Duchenne Muscular Dystrophy

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.
MUSCLE STRUCTURE
EPONYM: DMD is named after the French neurologist Benjamin Amand Duchenne (18061875), 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.
DMD Research:
Duchenne describedDuchenne Muscular Dystrophy. X-chromosomelinked inheritance pattern for DMD confirmed DMD Gene is identified by Louis Kunkels team
1984 1988
Corticosteroid prednisone confirmed to slow the progression of DMD.
1860 1900
1930 1960
1989 1994
Stem cells to treat DMD comes under consideration
Corticosteroids found to stimulate utrophin production
PTC124 found to restore dystrophin.

2005 2009
1995 2000
2000-2005
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
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.
Disease Development with age
THE GENE: Duchenne muscular dystrophy is caused by a mutation of the dystrophin gene at locus Xp21.
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
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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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DIAGNOSIS:
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.
Muscle biopsy:
Complete absence of the protein indicates the condition.
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) 1114 weeks. Amniocentesis can be done after 15 weeks. Fetal blood sampling can be done at about 18 weeks.
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.
Splinting and Orthoses.
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POSSIBLE COMPLICATIONS:
A complete neurological, heart, lung, and muscle exam may show: a. c. d.
b.
e.
a. b. c. d. e. f.
Cardiomyopathy Detoriation of heart muscle Muscular atrophy Scoliosis Curved spine Muscle contractures Muscle deformities Respiratory disorders
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ONGOING RESEARCH: o o o Exon-skipping. Stem cell replacement therapy. Analog up-regulation.
o
o
Supportive care.
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
CureDuchenne - Debra and Paul Miller, Newport Beach, USA.
United Parent Projects Muscular Dystrophy
Duchenne Parent Project, Netherlands.
The shakthi foundations, Chennai India.

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CHILDREN WITH DMD
Stan Groten - 5
Thomas Tonino - 2
Maarten Rooseleers 17months
Bram - 2
Jayden Hendricks - 3.5
Jonathan Spine fusion, 3 heart surgery, Lung infection
Howard Thomas San Pedro Sampler
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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

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Duchenne Muscular Dystrophy

Presented by: Sujitha B Subramaniam 11408044 IV yr Genetic Engineering SRM University