The pattern of inheritance of Duchenne muscular dystrophy (DMD)
is as follows:
- DMD is inherited in X - linked recessive pattern.
- It means that the mutated gene is present on the X
chromosome.
- Plus it is recessive. This means in the presence of a normal X
chromosome, its expression is suppressed.
- Therefore in case of a female offspring, she has an abnormal X
chromosome ( with the recessive allele)and a normal x chromosome.
As a result, the female child will be a carrier but will not
develop the disease.
- Now, let us understand this with Punnett squares. Punnett
squares help to understand the possible combination of genotypes
that can occur.
Here the 'x' denote the chromosome with the chromosome with the
mutated gene
The results are:
- All females are phenotypically normal
- 50% of the females are carriers
- 50% of the male offsprings are diseased. The male child
recieves his X chromosome from his mother. If he recieves an
abnormal X chromosome, he will develop the disease.
Pathogenesis:
- In DMD, the dystrophin gene present on the X chromosome ( short
arm ) is mutated.
- This gene produces a protein called dystrophin
- The dystrophin protein is responsible for connect the
cytoskeleton of each muscle fibre to underlying basal lamina.
- Absence of dystrophin leads to excessive influx of calcium into
the sarcolemma
- This leads to mitochondrial dysfunction. This leads to the
release of stress induced reactive oxygen species
- It also leads to release of Ca+ dependent proteases and
chemokines
- This leads to degeneration of muscle necrosis and
degeneration.
- This leads to regeneration of muscle fibres but is not able to
keep up with the rate of degeneration.
- The muscle are replace with fibro-fatty tissue.
Clinical manifestations:
Stage 1 - Presymptomatic phase:
- Asymptomatic but elevated creatine kinase
Stage 2 - Early ambulatory phase
- Waddling gait due to hip girdle muscle weakness
- Progressive weakness of the proximal muscles (neck, shoulders
and arms)
- Meryon's sign - when the child is lifted by the examiner by one
arm encircling the patient's chest, the child is unable to contract
shoulder muscles and slides through the examiner's grasp.
- Toe - walking
- The child is able to climb stairs
- Grower sign positive - the child climbs up his legs with his
hands to rise up from the floor
Stage 3 - Late ambulatory stage
- The patient develop difficulty in walking
- Difficulty in climbing up the stairs
- Respiratory muscle weakness develops gradually. the forced
vital capacity reduces and noturnal hypoxemia develops. This gives
rise to lethargy and early morning headache.
- Cannot rise from the floor
Stage 4 - Early non-ambulatory stage
- Patient is able to maintain postures and self propel onself for
sometime
Stage 5 - Late ambulatory stage
- Scoliosis develops
- The patient becomes more wheel chair dependent
- Respiratory or circulatory failure develop by the age of 30
yrs
- Contracture may also develop as the muscle tissue is replace by
fibrofatty tissue and lack of movement
Treatment: The treatment interventions can be divided into
- Non - Pharmacological treatment
- Positiing devices - these devices help the child to sit, lie
and stand
- Braces and splits - to prevent deformities from developing and
provide support
- Nutritional counselling - to prevent obesity
- Psychological counselling
- Pharmacological treatment
- Steroid therapy - prednisolone - suppress the cytotoxic t-cell
expression from the necrotic muscle cells.
- Deflazocort - this is a derivative of prednisolone which is
carbohydrate sparing and bone sparing. It has less weight gain side
effects
- Golodirsen - it is a antisense oligonucleotide. It increases
the level of dystrophin in the muscles
- Ataluren - This drug overrides the nonsense stop translation
signals induced by dystrophin mutated gene. This lead to the
production of the protein completely.
- Surgical intervention to release contracture
and spinal deformity