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.
The proteins involved in the different forms of muscular dystrophy
- Yellow circle: dystrophin protein
- Pink circle: sarcoglycan proteins
- Orange circle: dystroglycan protein
- Blue circle: integrin protein
- Purple boxes: collagen, laminin alpha2, glycosyltransferase enzymes (POMT1, POMT2, POMGnT1, FKRP, fukutin and LARGE), lamin A/C, selenoprotein
The dystrophin-dystroglycan complex on muscle cell membrane
- White backdrop: extracellular matrix (outside the muscle cell)
- Light blue backdrop: intracellular matrix (inside the muscle cell)
- Grey divider line: sarcolemmal muscle cell membrane
CMD: 6 Purple Boxes
- collagen (Ullrich and Bethlem)
- laminin (LAMA2/Merosin Deficient CMD, MDC1A)
- glycosyltransferases (Dystroglycanopathy: POMT1, POMT2, POMGnT1, LARGE, FKRP, fukutin)
- integrin alpha 7
- selenoprotein (SEPN1)
- lamin A/C (LMNA/L-CMD)
The gray dividing line across the diagram represents the muscle cell membrane, dividing the inside of the cell (light blue) from the outside of the cell (white), also called the extracellular matrix. The three circles represent the dystrophin-glycoprotein complex which spans the muscle cell membrane. Mutations in any of these proteins account for some forms of muscular dystrophy.
Inside the cell, you will find a yellow circle, called dystrophin. When there is a mutation in the gene encoding this protein, a child has Duchenne or Becker muscular dystrophy. Within the muscle membrane you will find two other groups of proteins, sarcoglycans and dystroglycan. The sarcoglycans are a group of proteins which when deficient, lead to limb girdle muscular dystrophy.
The CMD’s involve proteins in four locations of the cell.
- the extracellular matrix proteins(collagen, laminin, integrin alpha 7 and 9)
- the glycosyltransferase proteins: proteins that place a sugar on the alpha dystroglycan (dystroglycanopathies or glycosyltransferase deficiencies)
- intracellular protein deficiency (selenoprotein)
- intranuclear intermediate filament deficiency (lamin A/C) and nesprin 1
The CMD’s may involve proteins that interact with dystroglycan. Dystroglycan, symbolized by the orange circle, represents two proteins that sit on top of one another in the muscle cell membrane, alpha and beta dystroglycan. Alpha dystroglycan is thought to play a role in cell signaling and stability of the membrane, and interacts with the extracellular matrix (outside of the cell).
Extracellular Matrix Proteins (collagen VI, laminin alpha 2, integrin alpha 7 and 9):
1. A collagen VI problem.
The extracellular matrix forms the outside environment around the muscle cell. It performs critical functions by supporting muscle cell stability and regeneration while allowing the muscle cell to adhere to the matrix. The extracellular matrix contains collagen 6 (collagen VI) which is composed of three strands, abbreviated COL6A1, COLCA2 and COL6A3. A mutation in a gene encoding any of these strands can lead to either a deficient or abnormal strand or an absent strand. A mutation can lead to a partial deficiency or a complete deficiency. Both autosomal recessive and autosomal dominant mutations can cause Ullrich CMD have been recognized. Bethlem myopathy mostly presents with autosomal dominant inheritance. There is a variable clinical spectrum connecting Ullrich and Bethlem, a theme that is repeated throughout the CMD subtypes.
A mutation in any of these 3 genes, can lead to Ullrich congenital muscular dystrophy (UCMD). Bethlem myopathy is a milder version along the spectrum of collagen myopathies. Patients with UCMD typically present with muscle weakness, hip dislocation at birth, kyphoscoliosis, hyperpigmented skin lesions, prominent heel bones, elbow contractures and hyperextensible finger joints. Given that collagen is not found in the brain, these children have normal intelligence and no brain involvement. Problems breathing may lead to the need for breathing support in the first or second decade. UCMD likely represents the second most common form of CMD after laminin deficiency.
