of these genes is currently unclear. Early research findings suggest they may play a role in the normal folding of membranes that form various components of the muscle cell. One or more further genes that cause centronuclear myopathy have yet to be identified as not everyone affected by the condition has a change in one of these 3 genes.

1) X linked - Myotubularin (MTM1) OMIM 300415
2) Autosomal Recessive - Amphysin II (BIN) OMIM 601248
3) Autosomal Dominant - Dynamin 2 (DNM2) OMIM 602378

Further genetic clues

The search continues to identify further genes that cause CNM. Two interesting reports have been published recently. In 2006 Laporte and colleagues identified 2 people affected by CNM who had alterations in the hJUMPY gene. One of these patients also had an alteration in the DNM2 gene which causes the autosomal dominant form of CNM. In 2007 Jungbluth and colleagues found an alteration in the RYR1 gene that usually causes a separate congenital myopathy known as central core disease.

Early work suggests the hJUMPY gene seems to have a similar function to myotubularin which causes XMTM. The RYR1 gene functions as a calcium release channel in a part of the muscle known as the sarcoplasmic reticulum and also functions as a bridging structure between the sarcoplasmic reticulum and a structure called the T tubule. These structures have an important role in bringing about muscle contraction.

The significance of these unusual cases is not yet clear but further study of these genes may help us understand the mechanisms leading to CNM.

References:

Spiro AJ, Shy GM, Gonatas NK Myotubular myopathy Archives of Neurology 1966 14:1-14
Sher JH, Rimalovski AB , Athanassiades TJ, Aronson SM Familial centronuclear myopathy: a clinical and pathological study Neurology 1967 ( Minneapolis ) 17: 727-742
Laporte J, Hu LJ, Kretz C, Mandel J, Kiochis P, Coy JF, Klauck SM, Poustka A, Dahl N. 1996 A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast Nat Genet. 1996 13: 175-182

 

Recent publications in the field of myotubular myopathy and centronuclear myopathy:


Nicot AS, Toussaint A, Tosch V, Kretz C, Wallgren-Pettersson C, Iwarsson E, Kingston H, Garnier JM, Biancalana V, Oldfors A, Mandel JL, Laporte J.
Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy.
Nat Genet. 2007 Sep;39(9):1134-9 . Epub 2007 Aug 5

Bitoun M, Maugenre S, Jeannet PY, Lacène E, Ferrer X, Laforêt P, Martin JJ, Laporte J, Lochmüller H, Beggs AH, Fardeau M, Eymard B, Romero NB, Guicheney P.
Mutations in dynamin 2 cause dominant centronuclear myopathy.
Nat Genet. 2005 Nov;37(11):1207-9 . Epub 2005 Oct 16.

Jungbluth H, Zhou H, Sewry CA, Robb S, Treves S,Bitoun M, Guicheney Pf, Buj-Bello A, Bönnemann C, Muntoni F.
Centronuclear myopathy due to a de novo dominant mutation
in the skeletal muscle ryanodine receptor (RYR1) gene
Elsevier Publishing 2007. (Courtesy of Elsevier Publishing and Science Direct)

Buj-Bello A, Fougerousse F, Schwab Y, Messaddeq N, Spehner D, Pierson C R, Durand M, Kretz C, Danos O, Douar AM, Beggs A,Schultz P,Montus M, Denèfle P, Mandel JL
AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis.
Journal: Human molecular genetics, 2008 Apr 22; [Epub ahead of print]

Jungbluth H, Wallgren-Pettersson C, Laporte J
Centronuclear (myotubular) myopathy
Journal: Orphanet Journal of Rare Diseases, published 2008 September 2008

Jungbluth H, Zhou H, Sewry CA, Robb S, Treves S, Bitoun M, Guicheney P, Buj-Bello A, Bönnemann C, Muntoni F
Centronuclear myopathy due to a de novo dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene.
Neuromuscul Disord. 2007 Apr;17(4):338-45.

Tosch V, Rohde HM, Tronchère H, Zanoteli E, Monroy N, Kretz C, Dondaine N, Payrastre B, Mandel JL, Laporte J.
A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy.
Hum Mol Genet. 2006 Nov 1;15(21):3098-106.