Heinz Jungbluth is Professor of Paediatric Neurology at King’s College and a Consultant Paediatric Neurologist at the Evelina Children’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust, London. He runs specialist clinics for children and adolescents affected by neuromuscular and neurological disorders and has more than 20 years of clinical experience in the neuromuscular field. His main research interest is in neurogenetics, in particular the genetics of early-onset neuromuscular and neurodevelopmental disorders. Here Professor Jungbluth provides information about the forms of Myotubular and Centronuclear Myopathy
Myotubular (Centronuclear) Myopathy represents a group of very rare conditions characterised by the central location of the nucleus in muscle cells, in which it is normally found at the periphery. Myotubular myopathy (or XLMTM) usually refers to the X-linked form described below, but we also provide information about other manifestations of the condition, usually referred to as Centronuclear Myopathy (or CNM).
X-linked Myotubular myopathy (XLMTM)
This is the most commonly recognised form of the myotubular myopathies affecting 1 in 50,000 newborn males worldwide. It is usually the most severe form with profound muscle weakness (myopathy) and decreased muscle tone (hypotonia) present at birth. Primarily affecting the skeletal muscle, motor skills are predominantly affected, causing difficulties with sitting, standing and walking. In addition there are associated breathing and swallowing difficulties as the muscles involved in taking a breath, and the muscles involved in swallowing are also involved. Curvature of the spine (scoliosis) and contractures of the hips and knees can also be problematic. Affected boys also often have undescended testes, and in general tend to be long and have a relatively large head circumference at birth. Cognitive function is not thought to be affected.
Difficulties with feeding often result in the need for a feeding tube inserted into the stomach. Muscle weakness affecting breathing can often result in the need for mechanical ventilation, sometimes periodically in particular during sleep, or continuously. Due to these severe breathing problems, individuals with X linked myotubular myopathy (XLMTM) usually survive only into early childhood, however some with less severe breathing problems have lived into adulthood. It is generally not thought to be a progressive condition.
Autosomal-dominant centronuclear myopathy (AD-CNM)
Autosomal-dominant centronuclear myopathy also predominantly affects the skeletal muscles. Individuals with this form of myopathy often do have normal early development. However, even in those with normal early development muscle weakness usually becomes evident during adolescence or early adulthood.
Presenting symptoms are usually difficulty walking and, sometimes, muscle pain during exercise. Weakness often progressively deteriorates and wheelchair assistance may be required in mid to late childhood. More severe presentations begin in childhood and these individuals walk later than their peers and typically need wheelchair assistance in childhood or adolescence.
Autosomal recessive centronuclear myopathy (AR-CNM)
This condition also presents as progressive weakness, usually beginning at birth or childhood. Symptoms may include foot abnormalities, high arched palate (roof of the mouth) and abnormal side to side curvature of the spine (scoliosis). Mild to severe breathing problems may also be present. Much less commonly the heart muscle may also be weakened, but this is indeed very rare and to date has not been reported in any of the major genetic forms on CNM.
X-linked myotubular myopathy (XLMTM)
The X-linked form of myotubular myopathy (XLMTM) is caused by a mutation in the MTM1 gene. MTM1 is needed to produce myotubularin, an enzyme thought to be involved in the development and maintenance of muscle cells. MTM1 gene mutations are thought to disrupt the normal role of myotubularin in muscle cell development and maintenance. This then causes muscle weakness and other signs and symptoms of X-linked myotubular myopathy.
XLMTM is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes, the X and the Y chromosome. As with other X-linked recessive conditions, in males (who have only one X chromosome, plus one Y chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), the mutation in one X chromosome is compensated for by the healthy copy of the gene on the other X chromosome - a mutation would have to be present in both copies of the gene to cause the disorder. Because it is highly unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females, and affected females are indeed very rare in X-linked recessive disorders. A characteristic of X-linked inheritance is that affected fathers cannot pass X-linked traits to their sons, but all their daughters will be carriers of the condition.
In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. She can pass on the gene, but generally does not experience signs and symptoms of the disorder. In rare cases, however, carrier females have experienced some muscle weakness associated with X-linked myotubular myopathy. This is often associated with a mechanism called “skewed X-inactivation”: As females don’t need both of their X chromosomes, in any given cell half of all X chromosomes are switched off, in a process called “X inactivation” (or “lyonization”). This process usually occurs randomly but very rarely, one copy of the X chromosome may be active much more than the other (“skewed X-inctivation”); if this copy happens to carry a gene fault, females may develop symptoms of conditions that usually only affect males.
Autosomal centronuclear myopathy (dominant and recessive)
The majority of genetically resolved, autosomal centronuclear myopathy cases have been attributed to mutations in the DNM2, BIN1 and the RYR1 gene. More recently, mutations in the TTN gene have also been associated with centronuclear myopathy, but the frequency of this form is currently not certain.
