Congenital Muscular Dystrophies are a group of diseases of the muscles understanding and technology related to these diseases are progressing.
Congenital Muscular Dystrophies (CMD's) are a group of diseases of the muscles. Both understanding and technology related to these diseases are progressing, and CMD's are going from being poorly understood subsets of Muscular Dystrophy to diseases that are more clearly defined.
Congenital Muscular Dystrophies (CMD's) are a group of diseases of the muscles. Both understanding and technology related to these diseases are progressing, and CMD's are going from being poorly understood subsets of Muscular Dystrophy to diseases that are more clearly defined. There is only one epidemiological study of CMD's which comes from Italy, placing the prevalence of these diseases at 8 X 106. The study suggests that while CMD is rare, as a group they are among the more common of neuromuscular disorders. Perhaps one of the better ways to understand CMD's is through a classification scheme presented in an article based on the affected protein by Mendell in 2006.
The congenital muscular dystrophies represent a group of diseases of muscle. As technology and our understanding of these diseases progresses, the CMD's are emerging from being a poorly understood subset of muscular dystrophy into a dizzying array of distinct diseases that share the onset of muscle weakness in infancy or childhood.
The only epidemiological study of the CMD's comes from a study in northern Italy, which placed disease prevalence at 8 x 106 (Mostacciulo ML, et al, 1996). This suggests that CMD, though rare, as a group represents one of the more common neuromuscular disorders.
The best way to understand the CMD's is to follow a classification scheme proposed in a recent review article based on the location of the affected protein (Muntoni 2004, Mendell 2006). To better understand this classification, let us look at a model of the muscle cell membrane.
This image represents several things, including:
The proteins which are involved in the various forms of muscular dystrophy.
The Dystrophin-Dystroglycan complex on muscle cell membrane.
CMD: Six Purple Boxes - These six purple boxes illustrate:
The gray dividing line across the diagram is representative of the Muscle Cell Membrane, which is diving the inside of the cell (illustrated in light blue), from the outside of the cell (illustrated in white, also referred to as the, 'Extracellular Matrix.'
The three circles present in the image are representative of the,'Dystrophin-Glycoprotein Complex,' that spans the Muscle Cell Membrane. A mutation in any single of of these proteins accounts for some form of Muscular Dystrophy in the person affected.
On the inside of the cell you will find a yellow circle referred to as, 'Dystrophin.' Should there be a mutation present in the genetic encoding for this protein, the child affected as Duchenne or Becker's Muscular Dystrophy.
Within the muscle membrane are two additional groups of proteins, 'Sarcoglycans,' and, 'Dystroglycans.' The Sarcoglycans belong to a group of proteins that, when deficient, lead to Limb-Girdle Muscular Dystrophy.
The CMD's involve several proteins which can be found in four different locations in the cell:
1.) The Extracellular Matrix proteins(Collagen, Laminin, Integrin Alpha 7 and 9)
2.) The Glycosyltransferase proteins: These are proteins that place a sugar on the Alpha Dystroglycan (Dystroglycanopathies or Glycosyltransferase Deficiencies).
3.) Intracellular Protein Deficiency (Selenoprotein)
4.) Intranuclear Intermediate Filament Deficiency (Lamin A/C) and Nesprin 1
The CMD's potentially involve proteins that interact with Dystroglycan, illustrated by the orange circle, which represents two proteins that sit on top of each other in muscle cell membrane; Alpha and Beta Dystroglycan. Alpha Dystroglycan is believed to play a role in cell signaling and stability of the cell membrane. It also interacts with the Extracellular Matrix.
Extracellular Matrix Proteins (Collagen Six, Laminin Alpha 2, Integrin Alpha Seven and Nine):
A Collagen Six issue
The Extracellular Matrix forms the outside environment surrounding the muscle cell. The Extracellular Matrix is responsible for performing critical function through support of muscle cell stability and regeneration, while allowing muscle cells to adhere to the matrix. The Extracellular Matrix contains Collagen Six, composed of three strands; abbreviated, 'COL6A1,'COLCa2,' and, 'COL6A3.' Mutation present in the genetic encoding for any one of these strands may lead to either an abnormal or deficient strand, or an absent strand entirely. A mutation may lead to partial or complete deficiency as well. Both autosomal dominant and recessive mutations may cause Ullrich CMD. Autosomal dominant inheritance may present Bethlem Myopathy. There is a clinical spectrum which connects Bethlem and Ullrich; a theme repeated throughout CMD subtypes.
