Congenital muscular dystrophies
There are more than 30 different subtypes of CMDs, grouped based on the mutated gene and how the genetic fault in the protein affects the cells.
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This guide will focus on the most frequent CMDs:
- Merosin (or laminin-α2)-deficient CMD (also called MDC1A)
- Collagen Type VI-Related Disorders(Ullrich and Bethlem myopathy)
- The Dystroglycanopathies
Merosin (or laminin-α2)-deficient CMD (MDC1A)
Laminin-α2 related CMD, also known as MDC1A, occurs due to mutations in the LAMA2 gene on chromosome 6.This gene is responsible for the production of the protein laminin-α2. A deficiency in the laminin-α2 protein leads to a deficiency in the laminin 211 protein, also known as Merosin. Merosin helps to connect muscle basement membrane to the extracellular matrix (ECM) which surrounds the muscle fibers. A Merosin deficiency means that the ECM is less able to protect the muscle cells from damage.
Babies can be born with either a complete or partial absence of laminin-α2. A complete absence of laminin-α2 is generally associated with a more severe, non-ambulatory phenotype (observable characteristics).
Patients with a complete laminin-α2 deficiency are usually born with severe hypotonia (floppy baby) and muscle weakness. Symptoms may become worse in the first few weeks of life. Children with a complete laminin-α2 deficiency are rarely able to walk independently.
There may also be
- Spinal curvature
- Contractures (stiffness) in the hands and feet. Contractures occur when muscles or tendons shorten after having been tight for too long. They develop when inelastic tissues replace normally elastic tissues.
- Breathing problems.
- Seizures occur in about 20% of children with this subset of CMD.
- Intelligence is often normal.
Collagen-VI related myopathies (Ullrich and Bethlem myopathy)
Collagen-VI is an important component of the muscle extracellular matrix where it interacts with the basement membrane of all muscle fibers. The basement membrane surrounds the membrane of the muscle fibers and has an important role in the structure and function of the muscle. Collagen VI related myopathies occur due to a recessive or dominant mutation in any of the 3 genes that contain instructions to produce each of the 3 components of the collagen-VI protein. For information about recessive and dominant inheritance, see the ‘Inheritance’ section.
Collagen-VI related myopathies represent a spectrum of diseases, with Bethlem myopathy (BM) at the milder end of the spectrum, and Ullrich congenital muscular dystrophy (UCMD) at the more severe.
Despite different degrees of severity, BM and UCMD have the following common and characteristic symptoms:
- Progressive muscle weakness
- Muscle contractures (stiff joints)
- Joint hypermobility
- Follicular hyperkeratosis, hypertrophic (keloid) or atrophic scars. Follicular hyperkeratosis is a skin condition that occurs when the foliculi pilosi become thicker than usual giving to the skin a special rough touch. A hypertrophic scar (or keloid) is a scar much larger than the original wound due to overgrowth of granulation tissue. An atrophic scar is the opposite, an indented scar that heals below the normal layer of skin tissue.
Magentic resonance image (MRI) of muscle is a very helpful tool in the diagnostic approach of collagen-VI related myopathies due to the specific pattern of muscle involvement, only described in these diseases3.
Ullrich congenital muscular dystrophy
UCMD is a progressive disease, with severe muscle weakness apparent soon after birth. Most patients will lose the ability to walk unaided by adulthood and some may never achieve independent ambulation. Patients develop contractures in their knees, elbows and fingers. They may also experience hypermobility (unusual range of movement) in their wrists and ankles.
Infants may struggle to gain weight or grow at the usual rate, otherwise known as ‘failure to thrive’.
UCMD is usually inherited in an autosomal recessive pattern (see ‘Inheritance’ section), although dominant mutations have also been described. UCMD does not usually affect intelligence.
BM is a progressive disease affecting the skeletal muscles and connective tissue. Symptoms include slowly progressive muscle weakness, mainly proximal weakness, and contractures affecting both proximal and distal joints.
The symptoms usually become evident during 2º decade, although some patients present mild weakness during childhood. BM is usually inherited in an autosomal dominant pattern (see ‘Inheritance’ section), although recessive mutations have also been described.
Dystroglycanopathies occur due to alterations in the glycosylation of the α-dystroglycan protein (α-DG). α-DG is a critical component of the multimeric (large number of protein subunits) dystrophin-associated glycoprotein complex (DGC) in muscle membrane. It also maintains essential cellular functions in other tissues, such as brain and peripheral nerve1. The α-DG protein helps to stabilise and protect muscle fibres by anchoring the cytoskeleton to the ECM.
Several different genes coding for enzymes involved in the glycosylation of α-DG have been associated with the dystroglycanopathies. Researchers have determined that these individual genes can potentially be associated with more than one of the disorders described below. Although these disorders were once considered separate conditions, this subgroup of CMD is now considered a spectrum of disease that ranges from mild presentations (phenotypes) to severe ones. Mutations in certain genes that cause these dystroglycanopathies can also cause mild forms of limb-girdle muscular dystrophy.
- Walker-Warburg Syndrome
- Muscle Eye Brain Disease
- Fukuyama Congenital Muscular Dystrophy (FCMD)
- Congenital Muscular Dystrophies with Cognitive Impairment
- Congenital Muscular Dystrophies without Cognitive Impairment