Neuromuscular Disorders –Duchenne and Becker’s Muscular Dystrophy Dr. Kalpana Malla MD Pediatrics Manipal Teaching HospitalDownload more documents and slide shows on The Medical Post [ www.themedicalpost.net ]
Neuromuscular disordersConsists of - Motor neuron in brain stem - Ventral horn of spinal cord - Its axon with other axon forms peripheral nerve - Neuromuscular junction - All muscle fibers innervated by single motor neuron
May be• Genetic• Congenital• Acquired• Acute• Chronic• Progressive• Static
Myopathy• Proximal distribution of weakness and muscle wasting except- myotonic muscular dystrophy• Slow progression• Tendon reflexes – preserved• Sensation – intact
What is Duchenne Muscular Dystrophy?• The disease characterized by: - Early onset often before school age - Progressive muscular deterioration and death by 14 - 18 years of age - Defect on a large gene on X chromosome 17
FACTS• The abnormal gene is on the X chromosome at the Xp21 locus• Becker muscular dystrophy is the same fundamental disease as Duchenne dystrophy, with a genetic defect at the same locus, but clinically it follows a milder and more protracted course
X-Linked recessiveFeatures-1.Only males are affected. All his daughters will be carriers as they receive abnormal X from father2. Will not manifest in females- 50% sons affected 50% daughters will be carriers when the mother is a carrier 20
X-Linked recessive3.Normal sons do not transmit disease4.Pattern of inheritance is oblique as only males on the maternal side are affected5.Females may be affected when affected male marries a carrier female/or when only one X chromosome is present 23
X-Linked recessive6. Fresh mutations are known7. Carriers may have biochemical abnormalities 25
• A muscular dystrophy is distinguished from all other neuromuscular diseases by four obligatory criteria:(1) It is a primary myopathy(2) It has a genetic basis(3) The course is progressive(4) Degeneration and death of muscle fibers occur at some stage in the disease
DMD - Muscle wasting• In DMD - attachment of muscle fibers to their surrounding endomysium (extracellular matrix) becomes weakened due to mutations in the dystrophin gene.• The absence of dystrophin leads to increased death and destruction• In turn, scar tissue (a mix of collagen and blood vessels) replaces the muscle fibers, and it can gradually contract leading to increased muscle rigidity
Clinical features• Asymptomatic at birth - Early gross motor skills ( rolling over, sitting, standing) may be normal or mildly delayed• Poor head control in infancy may be the first sign of weakness• Walking achieved at the normal age - but hip girdle weakness may be seen in subtle form as early as the 2nd year - waddling gait
Clinical features• Weakness starts in pelvic girdle- Extensor muscles of back affected – lordosis to stabilize spine by bony opposition• Toddlers may assume a lordotic posture when standing to compensate for gluteal weakness.• Cannot bend forward without falling
• Presents – 2- 4 yrs• Frequently falls, has difficulty getting up, climbing stairs or getting in and out of a car• An early Gower’s sign is often evident by age 3 yr and is fully expressed by age 5 or 6 yr
• Enlargement of the calves (pseudohypertrophy) and wasting of thigh muscles is a classic feature.• Next most common site of muscular hypertrophy - tongue, forearm.
• Pseudohypertrophy also seen - triceps, quadriceps• Pseuhypertrophy of muscle fibers - infiltration of muscle by fat, and proliferation of collagen.• Fasciculations of the tongue do not occur.
• Pseudohypertrophy seen in supra, infraspinatus, deltoids – Valley sign 34
Clinical features• Hypertrophy of calf muscles with tightening of tendo achillis-toe walking• By 8 yrs –walking becomes difficult• Knee jerks disappear early but ankle jerk may be preserved• Positive valley sign
Clinical features cont.• By 12 yrs – wheel chair bound –• Loss of lordosis - lose stabilization of spine ↓ Tendency to tilt to one side ↓ Develop– Scoliosis ↓ Bunching of ribs leads to E. reflux with acute esophagitis, hematemesis, aspiration pneumonitis 36
Clinical features cont.• Intellectual impairment in all• 20- 30% - IQ < 70• Cardiac muscle may be affected – Cardiomyopathy• Die by 18 yrs – respiratory failure, pneumonia, aspiration, heart failure 37
Clinical features• By 12 yrs –wheel chair bound – loss of lordosis lose stabilization of spine – tendency to tilt to one side - develop –scoliosis-bunching of ribs leads to E. reflux with acute esophagitis, hematemesis, aspiration pneumonitis• Contractures most often involve the ankles, knees, hips, and elbows.• Scoliosis is common.
