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Dec 14, 2012 (4 years and 7 months ago)

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Duchenne Muscular Dystrophy

Presented by:

Sujitha B Subramaniam

11408044

IV yr Genetic Engineering

SRM University

DUCHENNE MUSCULAR DYSTROPHY

(
DMD
) is a recessive

X
-
linked

form
of

muscular dystrophy, which results in muscle degeneration, difficulty
in walking
,
breathing, and death.

Muscular
dystrophy
-

Group
of

hereditary

muscle diseases.

Duchenne Muscular Dystrophy

2

Duchenne Muscular Dystrophy

3

MUSCLE STRUCTURE

EPONYM:



DMD
is named after the French neurologist

Benjamin
Amand Duchenne



(1806

1875
), who first described the disease in 1861.

The Era of Modern

Neurology


His findings:




Neural
pathways,




The
effect of lesions on these
structures,



Deep tissue biopsy



Nerve
conduction tests (NCS
)



Clinical
photography.







Duchenne Muscular Dystrophy

4

DMD Research:

Duchenne Muscular Dystrophy

5


Duchenne
described
-
‘Duchenne Muscular
Dystrophy.’

1860


1900



X
-
chromosome
-
linked inheritance
pattern for DMD
confirmed

1930


1960




DMD Gene is
identified by
Louis Kunkel’s
team


1984


1988



Corticosteroid
prednisone confirmed
to slow the progression
of DMD.


1989


1994



Stem cells to treat
DMD comes
under
consideration

1995


2000


Corticosteroids
found to stimulate
utrophin

production

2000
-
2005


PTC124 found to
restore
dystrophin
.

2005


2009


SYMPTOMS:



The
main symptom of Duchenne muscular dystrophy,

A
progressive neuromuscular disorder, is

muscle weakness

associated with

muscle
wasting.


The Other Physical Symptoms Are:


o

Awkward manner of walking, stepping, or running.


o

Frequent falls


o

Fatigue


o

Difficulty with

motor skills

(running, hopping, jumping)


o

Pseudohypertrophy



Enlarging of calve



Duchenne Muscular Dystrophy

6

PREVALENCE:



DMD
has an incidence of 1 in
4,000 newborn males across the world.


o

Diagnosis in boys usually occurs between 16 months and 8 years.




INHERITANCE PATTERN:



Mother carries the recessive gene and passes it to her child.



Trait

is usually expressed in males only.

Duchenne Muscular Dystrophy

7

Disease Development with age

Duchenne Muscular Dystrophy

8

THE GENE:



Duchenne

muscular dystrophy is caused

by
a mutation of the
dystrophin

gene at

locus

Xp21.






Duchenne Muscular Dystrophy

9

Duchenne Muscular Dystrophy

10

MOLECULAR MAKEUP

o
Genomic DNA:
2.2 million base pairs.


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


o
There are 8 promoters.


o
N
-
terminal or
actin

binding sight:
binds
dystrophin

to membranes
surrounding striated muscle fiber.


o
Rod Domain:
contains 24 proteins that
repeat and maintain molecular
structure.


o
The
cysteine
-
rich domain


o
The C
-
terminal:
contains the
syntrophin

binding sight.

Dystrophin

-

protein

Duchenne Muscular Dystrophy

11

GENOTYPE OF DMD

o
Mutations which affect the DMD gene.



96% are frame
-
shift mutations.


2
-
3% are mutations involving changes in nucleotide.


10
-
20% of mutations occur in the gametocyte.


o
The most common mutation are repeats of the CAG nucleotides.


o
Mutations within the
dystrophin

gene can either be inherited or occur
spontaneously during
germline

transmission.


Duchenne Muscular Dystrophy

12



o

Muscle biopsy:



Complete absence of the protein indicates the condition.






o

DNA test:




The presence of
isoforms

of the gene.


The size of transcript should be 14kb, any change in this can be detected.


The common mutation prone regions
Exon

45
-
53 and 2 to 20 can be sequenced and
mutation can be done
.


DIAGNOSIS:

Duchenne Muscular Dystrophy

13

o

Prenatal tests:


The prenatal tests are done to check if the child has inherited the
mutated X chromosome from mother, who has a family history of the
disease.


The samples for the test are got by:



Chorionic
villus

sampling (CVS) 11

14 weeks.




Amniocentesis can be done after 15 weeks.




Fetal

blood sampling can be done at about 18 weeks.


o

Manual muscle testing
(MMT).



o

An

electromyography

(EMG) shows that weakness is caused by
destruction of muscle tissue rather than by damage to nerves.



Duchenne Muscular Dystrophy

14

TREATMENT:


o

There
is no current cure for
DMD.


o

Treatment
is generally aimed at controlling the onset of symptoms to maximize
the quality of life, and include the
following:



Corticosteroids


-


increase energy and strength
.



Mild
,
physical
activity such as swimming is
encouraged.



Physical Therapies.



Orthopedic

appliances.



Splinting and
Orthoses
.



Duchenne Muscular Dystrophy

15

Splinting and
Orthoses
.

POSSIBLE COMPLICATIONS:



A complete neurological, heart, lung, and muscle exam may show:


a.


Duchenne Muscular Dystrophy

16

a.
Cardiomyopathy



Detoriation

of heart muscle

b.
Muscular atrophy

c.
Scoliosis


Curved spine

d.
Muscle contractures

e.
Muscle deformities

f.
Respiratory disorders




b.

d.

c.

e.

ONGOING RESEARCH:



o


E
xon
-
skipping.


o


S
tem cell replacement therapy.


o


A
nalog up
-
regulation
.



o

Supportive care.


o

Gene therapy.


COUNSELING:



Genetic counselling is advised for people with a family history of the
disorder.
Duchenne

muscular dystrophy can be detected with about 95% accuracy by
genetic studies performed during pregnancy.

Duchenne Muscular Dystrophy

17

PATIENT ORGANIZATIONS:






Aktion

Benni

& Co
e.v
.
-

Conny

and Claus, Germany


Duchenne Muscular Dystrophy

18

CureDuchenne

-

Debra and Paul Miller,


Newport Beach, USA.



United Parent Projects Muscular Dystrophy

Duchenne Parent Project, Netherlands.

The
shakthi

foundations, Chennai


India.

Duchenne Muscular Dystrophy


Thomas
Tonino

-

2

Stan
Groten

-

5

Jayden Hendricks
-

3.5

Bram
-

2




Maarten
Rooseleers

-

17months

CHILDREN WITH DMD

Duchenne Muscular Dystrophy

20

20

Howard Thomas


San
Pedro Sampler



Jonathan


Spine
fusion, 3 heart
surgery, Lung
infection


Duchenne Muscular Dystrophy

‘LIFE IS SHORT, SO
WORK/PLAY HARD’.

References:

http://www.mja.com.au/

www.geneticseducation.nhs.uk

www.nature.com

www.mda.org

www.genomebiology.com

www.ncbi.nlm.nih.gov

www.wikipedia.com