The presence of a mutation in any of these three genes may lead to Ullrich Congenital Muscular Dystrophy (UCMD). Bethlem Myopathy is a milder version in the spectrum of Collagen Myopathies. Persons with UCMD commonly experience muscle weakness, kyphoscoliosis, hip dislocation at birth, prominent heel bones, hyper-pigmented skin lesions, hyper-extensible finger joints, and elbow contractures. The fact that collagen is not present in the brain finds children with normal intelligence and no brain involvement. Respiratory issues may lead to the need for breathing assistance in the person's first or second decade. Following Laminin Deficiency, UCMD very likely represents the second most common form of CMD.
A Laminin (also referred to as, 'Laminin Alpha 2,' and, 'Merosin') Issue
There are many forms of Laminin. Laminin-2 and Laminin-4 are particularly important to nerves and muscles. Laminin-2 is a protein that is a part of the Basment Membrane which covers muscle cells, attaching to Alpha Dystroglycan and Integrin; then binding both directly and indirectly to Collagen, Agrin and additional molecules in the Extracellular Matrix. Laminin-2 plays roles in cell-to-cell recognition, cell differentiation, and cell survival. Mutations in Laminin-2 lead to Merosin Deficient CMD.
Children with mutations in Laminin-2 experience weakness and floppy tone; some require both feeding and breathing support, depending on the severity of the illness. Many children do achieve the ability to sit unsupported, yet rarely achieve the ability to ambulate. They may develop contractures at the ankles, knees, hips and elbows; followed by spinal rigidity and Scoliosis. MRI scans show white matter changes; the children affected have normal intelligence unless there is there is a structural brain abnormality - this can happen in a small percentage of children. Whether or not there is a structural brain abnormality present, children may experience seizure activity. Laminin is also present in peripheral nerves, leading to peripheral neuropathy.
Respiratory difficulty is one of the main complications of this disorder. Muscle weakness and spinal deformities may cause children to develop breathing difficulties during the night which limits their ability to effectively exchange oxygen for carbon dioxide. The use of non-invasive ventilation or bipap overnight can help to overcome these difficulties. Difficulty with swallowing may require placement of a gastronomy tube. Primary Laminin Deficiency may account for approximately thirty to forty percent of the CMD's.
An Integrin Alpha Seven Issue
Integrin is a protein that spans the muscle cell membrane; both Alpha Dystroglycan and Integrin can bind to Laminin-2. Primary deficiency in Integrin has been found in only three people, who presented with delayed motor milestones and an abnormal muscle biopsy which were confirmed by genetic analysis to have a mutation in the Integrin gene.
An Integrin Alpha Nine Issue
Integrin Alpha Nine CMD has many similarities with the Collagen Six disorders, such as Ullrich and Bethlem. It is unclear as to whether Integrin Alpha Nine sits in the Extracellular Matrix, or whether it spans the Sarcolemmal Membrane (Integrin Alpha Seven). The genetic locus for Integrin Alpha Nine was initially reported in the French Canadian population because of an underlying founder mutation with subsequent gene identification as Integrin Alpha Nine.
Integrin Alpha Nine presents with distal extremity hyperlaxity, hypotonia, scoliosis, proximal contractures, normal to mildly elevated CPK, and normal intelligence. There are some features that differentiate Integrin Alpha Nine from Ullrich CMD including a lack of high arched palate, rigid spine, prominent calcaneus, and skin findings. Persons affected retain the ability to ambulate into the later decades of their lives, and while they demonstrate a diminished respiratory capacity, they do not require ventilatory support.