2.A laminin problem (also referred to as laminin alpha 2 and merosin)
Laminin comes in many forms, of which laminin-2 (also known as merosin) and laminin-4 is particularly important for muscle and nerve. Laminin-2 is a protein which is part of the basment membrane which covers muscle cells like a glove, attaching to alpha dystroglycan and integrin, and then binding directly and indirectly to collagen, agrin and other molecules in the extracellular matrix. Its roles are in cell to cell recognition, cell survival and cell differentiation. Mutations in laminin-2 lead to MDC1A (= merosin deficient CMD). Children with mutations in laminin-2 present in infancy with weakness and floppy tone, with some requiring breathing and feeding support depending on illness severity. Most children achieve the ability to sit unsupported, rarely achieving ambulation. Children may develop contractures at the hips, knees, elbows and ankles followed by spinal rigidity and scoliosis. MRI’s show white matter changes, however, children have normal intelligence unless there is an accompanying structural brain abnormality, which can occur in a smaller percentage of children. Children with or without an underlying structural brain abnormality may have seizures. 30% of children with MDC1A have seizures. Laminin is also found in peripheral nerves, leading to peripheral neuropathy.
One of the main complications of this disorder relates to breathing difficulties. Given chest wall and diaphragm muscle weakness and spinal deformities, children may develop breathing difficulties during the night that limits their ability to effectively exchange oxygen for carbon dioxide. These breathing difficulties can be overcome by using non-invasive ventilation or bipap overnight. Heart problems are rare. Swallowing difficulties may necessitate the placement of a gastrostomy tube (G-tube).Primary laminin deficiency is thought to account for 30-40% of the CMD’s (Muntoni F, Voit T, 2004).
3. An integrin alpha 7 problem.
Integrin is a protein which spans the muscle cell membrane. Integrin and alpha dystroglycan can bind to laminin-2. A primary deficiency in integrin has only been found in 3 patients, who presented with delayed motor milestones and an abnormal muscle biopsy, confirmed by genetic analysis to have a mutation in the integrin gene (Muntoni F, Voit T, 2004). For reference, see Hayashi YK et al. Mutations in the integrin alpha7 gene cause congenital myopathy. Nat Genet. 1998 May;19(1): 94-7.
An integrin alpha 9 problem
Integrin alpha 9 CMD shares many similarities with the Collagen VI disorders (Ullrich/ Bethlem); thus it will be listed under the extracellular matrix CMDs.However, it is unclear whether integrin alpha 9 sits in the extracellular matrix or spans the sarcolemmal membrane (integrin alpha 7).The genetic locus for integrin alpha 9 was initially reported in the French Canadian population due to an underlying founder mutation with subsequent gene identification as integrin alpha 9.
Integrin alpha 9 presents with hypotonia, distal extremity (finger/toe) hyperlaxity, proximal contractures, scoliosis, hypotonia, normal intelligence and normal to mildly elevated CPK. Features which distinguish integrin alpha 9 from Ullrich CMD, include lack of: rigid spine, high arched palate, skin findings and prominent calcaneus. Affected individuals retain the ability to ambulate into later decades and though they demonstrate diminished respiratory capacity do not require ventilatory support. (Brais B, 2006)
The Glycosyltransferase Problem: The Glycosyltransferase Proteins (affect alpha dystroglycan)
Alpha dystroglycan is coated with sugar molecules that have to be attached in a complicated process involving many different genes. The following group of CMD’s are the result of a partially functioning or missing enzyme whose job it is to place a sugar on the alpha dystroglycan. Alpha dystroglycan is found on many cells including both muscle cells and brain cells (astrocytes/neurons). This helps explain the combination of muscle cell weakness and brain involvement in these diseases. Some patients may also have eye involvement.
Six genes have been isolated so far, but there are more that remain undiscovered. Each of these genes encodes a protein that places a particular kind of sugar on alpha dystroglycan. The six genes are called: POMT1, POMT2, FKRP, LARGE, POMGnT1, and Fukutin. There is great variability in disease severity regardless of which protein is involved, based on the type of genetic mutation and whether there is some degree of functional protein. Children may show microcephaly (small head size), adducted thumbs, structural brain abnormalities on MRI, seizures and mental retardation/developmental delay. Eye involvement may be part of the presentation, with near sightedness and retinal detachment. Many children do not acquire the ability to ambulate. Muscle weakness, and sometimes enlarged appearing muscles (tongue and calf) are present.
