DMD Flashcards
What are dystrinopathies
a group of genetic hereditary disorders.
How many types of dystrionpathies
Over 40 types
How do they have progressive course?
They all have a progressive course, by which I mean the severity gets worse as an affected individual ages.
What are dystrionpathies based on?
They are based on the degeneration and death of muscle fibres, which are not renewed, hence why this is a progressive disorder, with age more and more muscle is lost.
Other than muscle, what else are affected? what type of disorder does it mean that it is?
They are multi system disorders, on that its not just muscle that is affects, they also suffer from intellectual disability and heart problems, or cardiomyopathy/
Why do dystrinopathies have such severe symptoms?
The reason is simply that muscle is the most abundant body tissue.
It accounts on average for 23% of female weight and 40% of male weight.
Name the types of MD
Duchenne MD
Becker MD
Emery-Dreifuss MD – joints and heart
Myotonic dystrophy – adult onset muscle wasting
Limb Girdle MD – legs and arms
Distal MD - lower arms, hands, lower legs and feet.
Oculopharyngeal MD - upper eyelids and throat
DMD gene related dytropinopathies
How often does it occur?
What does it encode for adn where is the gene located?
How is it inherited?
DMD gene related dystrinopathy occurs in 1 in 3500 male infants.
The DMD gene encodes the dystrophin gene, located on chromosome X at p21.2
The DMD gene is inherited in an X-linked recessive manner.
WHat does mutation of DMD cause?
Mutation of DMD causes group of conditions that cause muscle weakness
Muscle disease ranging from mild to severe, includes:
Duchenne muscular dystrophy (DMD)
Becker muscular dystrophy (BMD)
How was DMD discovered to cause Duchenne muscular dystrophy?
In the early 80s, cytogeneticists were reporting numerous patients with muscular dystrophy having apparently balanced translocations involving an autosome and the X chromosome,
There were various autosome chromosomes involved, but the breakpoint on the X chromosomes was always Xp21.
This led to the hypothesis that there must be a gene that is disrupted by the translocations which then causes the muscular dystrophy phenotype.
The DMD gene was then cloned and the dystrophin protein identified.
Describe the DMD gene
Largest known human gene
Covering 2.3megabases(0.08% of the human genome)
Chromosome Xp21
Takes 16 hours to transcribe
Mature mRNAmeasures 14 kilobases
79-exons
encodes 3685 amino acid residues
The 79 exons only account for 0.6% of the gene, rest is large non-coding introns
Describe dystrophin
In skeletal and cardiac muscle fibre cells
Rod shaped cytoplasmic protein
Part of Dystroglycan complex
Strengthen muscle fibres and protect them from injury
What happens if there’s a defect in dystrophin
Skeletal & cardiac muscle cells with absence of or reduced expression of functionaldystrophin
Become damaged as the muscles repeatedly contract & relax with use
The damaged cells weaken & die over time
Causing characteristic muscle weakness & heart problems seen in DMD and BMD
Duchenne Muscular Dystrophy (DMD) - Males
Most common dystrinopathy
Age of onset 3 to 5 years old
Delayed walking
Muscle weakness, lower limbs
Psuedohypertophy- enlarged calves
Cardiomyopathy – heart disease (by 14 years)
Breathing problems - caused by deformed bones and muscle weakness
Wheel chair bound by 12
Becker Muscular Dystrophy (BMD) - Males
Milder
Later-onset skeletal muscle weakness
Wheelchair dependency (after age 16 years); although some remain ambulatory (capable of walking) into their 30s – key difference from DMD
Cardiomyopathy (diagnosed at ~14 years)
Life span to mid 40s
X-linked recessive inheritance
The DMD gene is transmitted in an X-linked recessive manner.
So a carrier Heterozygous female has a 50% chance of transmitting the DMD gene with a pathogenic variant in each pregnancy.
Sons who inherit the pathogenic variant will be affected wit Duchenne or Beckers;
Daughters who inherit the pathogenic variant are heterozygous and may have a range of clinical manifestations, though mild/
Its worth considering that although Males with DMD usually do not reproduce, if they did all their daughters would be obligate carriers and the sons of course would be unaffected as they would not inherit the X chromosome with the mutated DMD gene.
Describe female carriers
i.e one mutated DMD allele, one wild type DMD allele
~76% of DMD and 81% of BMD have NO symptoms
Mild to moderate muscle weakness (20% of DMD, 15% of BMD)
Cardiomyopathy (8% in DMD, none in BMD)
Features vary dependent on X-inactivation
X-inactivation may be skewed favouring either wild type or variant allele
Three types of DMD gene variants
2/3 pathogenic variants are de novo
Two hotspots for variants
- Exons 3-8
- Exons 44-50
~70% have deletion of >1 exon
Distribution of variants in DMD protein
~ 20% have small variants within exons.
Half of these (~10% of all patients) have nonsense mutations
~35% are small deletions or insertions that disrupt the reading frame (7% of all patients)
Remaining 15% (3% of all patients) have splice variants
DMD gene variants Becker-MD
Variants that do not alter reading frame = BMD
E.g. Inframe deletion or duplication, may include a number of exons
BMD phenotype occurs when some dystrophin is produced
But shorter-than normal dystrophin protein, which retains partial function
DMD gene variants Duchenne-MD
Those that alter reading frame / premature truncation = DMD
Variants that lead to absence of dystrophin expression
E.g. Splice variants, out of frame deletions, frameshifts, nonsense, large deletions
They produce a severely truncated dystrophin protein molecule that is degraded
Leading to the more severe DMD phenotype
Genetic testing for gene variants
Blood sample, DNA
Sanger sequence – familial point mutations
Multiplex ligation dependent probe amplification – exon deletions / duplications
Large variant’s can be detected via microarray
Confirm these via MLPA
Next Generation Sequencing ( very expensive) can detect deletions, duplications & point mutations - also copy number changes
If looking for a known familial pathogenic variant, what genetic techqniue is used for one variant?
IF we are looking for known familial pathogenic variants, then sanger sequencing is an option for that one variant.
