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DYSTROPHY:•abnormal growth
MUSCULAR DYSTROPHY:A group of hereditary disorders characterized by:•a primary myopathy•has a genetic basis•has a progressive course•has degeneration & death of muscle fibers stage
MD is painless & affects skeletal or voluntary muscles WITHOUT involvement of the nervous system.
INTRODUCTIOINTRODUCTIONN
Duchenne MD Becker MD Emery-Dreifuss MD Myotonic dystrophy Limb-girdle MD Facioscapulohumeral MD Congenital MD Oculopharyngeal MD Distal MD
Most common form
1:3600 liveboy infant boys
Affects MAINLY boys
Symptoms usually start between ages 2-6 YEARS OLD
X-linked recessive inheritance,30% patients have new mutation
DYSTROPHIN: 427-kd cytoskeletal protein encoded by the gene at Xp21.2 locus
Molecular defects in the dystrophinopathies: intragenic deletions, duplications, or point mutations
Most mutations are due to deletion of exons 46-51
Defect causes alteration of the translational reading frame of mRNA
DYSTROPHIN
absence of dystrophin
membrane defect
Increased calcium influx
Increased intracellular calcium
Increases proteases
Increases phospholipases
Increases ATPase
Increases endonucleases
Reduces oxidative phosphorylation
Cell death
Gradually lost of muscles Progressive weakness
Lost of muscle is replaced by fat & fibrous tissue
Fibrous tissue causes contractures and stiffness
Cell death
hypertrophy
Motor functions problem-poor head control-hip girdle weakness-lordotic posture
Motor functions problem-poor head control-hip girdle weakness-lordotic posture-Gowers sign
Lordotic posture
Motor functions problem-poor head control-hip girdle weakness-lordotic posture-Gowers sign-Trendelenburg sign
Gowers signTrendelenburg sign
Restrictive ambulationwithout orthopedic intervention: -confined to wheelchair by 7 y.o-walk with difficulty up to 10 y.owith orthopedic intervention:-most are able to walk up to 12 y.o
Respiratory muscle weakness-ineffective cough-frequent pulmonary infections-decreasing respiratory reserve
Pharyngeal muscle weakness-aspiration-nasal regurgitation-airy / nasal voice quality
Muscle hypertrophy & muscle wasting-calves+++, thigh –---tongue++-muscle of the forearm+
Scoliosis
Contractures
Cardiomyopathy-persistent tachycardia-myocardiac failure
Smooth muscle dysfunction-GIT is the most common
CNS manifestations-intellectual impairment-mentally retarded-epilepsy
Facial muscle weakness
GIT and GUT symptoms-incontinence
Duchenne MD usually preserves:-distal muscle functions-extraocular muscles-voluntary sphincter muscles-deep tendon reflexes
ankle reflex > knee reflexbrachioradialis reflex > biceps / triceps brachii reflexes
Positive clinical features
INCREASED serum CK
NORMAL serum CK
Blood polymerase chain reaction
(PCR)
Muscle biopsy
MUSCULAR DYSTROPHY
WITH family history
WITHOUT family history
Western blotImmunohisto-
chemical method
or
PARAMETERS LABORATORY FINDINGSSerum CK(N: < 160 IU/L)
•Consistently elevated in Duchenne MD, even in presymptomatic and at birth stage•Usually: 15 000-35 000 IU/L•At terminal stage: will be lower than a few years earlier
Aldolase •Less specific•Increased
Aspartate aminotransferase
•Less specific•Increased
Echocardiography (ECG)
•Essential•Should be repeated periodically
Electromyography (EMG)
•Less specific•Result: -no denervation -motor & sensory nerve conduction velocities are normal
PARAMETERS LABORATORY FINDINGSPolymerase Chain Reaction (PCR)
•Can identify 98% of deletions but cannot detect duplications•About 1/3 of boys with Duchenne or Becker MD have a false-normal PCR
Immunohistochemistry of muscle
•Diagnostic and prognostic factor•Myopathic changes:1. endomysial CT proliferation2. scattered degenerating & regenerating myofibers3. foci of mononuclear inflammatory cell infiltration4. architectural changes of functioning fibers5. dense fibers
1. endomysial CT proliferation2. scattered degenerating & regenerating myofibers3. foci of mononuclear inflammatory cell infiltration4. architectural changes of functioning fibers5. dense fibers
PARAMETERS LABORATORY FINDINGSWestern blot analysis
•More accurate than immunohistochemistry test•Result: DMD: <3% of normal BMD: -80% patient: 80-90% of normal -5%: normal size but reduced quantity -5% : abnormally large protein
Permanent disability
Mental impairment
Pneumonia or other respiratory infections
Respiratory failure
Cardiomyopathy
Most patients do not survive beyond their teens or early adulthood. Death occurs usually at about 18-20 y.o
Mostly due to respiratory failure in sleep, intractable heart failure, pneumonia, or occasionally aspiration and airway obstruction
There is NEITHER a medical cure NOR a method of slowing its progression
Much can be done to TREAT COMPLICATIONS and to IMPROVE THE QUALITY OF LIFE of affected children
Preservation of GOOD NUTRITION state-adequate calcium intake
DIETary restrictions-to avoid obesity
Take a good HEALTH CARE-avoid contact respiratory or contagious illness patient-promptly treat respiratory infections-immunization
PHYSIOTHERAPY-delays contractures
DRUGS-glucocorticoids
FOLLOW-UP6 monthly to observe progression of:- weakness in skeletal muscle- drug side effects - development of deformities- cardiac status
CARRIER DETECTION in female relatives at risk
PRENATAL DIAGNOSIS for new mutation in the embryo
Becker muscular dystrophy has the same fundamental disease as Duchenne MD (DMD)
ETIOLOGYETIOLOGY
Genetic defect is same as DMD; involving dystrophin gene at locus Xp21.2
Mutations preserve the reading frame and still permit translation of coding sequences but produce semifunctional dystrophin
Clinically it follows a milder and more protracted course.
