Genetics in the framework of muscular dystrophies

Question 1

duchenne muscular dystrophy

Answer 1

• X-linked disorder –> females mostly unaffected (only 10/20% when X-chromosome is inactive)
• Prevalence 1:35000
• Absence of dystrophin
• Age of onset 5 year
• Death follows in their 20s
• Widespread effects in the body
• Neurological
• Diaphragm weakness
• Cardiomyopathy
• Muscle weakness
• Bones weakness

Question 2

DMD - muscle effects

Answer 2

• Less organisation
• Fat accumulation
• Fibrosis
• Inflammation
• Atrophy
• No dystrophin
• Not all muscles are affected equally

Question 3

dystrophin

Answer 3

• Dystrophin is a cytoskeletal protein that is a scaffold protein of the sarcolemma
  o Involved in many signalling pathways
• Largest gene in the human genome (79 exons and 1.5 mil bp)
• 1/3 DMD are spontaneous mutations due to the shear size of the gene
• Over 200 mutations have been identified

Question 4

becker muscle dystrophy

Answer 4

• Still some dystrophin left
• Deletion of an exon (48) or duplication that leads to open reading frame mutation(no stop codon) leads to functional (partial) dystrophin
• Milder but more variability and slower progression than DMD

Question 5

DMD treatment

Answer 5

• No cure for DMD
• Corticosteroids to control immune response in muscle
• Physical therapy
• Eteplirsen –> exon skipping drug of exon 51
  o 14% of people have mutation here –> stop codon
• Ataluren –> bypass nonsense mutations (15%)
• Vyondys and viltepso are exon skipping drugs of exon 53  all these drugs restore the reading frame
• Genethon –> gene therapy using AAV to deliver mini-dystrophin to muscle cells
• Crispr-Cas9

Question 6

Myotonic dystrophy type 1

Answer 6

• Most frequent dystrophy in adults
• Multisystemic disorder
• Prevalence 1/2100
• Myotonia –> skeletal muscle hyperexcitability and slower relaxation time
• Slow progressive muscle weakness starts in distal muscle
• Cardiac conduction defects
• Reduced lifespan

Question 7

MDT1 - pathomechanism

Answer 7

• DMPK repeat CTG mutation
• Leads to RNA-induced toxicity, haploinsufficiency and altering of neighboring genes

Question 8

MDT2

Answer 8

• Does not start in distal but in proximal muscles
• Less severe
• CCTG repeat in intron 1 of ZNF9

Question 9

treatment

Answer 9

• No cure
• Symptomatic treatment
• Development:
  o Crispr get mutation out
  o Remove RNAs from nucleus
  o Increase of MBML protein
  o Alternative splicing
  o Decoy RNA-binding protein to displace the MBNL

Question 10

McArdle disease

Answer 10

• Recessive disorder –> PYGM mutation
• Exercise intolerance
  o Stiffness
  o Muscle weakness
  o Fatigue
  o Myalgia
• Rhabdomyolysis –> myoglobinuria
  o Muscle breakdown and cause kidney failure
• Second wind
• exercise is only treatment

Question 11

McArdle - pathomechanism

Answer 11

• Block in the glycogen degradation
• Depend highly on glucose that enters muscle cells via blood
• Prevalence 1/139.543 (probably 2x lower)
• Young patients have high creatine kinase in blood
• PYGM gene is mutated (183 mutations)
• Most common is p.R50 stop codon
• The myophosphorylase is only expressed 100% in muscle cells (very little in heart and brain)

Question 12

Nonsense mediated mRNA decay

Answer 12

• Surveillance pathway that reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons.
• After splicing in the nucleus EJCs (exon junction complexes) are removed by ribosomes –> when an intron was left in the mRNA the ribosome will stop translating at a stop codon in the intron therefore leaving an EJC later in the mRNA -_> Upf proteins recognise this and degrade this mRNA to stop further translation