• The function of distal muscles is usually well preserved - child can continue using eating utensils, a pencil, and a computer keyboard.• Respiratory muscle involvement - weak and ineffective cough, frequent pulmonary infections• Pharyngeal weakness - episodes of aspiration, nasal regurgitation of liquids, and an airy or nasal voice quality• Extraocular muscles - well preserved
• Death occurs usually at about 18 yr of age.• The causes of death are respiratory failure in sleep, intractable heart failure, pneumonia, or occasionally aspiration and airway obstruction
Laboratory findings• Serum creatinine phosphokinase (CPK) even in presymptomatic stages, including at birth > 10,000 units ( range 15,000 – 35,000 IU/L) Normal level < 160 IU/L - In severe cases, maybe lower• Other lysosomal enzymes of muscles: Aldolase, Aspartate aminotransferase – increased (less specific) 42
EMG• Electromyography (EMG) shows characteristic myopathic features but is not specific for Duchenne muscular dystrophy• Nerve conduction velocity- normal, No evidence of denervation
• Physiotherapy delays but does not always prevent contractures.
• Preservation of a good nutritional state• Adequate calcium intake - to minimize osteoporosis• sedentary children burn fewer calories than active children and depression is an additional factor – these children tend to eat excessively and gain weight – Obesity makes a patient with myopathy even less functional
Management• Pharmacological-treat complication• Suggestion – To reduuce rate of deterioration cyclical ( 10 days /month)-catabolic steroid – prednisolone low dose -decreases the rate of apoptosis and may decelerate the myofiber necrosis• Cyclosporin – under study
Some approaches• Experimental approach – Myoblast transfer therapy• Unproven approach – I/M injection of recombinant dystrophin gene• "minigenes," which carry instructions for a slightly smaller version of dystrophin 53
Advances in Gene Therapy• Researchers - created the so-called gutted virus, a virus that has its own genes removed so that it is carrying only the dystrophin gene
To improve breathing:• Pulmonary infections should be promptly treated.• O2 therapy• Ventilator• Scoliosis surgery• Tracheotomy
• Cardiac decompensation often responds well to digoxin, at least in early stages.• Immunizations for influenza virus and routine vaccinations are indicated.
GENETIC COUNCELLING• Prenatal diagnosis for women having risk pregnancies - with a family history of muscular dystrophy.• Identification of dystrophin gene exon deletions in a male fetus - Couples may elect to terminate the pregnancy if the fetus is affected.• Carrier status may be determined in the mother and siblings of the proband.
Becker muscular dystrophy• This Ds was first described by Becker and Klener in 1955• X-linked recessive• Late onset – ambulatory till late adolescence• Calf pseudohypertrophy, cardiomyopathy, increased CPK are similar to DMD• Learning disabilities are less• Death – in late 20s but severely disabled; fewer than half of patients are still alive by age 40 yr
DermatomyositisPathognomonic feature -Gottronspapules overlying the dorsalinterphalangeal joints.
Gottrons sign: Erythematous or violaceous atrophic macules and plaques overlying the dorsal interphalangeal joints and sparing the interphalangeal spaces
HeliotropeCharacteristic finding a violaceous eruption with periorbital edema.
Shawl sign. Poikilodermatous macules appear in a "shawl" distribution over the shoulder, arms and upper back
Mechanics hand.Fissured, scaly, hyperkeratotic and hyperpigmented hands are suggestive of manual labor
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