Download results in impaired pulmonary function

•inherited group of progressive myopathic disorders resulting from defects in a
number of genes required for normal muscle function
•Muscle weakness is the primary symptom..
•X-linked inheritance occurs with the following dystrophies: Duchenne and
Becker muscular dystrophies Emery-Dreifuss muscular dystrophy
dystrophinopathies.
• are caused by mutations of the dystrophin
gene
• Duchenne muscular dystrophy (DMD) is
associated with the most severe clinical
symptoms
• Becker muscular dystrophy (BMD) has a
similar presentation to DMD, but a relatively
milder clinical course
Duchenne
• Duchenne muscular dystrophy (DMD) is the
most common dystrophinopathy,
• resulting from complete absence of the
dystrophin gene product: the subsarcolemmal
protein, dystrophin
The dystrophin molecule anchors
the cytoskeleton of muscle cells
to the extracellular matrix, via the
dystrophin glycoprotein complex.
This includes the sarcoglycans
(mutations in which cause limbgirdle muscular dystrophies) and
dystroglycans.
Muscle cells that lack dystrophin
are mechanically fragile, and fail
after a few years, hence
progressive muscle weakness.
Fig. 6.4 ©Scion Publishing Ltd
GENETICS AND PATHOGENESIS
• DMD is a relentlessly progressive skeletal muscle disorder,caused by a
mutation in the X-linked dystrophin gene, resulting
in absence of a critical protein, dystrophin
• The gene spans a distance of more than2.5 million base pairs and is the
largest human gene isolated
to date
• In more than90 percent of males with the DMD genotype, there is an
absence of dystrophin resulting from an “out-of-frame” mutation that
disrupts normal dystrophin transcription
GENETICS AND PATHOGENESIS,….
• Dystrophin is located on the cytoplasmic face of
the plasma membrane of muscle fibers,
functioning as a component of a large, tightly
associated glycoprotein complex
• Dystrophin normally stabilizes the complex,
thereby shielding it from degradation.
• In its absence, the glycoprotein complex is
digested by proteases.
• Loss of these membrane proteins may initiate the
degeneration of muscle fibers, resulting in muscle
weakness
Duchenne muscular dystrophy
• the clinical onset of weakness usually occurs
between two and three years of age
• In some cases, the onset of symptoms occurs
later.
• Children also frequently have varying degrees
of mental retardation.
• an occasional child may have average or
above-average intelligence.
DMD: Clinical manifestation
• Weakness
• Cardiomyopathy
• Orthopedic complications
Weakness
• proximal before the distal limb muscles,
• the lower before the upper extremities.
• has difficulty running, jumping, and walking up steps.
• When arising from the floor, affected boys may also use hand
support to push themselves to an upright position, an action
termed Gower's sign.
• An unusual waddling gait, lumbar lordosis, and calf enlargement
are usually observed.
• Complaints of leg pain may also be found with early disease.
Patients are usually wheelchair bound by the age of twelve.
Cardiomyopathy
• primary dilated cardiomyopathy (DCM)
• conduction abnormalities, especially
intraatrial and interatrial but also involving the
AV node, and a variety of arrhythmias,
primarily supraventricular
• The cardiomyopathy is characterized by
extensive fibrosis of the posterobasal left
ventricular wall
• Significant mitral regurgitation
Cardiomyopathy,...
• The incidence of symptomatic cardiomyopathy
in patients with DMD increases gradually in
the teenage years
• about one-third of patients by age 14 years,
one half by 18 years, and all patients older
than 18
Orthopedic complications
• Fractures involving the arms and legs are
frequent. One series of 378 patients (ages 1 to 25
years) with DMD found that 79 (21 percent) had
experienced fractures The most common
mechanism was falling
• A progressive scoliosis develops in nearly all
children with DMD.
• Scoliosis, in combination with progressive
weakness, results in impaired pulmonary
function. With progressive disease, patients may
eventually suffer acute respiratory failure.
Physical examination
• pseudohypertrophy of the calf and
(occasionally) quadriceps muscles
• lumbar lordosis
• a waddling gait
• shortening of the Achilles tendons
• hyporeflexia or areflexia
DMD: Diagnosis
Gower’s sign
Becker muscular dystrophy
• the age of onset of symptoms of those with BMD
is usually later
• the degree of clinical involvement milder
• remain ambulatory at least until age 15 and
commonly into adult life
• Mental retardation and contractures are also not
as common or severe
• The distinction between BMD and limb-girdle
dystrophy is often hard to make in patients with a
negative family history for BMD
Becker muscular dystrophy,…
• cardiac involvement in BMD can be more severe
• echocardiography revealed evidence of cardiac
involvement in 60 to 70 percent of patients (mean age 18)
with subclinical or benign BMD
• Echocardiography reveals early right ventricular
involvement with the later development of left ventricular
dysfunction
• All four chambers are eventually involved with fibrosis,
• a cardiomyopathy with heart failure can be rapidly
progressive
• abnormalities of the AV node and infranodal conduction
system can result in fascicular and bundle branch block and
can progress to complete heart block.
Prognosis
• Patients with DMD are often confined to
wheelchair by about age 12 years and die in
their late teens or twenties from respiratory
insufficiency or cardiomyopathy
• Patients with BMD typically remain
ambulatory beyond the age of 16 years and
into adult life, and usually survive beyond the
age of 30 years
LABORATORY AND PATHOLOGIC
FINDINGS
•
•
•
•
•
•
Creatine kinase
Electrocardiogram
Electromyography
Muscle biopsy
Dystrophin analysis
Genetic analysis
SYMPTOM MANAGEMENT
•
•
•
•
Vaccination
Cardiac disease
Pulmonary complications
Complications related to anesthesia and
sedation
• Orthopedic interventions
• Nutrition
TREATMENT
•
•
•
•
•
Glucocorticoids
Gene therapy
Aminoglycosides
PTC124 therapy
Creatine
PROGNOSIS
• there may be some improvement between three
and six years of age. However, this is followed by
gradual but relentless deterioration, leading to
wheelchair confinement by the age of
approximately 12 years
• Most patients with DMD die in their late teens or
twenties from respiratory insufficiency (most
commonly) or arrhythmia secondary to
cardiomyopathy
• patients with BMD typically remain ambulatory
beyond the age of 16 years and into adult life;
they usually survive beyond the age of 30 years
and have a mean age of death in the mid 40s
• The most common cause of death is heart failure
from dilated cardiomyopathy, which also causes
considerable morbidity in these patients despite
their milder skeletal muscle involvement