In the past, prior to understanding the genetic mutations underlying these diseases, the diseases were named Walker Warburg syndrome (WWS), Fukuyama, and Muscle-Eye Brain (MEB) disease. WWS represents the most severely affected children with CMD, with striking brain and eye abnormalities and mortality under age 3. Fukuyama CMD was first described in Japan in 1960 and is characterized by muscle weakness, severe brain involvement with seizures, mental retardation and milder eye involvement. Children with Fukuyama CMD between the ages of 2-8 may achieve the ability to stand, however progressive weakness develops with breathing problems and then heart involvement in the second decade. MEB is somewhat milder compared to WWS but presents with as similar combination of findings. CMD with FKRP mutations have been classified as MDC1C and those with LARGE mutations, MDC1D.
Now it is becoming more and more apparent that this disorders really form a spectrum from very severe to much milder presentations. Thus, mutations in these same 6 genes can lead to either CMD or limb girdle muscular dystrophy. This demonstrates the great variation in severity from children who have a significant brain involvement and die early, to young adults with weakness and normal intelligence. The severity depends on where on the gene the mutation is located and what that type of mutation does to the protein it encodes. To demonstrate the degree of variability in disease presentation, different mutations in the same FKRP gene can lead to either a WWS-like presentation or a limb girdle muscular dystrophy (LGMD2I) presenting in adulthood with normal intelligence.
Another form of dystroglycanopathy maps to chromosome 1 (1q4) without known gene product and has been labeled MDC1B.
Selenoprotein N is an intracellular protein, meaning inside the cell, located on the endoplasmic reticulum. A mutation in this gene leads to rigid spine syndrome (RSMD1) with difficulty walking secondary to thigh muscle weakness, mild Achilles tendon tightness and spinal rigidity. Most children achieve the ability to walk, but may develop scoliosis, and breathing difficulties. Breathing difficulties may go unnoticed initially and may start prior to difficulty walking. Mutations in the same gene are also responsible for a form of congenital myopathy referred to as multi-minicore myopathy, so named because of characteristic microscopic changes in the muscle. Moghadaszadeh E, et al. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nat Genet. 2001 Sep;29(1):17-8.
An Intranuclear Protein (lamin A/C)
Lamin A/C is an intranuclear intermediate filament that attaches to the inner nuclear membrane. Mutations in lamin A/C can lead to a dizzying spectrum of disorders, most notably Emery Dreifuss muscular dystrophy which may also include cardiomyopathy with conduction abnormalities. More recently children with congenital onset of lamin deficiency were recognized presenting with prominent neck weakness (dropped head syndrome), prominent weakness in scapuloperoneal distribution and spinal rigidity and scoliosis. Muscle wasting and weakness is generalized but particulary pronounced in the neck, arms and feet. For reference, see Mercuri E, et al. Extreme variability of phenotype in patients with an identical missense mutation in the lamin A/C gene: from congenital onset with severe phenotype to milder classic Emery-Dreifuss variant. Lamin A/C is distinct from laminin alpha 2 (merosin deficiency). Arch Neurol. 2004 May: 61(5):690-4.
Merosin Positive CMD refers to individuals who fit a CMD picture with floppy muscle tone, who may have breathing and feeding problems and whose muscle shows the presence of merosin and a dystrophic pattern. The exact etiology or genetic mutation has not been found. Merosin positive CMD is a nonspecific diagnosis, as such, individuals with merosin positive CMD may have a variable presentation. There may be several genes that account for a merosin positive picture. By finding these genes, one can hope that new therapeutic targets will be identified and the findings will contribute to greater understanding of muscular dystrophy.
Mutations in two extended families with merosin positive CMD mapped to chromosome 4. Affected family members presented with hypotonia at birth without feeding or breathing problems, normal to mildly elevated CK and no contractures. Muscles most affected: trunk, shoulder girdle and facial/neck and proximal limb muscles without muscular hypertrophy. Echocardiograms were normal. Intelligence is normal. Most affected family members had a stable course with regard to muscle weakness, achieving and maintaining ambulation through adulthood. (Houlston RS, 2005).