Weakness usually start later than DMD
Boys usually remain ambulatory until late adolescence or early adult life
Calf pseudohypertrophy, cardiomyopathy, elevated serum CK level are similar with DMD
Learning disabilities are less frequent
Death often occurs in the mid to late 20s
Fewer than half of the patients are still alive by age 40 y.o
However, these survivors are severely disabled
Etiology:•X-linked recessive(Xq28)•Autosomal dominance (1q)
Clinical manifestat ions:•Onset: 5-15 y.o
+contractures of elbow & knee+scapulohumeroperoneal muscle wasting+normal intellectual function+severe cardiomyopathy
˚ hypertrophy of muscles ˚ facial weakness ˚ myotonia
•Laboratory f indings:•Serum CK : mildly elevated•Muscle biopsy
•Prognosis•Slow progression•Most survive to late adult
Managements:•Supportive treatments•Special attention to cardiac conduction defects
Etiology •Autosomal dominanceClinical manifestat ion
•Appear normal at birth / hypotonia / facial wasting•Onset at 5 y.o
+: -facial weakness -wasting: distal muscles, dorsal forearm, anterior compartment muscle of LL, sternocleidomastoid, tongue, proximal muscle -scapular winging -Gowers sign -speech: poorly articulated -smooth muscle weakness -cardiac: heart block & arrythmia -endocrine abnormalities -immunologic deficiency -eye: cataracts, ophthalmoplegia -CNS: intellectual impairment
Laboratory f indings
•Serum CK: Normal / mildly elevated•DNA analysis: abnormal gene•Muscle biopsy
Managements •Treat complications•Physiotherapy & orthopedic treatment•Drugs for myotonia
Myotonic MD Myotonic MD (cont…)(cont…)
Etiology•Autosomal recessive•Autosomal dominance
Clinical manifestat ions:•Onset before middle or late childhood•Affect muscles of hip & shoulder girdle
+hypertrophy of the calves & ankle+lordotic posture+weakness of flexors & extensors+diminished tendon stretch reflexes+cardiac involvement
Laboratory f indings:•Serum CK: elevated•EMG & muscle biopsy: evidence of muscular dystrophy, but less specific•ECG: normal
Prognosis:•Rate of progression varies•Usually confined to wheelchair by 30 y.o
Etiology:•Autosomal dominance
Clinical manifestat ions:•Onset before middle or late childhood•Affect muscles of facial & shoulder girdle
+facial and shoulder girdle muscles weakness+pharyngeal & tongue weakness+hearing loss & retinal vasculopathy+scapular winging+Gowers sign +Trendelenburg sign
Laboratory f indings:•Serum CK: greatly elevated•EMG: nonspecific myopathic muscle potential
Prognosis:•Mild diseasew that leads to minimal disability
Etiology •Autosomal recessive-Ullrich type: defect in ≥1 of collagen VI genes-Fukuyama type: defect at 8q31-33 locus
Clinical manifestat ions
+: -arthrogryposis -hypotonia -thin muscle mass -hypoactive/absent tendon stretch reflexes -cardiomegaly & brain malformation (Fukuyama) -accompanied by other neurologic disease (exc Fukuyama) -microcephaly & mental retardation
Laboratory f indings
•Serum CK: moderately elevated•EMG: nonspecific myopathic features•Cardiac assessment•Brain imaging study•Muscle biopsy: essential for diagnosis-IHC study: absent of merosin protein
Managements •Supportive therapy
Arthrogryposis
Nelson Textbook of Pediatric (18th edition) by M. Kliegman, E. Behrman, B. Jenson & F. Stanton
Duchenne Muscular Dystrophy (3rd edition) by A. Emery & F. Muntoni