Duchenne Muscular Dystrophy

Curtis Kendall
December 5, 2006
Duchenne Muscular
Dystrophy
Facts
DMD affects mostly males at a rate of 1 in 3,500
births.
There are over 200 types of mutations that can cause
any one of the forms of muscular dystrophy.
There are also mutations that occur within the same gene that
cause other disease types.
DMD is the most severe and common type of
muscular dystrophy.
DMD is characterized by the wasting away of muscles.
DMD is the most aggressive form of muscular
dystrophy.
Diagnosis in boys usually occurs between 16 months
and 8 years.
Parents are usually the first to notice problem.
Death from DMD usually occurs by age of 30.
Clinical Features
Genotype of DMD
Females carry the DMD gene on the X
chromosome.
Females are carriers and have a 50%
chance of transmitting the disease
in each pregnancy.
Sons who inherit the mutation will
have the disease.
Daughters that inherit the mutation
will be carriers.
The DMD gene is located on the Xp 21
band of the X chromosome.
Mutations which affect the DMD gene.
96% are frameshift mutations
30% are new mutations
10-20% of new mutations occur in
the gametocyte (sex cell, will be
pass on to the next generation).
The most common mutation are
repeats of the CAG nucleotides.
Genotype of DMD
(Cont.)
During the translocation process, a
mutation occurs.
Mutations leading to the absence of dystrophin
Very Large Deletions (lead to absence of dystrophin)
Mutations causing reading errors (causes a
degraded, low functioning DMD protein
molecule)
Stop mutation
Splicing mutation
Duplication
Deletion
Point Mutations
Clinical Features
Phenotype of DMD
Delays in early childhood stages involving muscle use, in 42% of
patients.
Delays in standing alone
Delays in sitting without aid
Delays in walking (12 to 24 months)
Toe walking or flat footednees.
Child has a hard time climbing.
Learning difficulties in 5% of patients.
Speech problems in 3% of patients.
Leg and calf pain.
Mental development is impaired. IQs usually below 75 points.
Memory problems
Carrying out daily functions
Increase in bone fractures due to the decrease in bone density.
Increase in serum CK (creatine phosphokinase) levels up to 10
times normal amounts.
Wheelchair bound by 12 years of age.
Cardiomyopathy at 14 to 18 years.
Few patients live beyond 30 years of age.
Reparatory problems and cardiomyopathy leading to congestive heart
failure are the usual cause of death.
Molecular Makeup

There are 79 exons: which makeup 0.6% of the entire gene.

There are 8 promoters (binding sights).
Introns: make up 99.4% of the entire gene.
Genomic DNA: 2.2 million base pairs.
N-terminal or actin binding sight: binds dystrophin to membranes
surrounding striated muscle fiber.
Rod Domain: contains 24 proteins that repeat and maintain molecular
structure.
It is thought to give the rod its flexibility.
The main rod is interrupted by 4 hinge regions.
The cysteine-rich domain: regulates ADAM protease which are cell
membrane anchors that are important in maintaining cell shape and
structure.
The C-terminal: contains the syntrophin binding sight (for binding
internal cellular components)
DMD Gene and Dystrophin
Function
The DMD gene encodes for the protein
dystrophin, found in muscle cells and
some neurons.
Dystrophin provides strength to muscle cells
by linking the internal cytoskeleton to the
surface membrane.
Without this structural support, the cell
membrane becomes permeable. As
components from outside the cell are allowed
to enter the internal pressure of the cell
increases until the cell bursts and dies.
Under normal wear and tear stem cells within the
muscle regenerate new muscle cells and repair
the damage.
In DMD the damage to muscle cells is so extreme
that the supply of stem cells are exhausted and
repair can no longer occur.
Allelic Variants
Disease Mutation Effect of Phenotype
Mutation
Duchenne Muscular Very Large Deletions Severely Functionally As Discussed In Prior
Dystrophy caused by: Stop Impaired Dystrophin Slides
mutations Protein
Splicing mutations
Deletions
Duplications

Becker Muscular Deletion or Duplication Creates A Protein That Same As But Less
Dystrophy That Change In-Frame Is Partially Functional Sever Then DMD But
Exons Onset At Greater Then
7 Years Old
DMD Related Dilated Effects The Cardiac No Dystrophin Tachycardia (Fat Heart
Cardiomyopathy Muscle Promoter and Transcriptions Being Beat) Leads To
The First Exon Carried Out In Cardiac Congestive Hear
Muscle Failure

Limb-Girdle Muscular In Gene That Encodes Decrease In Pelvic and Shoulder

Dystrophy Scarcoglycans and Scarcoglycans Proteins Girdle Can Look Like
Other Proteins of DMD or BMD
Muscle Cells
Allelic Variants
(Cont.)
Disease Mutation Effect of Phenotype
Mutation
Proximal Myotonic Repeats In The Gene Lack of Zinc Finger Stiffness or Pain In
Myopathy That Encodes For Zinc Protein 9 Causes Limb Girdle Distribution
Finger Protein 9 Weakness In Muscle
Cells
Myotonic Dystrophy Increase In CTG Repeats of CTG Cause Frontal Balding,
Nucleotide Repeats Neurological Disorders Cataracts, Diabetes,
Distal Limb Weakness
Emery-Dreifuss EMD That Codes For Lack of Specificity of Joint Contractures
Muscular Dystrophy Emerin and LMNA The Dystrophic Leading To Muscle
(EDMD) Which Codes For Changes Observed. Weakness and Wasting
Lamins A Usually Some Cardiac
Involvement

Spinal Muscular Mutation In The SMN Degeneration of Motor Poor Muscle Tone,
Atrophy Gene Neurons Which Are Absence of Deep
Nerve Cells In The Tendon Reflexes
Spinal Cord.
3D Images of The Actin
Binding Sight Of Dystrophin
Bibliography
OMIM
MUSCULAR DYSTROPHY, DUCHENNE TYPE; DMD
#310200
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=310200
DYSTROPHIN; DMD
#300377
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=300
377
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Editor-in-chief: Pagon, Roberta A. Associate editors: Cassidy, Suzanne
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 Bibliography (Cont.)
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