http://www.ensembl.org/Homo_sapiens/geneview?gene=ENSG00000157630

It Affects…

Cardiac Muscle

Skeletal Muscle

Nervous Systemincrease in serum Creatine Kinase which is a marker for muscle damage

Schizophrenia or related spectrum disorders

susceptibility to mental illnesses

mental retardation

It Increases Chances of…

Exertional cramping and Myoglobinuria (severe muscular problems

Exercise intolerance

A fault in Dystrophin leads to the formation of a faulty protein in muscle fibers.

When Dystrophin is abnormal the muscle fibers gradually break down and the muscles

slowly become weaker.

These Dystrophin abnormalities in muscle provide a very good test for the diagnosis

of Becker MD.

? ?

X• Several affected males in a large portion of people reported by Becker (1957) had produced children and the resulting pedigree pattern was consistent with X-linked inheritance.

Since it is X-Linked recessive, Becker MD ONLY affects males, but may be transmitted by unaffected female carriers of the gene to their sons.

The sons of carriers each have a 50:50 chance of being affected. The daughters of carriers each have a 50:50 chance of being carriers. The mothers and sisters of affected males may be carriers and may need to be tested. The sons of affected males do not carry the gene and will not be affected or transmit the gene. However, all the daughters of affected males are carriers of the gene and may transmit the disorder to the following generation.

Cure? There is no cure at present

Research is proceeding to try to find a way to induce the muscles to form Dystrophin.

Any treatment, which may be found to be effective in Duchenne MD, would

theoretically be effective also in the Becker type.

Diagnosis before the age of two or three (before symptoms are very obvious) is possible through:

A blood test - this will show very high levels of a protein called Creatine Kinase (CPK).

A muscle biopsy - removal of a small piece of muscle tissue for examination. This will show if there is a severe Dystrophin deficiency.

Electromyography (EMG) - an examination of muscle activity. It involves inserting a needle into the muscle.

Human Mutation Database Says…

The Mutation is in…Dystrophin

Location : Xp21 Mutations in this gene were

first reported in 1987Cause: X-Linked recessive, low

Dystrophin levelsOccurrence: 1/15000 boys

Muscle Hypertrophy: Similar to Duchenne MD, but less severe

Onset: Appears in teens, progressive

Weakness (Cardiomyopathy)

• May be especially prominent in quadriceps or hamstrings

• Extreme calf pain upon exercise

• Failure to walk during the 16-80 year period

• Mental Retardation

• Varied muscle fiber size

Methods Of Treatment Very Little Known about Human Muscle Diseases

All Patients are treated differently

Some Treated with:

Drugs, Diet, Exercise

Gene Therapy

Viral Vector/ Anti-Viral ( bacterial plasmids)

Cell Therapy

Myoblast Transplantation-Myoblasts, the precursors of myofibers can be generated to cause the formation of mosaic fibers which can then be used as an alternative for low levels of Dystrophin.

Mutations/Variations in Gene

Effect of Dystrophin Mutation on Gene Reading Frame

Cause of Mutation: Reading Frame Not Shifted

Result: No Stop Codons, Produces internal deletions or duplications of protein

Cause of Mutation: Reading frame shifted ("Out-of-frame") Result: Production of stop codons and the production of small, unstable protein, with impaired membrane attachment = absence of Dystrophin

Types of Mutations: Deletions/Duplications

• Point Mutations- Along the entire gene

• Causes premature translation (out of frame)

• Deletions / DuplicationsLocation

•Majority of deletions found at the 3' end region

•5' end deletions in 18% of cases

THESE LARGE CHROMOSOMAL MUTATIONS CAUSE DMD AND BMD!

Types of Mutations (cont)

Nucleotide substitutions (missense / nonsense) 122Nucleotide substitutions (splicing) 49Nucleotide substitutions (regulatory) 0Small deletions 67Small insertions 26Small indwells 7Gross deletions 93Gross insertions & duplications 45Complex rearrangements (including inversions) 2Repeat variations 0TOTAL 411

Most prominent in children under 12 years

Left- Degeneration of several neighboring muscle fibers

Center- Regeneration- Numerous small rounded muscle fibers

Right- A group of intermediate sized muscle fibers

• Increased Endomysial Connective Tissue

• Variable Fiber Size- Small Fibers are Rounded

• Internal Nuclei

Normal Dystrophin Staining around the rim of the muscle fibers

Reduced Dystrophin

Staining

Expression in Human Tissues

Contrast Through Electrophoresis of

Duchenne/Becker MD Lane 1- Becker MD, Dystrophin normal in size but reduced abundance

Lane 2- Becker MD, Dystrophin reduced in size and abundance

Lane 3- Normal Dystrophin and normal amount and size

Lane 4- Duchenne MD, almost no protein present

Lane 5- Dystrophin has severely reduced in abundance

Delivering a Boost to Dystrophinlike Proteins•At least two proteins have a function similar to that of Dystrophin, and efforts are under way to identify drugs that could boost those proteins in Dystrophin-deficient muscle.

•Utrophin is a small protein that looks a lot like Dystrophin; it actually stands in for Dystrophin in fetal muscle, but gets largely replaced and ends up in small patches in mature muscle.

•Supported researchers have shown that when Dystrophin-deficient mice are genetically engineered to overproduce utrophin or integrin, they're protected against BMD.

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BMD Drugs in the Pipeline

• The only drugs of clinically proven benefit for DMD are Prednisone and related anti-inflammatory steroids.

•Side effects: Weight gain, loss of bone density

Albuterol — A medication that relaxes smooth muscle in the airways, and is traditionally used to treat asthma. Two provocative studies showed that it appears to increase strength in people without neuromuscular disease.

Coenzyme Q10 —It's available as a dietary supplement, and might increase the energy store available to muscle while cleaning up destructive free radicals.

Creatine — Also involved in cellular energy production, and available as a dietary supplement. Athletes use it to build muscle.

Gentamicin — An antibiotic that might be able to override genetic mutations that cause protein shortening. Toxicity with prolonged exposure may limit its use.

Glutamine — An amino acid (protein building block) that's available as a dietary supplement. It's used by body builders, and may help those with muscle injuries maintain or build muscle.

Oxatomide — An antihistamine used to treat hay fever. It may cut down inflammation that contributes to muscle damage in DMD.