The Glycosyltransferase Issue: The Glycosyltransferase Proteins affect Alpha Dystroglycan
Alpha Dystroglycan is coated with sugar molecules which must be attached through a complicated process that involves a number of different genes. The following group of CMD's are the result of either partially functioning or missing enzymes whose job is to place a sugar on the Alpha Dystroglycan. Alpha Dystroglycan is found on a number of cells, including brain and muscle cells; this helps to explain the combination of muscle cell weakness and brain involvement in CMD's. Many persons may also experience eye involvement.
Six genes have been isolated to date; there are more remaining to be discovered. Each gene encodes a protein that places a particular form of sugar on Alpha Dystroglycan. The six genes are called, 'POMT1,' 'POMT2,'FKRP,' 'LARGE,' 'POMGnT1,' and, 'Fukutin.' There is a wide variability in disease despite the protein that is involved, based on the type of genetic mutation and the degree of functional protein. Children may show Microcephaly, structural brain abnormalities, adducted thumbs, mental retardation/delays, and/or seizures. Eye involvement may be a part of the presentation; retinal detachment or near sightedness may be involved. A number of children do not achieve the ability to ambulate. Muscle weakness and sometimes muscles which appear enlarged are present.
Historically, these diseases were named, 'Walker Warburg Syndrome (WWS),' 'Fukuyama,' and, 'Muscle-Eye Brain (MEB),' Disease; this was before understanding of the genetic mutations underlying these diseases. The formerly called, Walker Warburg Syndrome represents the most severely affected children with CMD, which affects children under the age of three causing both brain and eye abnormalities. Fukuyama CMD was first described in Japan in the year 1960; characterized by severe brain involvement, muscle weakness, mental retardation, seizures, and milder eye involvement. Children affected by Fukuyama CMD between the ages of two and eight may achieve the ability to stand up, yet progressive weakness develops with both respiratory and heart involvement in their second decade of life.
An Intracellular Protein (Selenoprotein N1 deficiency)
Selenoprotein N1 is an intracellular protein, meaning that it is inside the cell, located on the Endoplasmic Reticulum. A mutation in this gene leads to Rigid Spine Syndrome (RSMD1). Persons affected with RSMD1 experience difficulty walking due to thigh muscle weakness, spinal rigidity, and mild Achilles tendon tightness. Most children with RSMD1 achieve the ability to walk, yet may develop Scoliosis as well as respiratory difficulty. Breathing difficulties may go unnoticed initially, and may be experienced prior to difficulties with walking. Mutations in the same gene are responsible for a form of congenital myopathy called, 'Multi-Minicore Myopathy,' name for a characteristic microscopic change in the muscle.
An Intranuclear Protein (Lamin A/C)
Lamin A/C is an Intranuclear Intermediate Filament which attaches to the Inner Nuclear Membrane. Mutations in Lamin A/C may lead to a number of different disorders; notably Emery Dreifuss Muscular Dystrophy that may also include Cardiomyopathy with Conduction abnormalities. Recently, children with congenital onset of Lamin deficiency were found presenting with prominent weakness in the neck known as, 'Dropped-head Syndrome,' as well as spinal rigidity, scoliosis, and prominent weakness in Scapuloperoneal distribution. Muscle weakness and wasting is generalized yet particularly pronounced in their feet, arms and neck.
Merosin Positive CMD
The term, 'Merosin Positive CMD,' refers to persons who fit a CMD picture with floppy muscle tone and may present with respiratory and feeding difficulty, and whose muscle shows the presence of Merosin and a Dystrophic pattern. The exact genetic mutation and etiology has not been found. Merosin positive CMD is a nonspecific diagnosis; because of this, persons with Merosin positive CMD may have a variable presentation. There are a potential number of genes that can account for this Merosin positive picture. Through finding these genes, it is hoped that new therapeutic targets will be identified, as well as findings that will contribute to a greater understanding of Muscular Dystrophy as a whole.
Mutations found in two extended families with Merosin positive CMD mapped to Chromosome four. Family members affected presented with hypotonia at birth, without respiratory or feeding issues, normal to mildly elevated CK, and no contractures. The muscles which were affected included trunk, shoulder, girdle, facial, neck and proximal limb muscles without muscular hypertrophy. Their echocardiograms were normal; their intelligence is as well. Most of the affected family members had a stable course with regard to muscle weakness; they achieved and maintained ambulation throughout adulthood.