INTERNATIONAL SCHOOL OF MEDICINE

Research studies on Duchenne Muscular Dystrophy.

Presented By:-Mohammed Abdul Aziz -4th GroupDinesh Pal Singh- 3rd GroupTanwee Fatima - 3rd GroupSana Momin - 3rd Group

Definition

Ducchenne muscular dystrophy is most common ofseveral childhood muscular dystrophies and it is aninherited disorder ( X-linked recessive ) Characterizedby progressive degeneration of muscle.

Dystrophin-Glycoprotein complex:-

Dystrophin is part of a group of proteins (a proteincomplex) that work together to strengthen musclefibers and protect them from injury as musclescontract and relax.

The dystrophin complex acts as an anchor,connecting each muscle cell's structural framework(cytoskeleton) with the lattice of proteins andother molecules outside the cell (extracellularmatrix).

Dystrophin provides strength to muscle cells bylinking the internal cytoskeleton to the surfacemembrane

Its Effect on cell:-

Dystrophin provides strength to muscle cells by linking the internal cytoskeletonto the surface membrane. Without this structural support, the cell membranebecomes permeable.

Mitochondrial dysfunction gives rise to an amplification of stress-inducedcytosolic calcium signals and an amplification of stress-induced reactive-oxygenspecies production. In a complex cascading process that involves severalpathways and increased oxidative stress within the cell damagesthe sarcolemma and eventually results in the death of the cell.

As components from outside the cell are allowed to enter the internal pressureof the cell increases until the cell bursts and dies.

Muscle fibers undergo necrosis and are ultimately replacedwith adipose and connective tissue.

How Gene Defects:-

Mutations of dystrophin gene lead to an absence of or defect in the proteindystrophin, which results in progressive muscle degeneration.

Mutation of the DMD gene is deletion of 1 or more exons, Duplications ,nonsense or splice site mutations

The most common mutation are repeats of the CAG nucleotides.

Although there is no clear correlation found between the extent of the deletionand the severity of the disorder, DMD deletions usually result in frameshift.

Mutations within the dystrophin gene can either be inherited or occurspontaneously during germline transmission.

Disease overview:-

DMD is a severe type of muscular dystrophy. Thesymptom of muscle weakness usually begin aroundthe age of four in boys and worsens quickly.

Typically muscle loss occurs first in the upper legsand pelvis followed by those of the upper arms.

The disorder is X-linked recessive. Females typicallyare carriers for the disease, while males are affected.A female carrier will be unaware she carries amutation until she has an affected son.

Symptoms :-

Delayed Onset Walking , Difficulty in performing a standing jump Waddling when walking Difficulty standing up Enlarged Calves ( Pseudo hypertrophy due to fat infiltration )

Muscle contractures of Achilles tendon and hamstrings impair functionality because the muscle fibers shorten and fibrose in connective tissue

Difficulty with motor skills.

Skeletal deformities (including scoliosis in some cases)

Higher risk of neurobehavioral disorders

learning disorders (dyslexia)

non-progressive weaknesses in specific cognitive skills (in particular short-term verbal memory), which are believed to be the result of absent or dysfunctional dystrophin in the brain.

Signs:-

Gower’s sign

Signs:-

Diagnosis:-

The diagnosis of a dystrophinopathy is suspected based upon:

Characteristic age and sex

Presence of symptoms and signs suggestive of a myopathicprocess

Markedly increased serum creatine kinase values

Myopathic changes on electromyography and muscle biopsy

A positive family history suggesting X-linked recessive

Serum muscle enzymes:-

Markedly raised serum CK level, 10-20 times the upper limit ofnormal

– Levels peak at 2-3 years of age and then decline withincreasing age, due to progressive loss of dystrophic musclefibres

Elevated serum ALT, AST, aldolase and LDH

Electromyography

Needle electromyography

Short duration, low amplitude polyphasic motor unitpotentials in proximal muscles

Over time, some of these areas become electrically silent

Muscle biopsy

Gold standard fordiagnosis

Performed when genetictesting is negative, or theclinical phenotype isatypical

Molecular Genetic Testing

Multiplex polymerase chain reaction (PCR),

Multiplex ligation-dependent probe amplification (MLPA) hasprovided a more sensitive technique for detecting deletions.

If MLPA testing is negative, the DMD gene can be tested forpoint mutations.

Genetic Analysis

Molecular genetic testing is indicated for patients with anelevated serum CK level and clinical findings suggestive of adystrophinopathy.

The diagnosis is established if a disease-causing mutation of thedystrophin gene (DMD) is identified

Deletion of one or more exons of DMD gene

Duplication of one or more exons of DMD

Small insertions/deletions/point mutations/splicingmutations of DMD gene

Treatment:-

There is no cure yet for DMD, however case and symptom management is currently “successful”.

Treat respiratory problems.

Treat cardiac problems.

Glucocorticoids therapy.

Drugs used to improve muscle strength.

Utrophin (sometimes can be substituted for dystrophin)

Complications:-

Cardiomyopathy

Congestive heart failure (rare)

Deformities

Heart arrhythmias (rare)

Mental impairment (varies, usually minimal)

Permanent, progressive disability

Decreased mobility

Decreased ability to care for self

Pneumonia or other respiratory infections

Respiratory failure .