Mutations in the DNM2 gene causing CNM are usually associated with dominant inheritance, mutations in the RYR1 and the TTN gene are usually associated with recessive inheritance, whereas mutations in the BIN1 gene have been associated with both dominant and recessive inheritance.
Dominant inheritance is a method of genetic inheritance, whereby a single abnormal copy of a gene causes disease, even though a good copy of the gene is also present. We inherit one copy of each gene from our mother and one from our father. Individuals with a dominant condition have a 50% chance of passing on the altered gene, and resulting disease, to their children. Recessive inheritance is a form of inheritance in which a faulty copy of a gene is inherited from each parent. In order to develop the disorder an individual has to have two copies of the faulty gene.
The DNM2 gene provides instructions for making a protein called dynamin 2 and the BIN1 gene encodes a protein called amphiphysin 2. Both proteins are involved in trafficking of cell membranes and do interact with each other. The RYR1 gene encodes the skeletal muscle ryanodine receptor, which is involved in intramuscular calcium release and excitation-contraction coupling, the process whereby the nerve impulse from the brain is translated into muscle contraction. The TTN gene encodes Titin, a giant protein that is fundamental in giving muscle its structure. Of note, mutations in TTN have also been associated with inherited forms of cardiomyopathy and it is therefore conceivable that the few cases of CNM with associated heart involvement were in fact due to TTN mutations, although this has not yet been conclusively proven.
Normally, the nucleus is found at the edges of muscle cells, however, in people with centronuclear myopathy, the nucleus is located in the centre of these cells. It is not well understood how mutations in the DNM2, BIN1, RYR1 or TTN genes lead to muscle weakness and the other specific features of centronuclear myopathy, however, there is likely to be more than one mechanism in place, including disturbances of muscle membrane trafficking; muscle fibre integrity; intracellular calcium metabolism; and/or excitation-contraction coupling (an intricate process, the end of which causes muscle contraction).
Additional genes associated with centronuclear myopathy
Mutations in other genes, namely SPEG and CACNA1S have recently been identified as leading to a CNM-like phenotype in some patients. There are also a proportion of cases of myotubular and centronuclear myopathy which are genetically unresolved - the gene involved is as yet unidentified, even though a diagnosis of centronuclar myopathy has been made by muscle biopsy. Considering recent rapid genetic advances, it is likely that additional genes implicated in centronuclear myopathy will be identified in future.
Next generation sequencing for molecular diagnosis of neuromuscular diseases, J. Böhm and S. Le Gras et al (2012)
Myotubular myopathy and the neuromuscular junction: a novel therapeutic approach from mouse models, J. Dowling and A. Buj-Bello and C. Pierson et al (2012)
X-linked myotubular myopathy due to a complex rearrangement involving a duplication of MTM1 exon 10, N. Trump, T Cullup et al (2012)
Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy, M. Lawlor et al (2013)
MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers, A. Beggs and J. Böhm et al (2013)
Gene therapy prolongs survival and restores function in murine and canine models of Myotubular Myopathy, M. K. Childers et al (2014)
N-WASP is required for Amphiphysin 2/BIN1 dependent nuclear positioning and triad organization in skeletal muscle and is involved in the pathophysiology of centronuclear myopathy E. R. Gomes et al (2014)
Reducing dynamin 2 expression rescues X-linked centronuclear myopathy. J. Laporte et al (2014)
Pathogenic mechanisms in centronuclear myopathies. Heinz Jungbluth and Mathias Gautel (2014)
A Better Molecular Understanding of Myotubular Myopathy. V Haucke et al (2016)
Current and future therapeutic approaches to the congenital myopathies
Jungbluth H, Gautel M et al (2016)
Skeletal Muscle Pathology in X-Linked Myotubular Myopathy: Review With Cross-Species Comparisons. M. Lawlor et al (2016)
Congenital myopathies : not only a paediatric topic
Jungbluth H & Voermans N (2016)
PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models J. Dowling et al (2016)
Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs A. Buj-Bello and M. Childers (2017)Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice.
Thanks to the Authors for providing us with copies of their publications.
Other Selected Publications:
Medical implications in long-term survivors with x-linked myotubular myopathy, G. Herman et al (1999)
Genotype–phenotype correlations in X-linked myotubular myopathy, M. McEntegert et al (2002)
X-inactivation patterns in carriers of X-Linked Myotubular Myopathy M. Kristiansen et al (2003)
Mutations in DNM2 cause dominant Centronuclear Myopathy J. Laporte et al (2005)
Centronuculear (myotubular) myopathy H Jungbluth, C Wallgren-Pettersson, J Laporte (2008)
Myotubular Myopathy and the Neuromuscular Junction, J. Dowling et al (2012)