The Duchenne Diagnosis: What Does it Mean?

The Duchenne Diagnosis:
What Does it Mean?
Kevin M. Flanigan, MD
University of Utah
Outline (I)
• A very little bit of:
– History
– Clinical overview
– Biology
• Muscle
• The dystrophin protein
• The DMD gene
• Terms that are thrown around a lot (and that you will hear a lot over the coming days)
• Guillaime Duchenne
de Boulogne (Paris)
– Pseudohypertophic
paralysis, or myosclerotic
paralysis (1868)
• Edward Meryon
(London), 1851
• Gaetano Conte (Naples), 1836
Roberts, Genome Biology, 2001
The dystrophinopathies:
a spectrum of phenotypes
• Duchenne Muscular Dystrophy
– Onset age 3‐5
– Loss of ambulation before age 12
• “Intermediate Muscular Dystrophy”
– Loss of ambulation age 12‐15
• Becker Muscular Dystrophy
– Loss of ambulation after age 15
Detection of protein using antibodies
Immunofluorescent = = Immunohistochemical
Immunoblot
or
Western blot
N
B
D
N
Dystrophin
(427 kd)
Muscle is ground up, and the protein is:
1. Run out on a gel
2. Transferred to a membrane
3. Visualized using an antibody
Tells us the size
and the amount of the protein
GAPDH
Dystrophin Mutations: The DMD gene
• The DMD gene is huge: – 2.2 million base pairs
– 79 exons and 8 promoters
• Spectrum of genotypes:
– Large deletions (≥ 1 exon) account for ~60% of DMD/BMD patients – ~5% have duplications
– ~15% of boys have premature stop codon mutations
– Frameshifting insertions/deletions, splice site mutations, missense mutations
Reading Frame
THE BIG RED DOG RAN AND SAT
T HEB IGR EDD OGR ANA NDS AT
TH EBI GRE DDO GRA NAN DSA T
Reading Frame
• THE BIG RED DOG RAN AND SAT
Reading Frame
• THE BIG RED DOG RAN AND SAT
• THE BIR EDD OGR ANA NDS AT
Reading Frame
• THE BIG RED DOG RAN AND SAT
• THE BIR EDD OGR ANA NDS AT
• THE DOG RAN AND SAT
Reading Frame
• THE BIG RED DOG RAN AND SAT
• THE BIR EDD OGR ANA NDS AT
= Duchenne (more severe) Muscular Dystrophy
• THE DOG RAN AND SAT
= Becker (less severe) Muscular Dystrophy
Antisense oligonucleotides that induce exon skipping
Exon B
Exon A
THE BIG RED DOG RAN AND SAT
Out‐of‐frame deletion (DMD) pre‐mRNA:
THE BID OGR ANA NDS AT
In‐frame deletion (BMD) mRNA:
THE DOG RAN AND SAT
• Exon skipping aims to turn a Duchenne
mutation into a Becker mutation
• How much benefit will depend upon several factors, including:
– Which exons are skipped
– How much skipping occurs (percentage of the gene transcript)
Outline (II)
• What can one expect from:
–Future therapies/Clinical Trials
• Personal perspective
–Cautions (not hopelessness, but cautions)
–Current therapies
• Clinics/clinical care
• Need for further trials
Genetics isn’t everything
Knowing your son’s mutation is:
– Useful for counseling
– May help with prognosis
– Potentially important for specific therapies
But it isn’t:
– A guaranteed entry into trials
– A guarantee that therapies in trials will work
Trials are trials:
No one knows if the therapies will work
• Mice aren’t humans, and don’t have Duchenne muscular dystrophy
• Caution against having all of your eggs in one basket.
– “Lucky” vs. “unlucky” mutations
– “Should we hold off treatment X until an exon
skipping trial is here?”
– PTC124/nonsense mutations
Things parents need to remember
about trials
• You may get a placebo
• Trials are an enormous investment:
– In time away from school (and work)
– In energy
– In hope
• They may require more effort than you originally expect
• A positive result may not be improvement, but only stabilization
Therapeutic trials can’t substitute for good clinical care
• Good clinical care for DMD:
– Extends life expectancy
– Improves quality of life
– Improves chances of benefiting from new therapies down the road
• Excellent program over the next few days
• Communication with the clinical team is key
There is no single recipe for what is good clinical care
• Caution patients to be wary of any conversation that starts “But you have to…” • Every family is different, and will have to find their own “best way”
– Prednisone vs. deflazacort
– Daily vs other regimens
– Supplements Costs
• Steroids: 35 kg boy
– Prednisone 20 mg 60 tablets + 5 mg 60 tablets = $18
– Deflazacort 30 mg 60 capsules = $100
• Supplements:
– Protandim 30 capsules = $45 ($1.50/day)
– Haelan 951 8 oz bottle = $51 ($25.50/day at 4 oz/day, or $9307/year)
• HGH: (16 y.o.) = $171/day ($62,415/year)
We need more trials
Not only
• Supplements
• Exon skipping
But also:
• Steroid regimens
• Losartan
• Presymptomatic ACE inhibitors
• Human Growth Hormone
• etc.
Not pessimism!
Extraordinary progress has been made:
• Research
– Understanding mechanisms
– Approaching new therapies
• Generating standards of care
• Getting this information to families Acknowledgments
• The boys and young men with DMD and BMD (and their parents) who
– Have allowed me to take part in their care
– Have participated in research studies for the benefit of the whole dystrophinopathy community