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Duchenne Muscular Dystrophy Presented by: Sujitha B Subramaniam 11408044 IV yr Genetic Engineering SRM University
Duchenne Muscular Dystrophy
Presented by:Sujitha B Subramaniam
11408044IV 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
Duchenne Muscular Dystrophy 3
MUSCLE STRUCTURE
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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
DMD Research:
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uscular Dystrophy
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• 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
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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
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Duchenne Muscular Dystrophy 8
Disease Development with age
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THE GENE:
Duchenne muscular dystrophy is caused by a mutation of the dystrophin gene at locus Xp21.
Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy
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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.
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Dystrophin - protein
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.
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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 M
uscular Dystrophy
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.
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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.
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Splinting and Orthoses.
POSSIBLE COMPLICATIONS:
A complete neurological, heart, lung, and muscle exam may show:
a.
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a. Cardiomyopathy – Detoriation of heart muscleb. Muscular atrophyc. Scoliosis – Curved spined. Muscle contracturese. Muscle deformitiesf. Respiratory disorders
b.
d.c.
e.
ONGOING RESEARCH: o Exon-skipping.
o Stem cell replacement therapy.
o Analog 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.
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PATIENT ORGANIZATIONS:
Aktion Benni & Co e.v. - Conny and Claus, Germany
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uscular Dystrophy
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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 - 2Stan Groten - 5
Jayden Hendricks - 3.5Bram - 2
Maarten Rooseleers - 17months
CHILDREN WITH DMD
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uscular Dystrophy
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Howard Thomas – San Pedro Sampler
Jonathan – Spine fusion, 3 heart surgery, Lung infection
Duchenne M
uscular Dystrophy
‘LIFE IS SHORT, SO WORK/PLAY HARD’.
References:http://www.mja.com.au/www.geneticseducation.nhs.ukwww.nature.comwww.mda.orgwww.genomebiology.comwww.ncbi.nlm.nih.govwww.wikipedia.com
