DUCHENNE MUSCULAR DYSTROPHY

BY ANIEDU, UGOCHUKWU I.

(B.Sc, MD(in view)

History

Introduction

Genetics

Pathogenesis

Clinical features/Diagnosis

Prognosis

Treatment

Summary and Conclusion

References

The disease was first described by the Neapolitan physician Giovanni Semmola in 1834 and Gaetano Conte in 1836

DMD is named after the French neurologist Guillaume Benjamin Amand Duchenne

In an 1861 publication, Duchenne established the diagnostic criteria that are still used

William Richard Gowers was the first to deduce the genetic basis for the disease

In 1986, Louis M. Kunkel provided molecular genetic confirmation of the X-linked recessive inheritancepattern

The muscular dystrophies are a group of genetically determined, progressive diseases of skeletal muscle

They are non-inflammatory and have no neurological cause

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy affecting 1 in 3500 males born worldwide.

Seen in males only (expect in females with TURNER’S SYNDROME)

DMD is inherited in an X-linked recessive

pattern(defect at Xp21 locus)

Females will typically be carriers for

the disease while males will be

affected

The son of a carrier mother has a 50%

chance of inheriting the defective gene

from his mother.

The daughter of a carrier mother has a

50% chance of being a carrier or having

two normal copies of the gene.

The disorder is caused by a mutation in

the dystrophin gene, the largest gene

located on the human X chromosome which

codes for the protein dystrophin

Without dystrophin, muscles are susceptible

to mechanical injury and undergo repeated

cycles of necrosis and regeneration.

Ultimately, regenerative capabilities are

exhausted or inactivated

Dystrophin is responsible for connecting

the cytoskeleton of each muscle fiber to the

underlying basal lamina

The absence of dystrophin permits

excess calcium to penetrate the sarcolemma

leading to mitochondrial dysfunction

mitochondrial dysfunction gives rise to an

amplification of stress-induced cytosolic calcium

signals and an amplification of stress-

induced reactive-oxygen species (ROS) production.

Increased oxidative stress within the cell damages the sarcolemma and

eventually results in the death of the cell.

Muscle fibers undergo necrosis and are ultimately replaced

with adipose and connective tissue

Age of onset is between 2-6 years of age

Stage 1 – Presymptomatic

Creatine kinase usually elevated

Positive family history

Stage 2- Early ambulatory

clumsy & Waddling gait, manifesting in children aged 2-6 years; secondary to hip girdle muscle weakness

Inexorable progressive weakness in the proximal musculature, initially in the lower extremities, but later involving the neck flexors, shoulders, and arms

Meryon’s sign

child slips through examiner’s grasp when lifted under arms

Possible toe-walking

Can climb stairs

Gower's sign

-'climbing up legs' using the hands when rising from the floor

Stage 3- Late ambulatory

More difficulty walking

Around age 8 years, most patients notice difficulty with ascending stairs

and respiratory muscle strength begins a slow but steady decline

Cannot arise from the floor

The forced vital capacity begins to gradually wane, leading to symptoms

of nocturnal hypoxemia such as lethargy and early morning headaches

Stage 4 – Early nonambulatory

Can self-propel for some time

Able to maintain posture

Possible development of scoliosis

Stage 5 – Late nonambulatory

Scoliosis may progress, especially when more wheelchair dependent

If wheelchair bound and profoundly weak, patients develop terminal

respiratory or cardiac failure, usually by the early 30s

poor nutritional intake can also be a serious complication in

individuals with severe end-stage DMD

Contractures may develop

most are unable to ambulate independently by age 10

most are wheelchair dependent by age 15

most die of cardio respiratory problems by age 25-30

There is no cure yet for DMD, howevercase and symptom management such as:

• physical therapy • positioning aids - used to help the

child sit, lie, or stand • braces and splints - used to prevent

deformity, promote support, or provide protection • medications

• nutritional counseling • psychological counseling

is currently successful

Conclusively, there are many clinical trials in process, like

administering Albuterol (beta adrenergic receptor agonist drug

that increases strength and muscle mass) also, they want to

treat with Utrophin (sometimes can be substituted for

dystrophin)

Embryonic stem cell transplants is another treatment they are

looking into. It is hoped that injecting healthy, nonspecialized

stem cells into DMD victims will cause the stem cells to

specialize and produce structurally and functionally correct

dystrophin. If dystrophin can be produced, it may slow the

progression of the disease, or cure it altogether.

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