Neuromuscular Disorders –Duchenne and Becker’s Muscular

Dystrophy

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Dr. Kalpana MallaMD Pediatrics

Manipal Teaching Hospital

Neuromuscular disorders

Consists 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

Neuropathy

• Distal distribution (except- juvenile spinal muscular atrophy

• Acute onset• Tendon reflexes – lost• Sensory abnormalities –neuropathy

Classification

1. Muscular dystrophies: -X-linked recessive -Duchenne / becker Limb –girdle MD - Cong muscular dystrophies - Facioscapulohumeral - Oculopharyngeal - Myotonic dystrophy - Scapuloperoneal dystrophy

Classification 2.Disorder of neuromuscular junction - Myesthenia gravis3.Myotonic syndromes4. Myopathies a ) Congenital myopathies b ) Endocrine - Hypothyroidism - Hyperparathyroidism

Classification

b ) Endocrine - Steroid-induced - Hyperaldosteronism

C ) Metabolic – K-related periodic paralysis - Mitochondrial disorders

Classification

5. Inflammatory myopathies (myasthitis):A. Idiopathic – Juvenile dermatomyositis - polymyositisB. Infectious – viral, parasitic, bacterial, fungal

6. Floppy infant syndrome

Evaluation

Clinical – • Muscle – bulk, tone ,power, • Head lag• See involvement of face, tongue, palate ,extra- ocular muscles• Fasciculations – sign of denervation

Evaluation

• Undescended testes, funnel shaped thorax -congenital NMD

• Generalized hypotonia, delayed motor development

Laboratory findings

• Serum enzymes – CPK

• Nerve conduction velocity- motor & sensory conduction measured electrophysiologically

• Electromyelography - records maximum voluntary contraction of muscle

Laboratory findings

• Muscle biopsy – most important, specific and diagnostic (Vastus lateralis)• Nerve biopsy (sural nerve)• ECG-cardiac evaluation in myopathies

Duchenne muscular dystrophy

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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

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Duchenne Muscular Dystrophy

• Commonest muscular dystrophy

• Incidence- 1/3600 male birth

• Inheritance – X- linked recessive 30% - new mutations sporadic

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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 recessive

Features-1.Only males are affected. All his daughters will be

carriers as they receive abnormal X from father

2. Will not manifest in females- 50% sons affected 50% daughters will be carriers when the mother is a carrier

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X-Linked recessive

3.Normal sons do not transmit disease

4.Pattern of inheritance is oblique as only males on the maternal side are affected

5.Females may be affected when affected male marries a carrier female/or when only one X chromosome is present

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X-Linked recessive

6. Fresh mutations are known

7. Carriers may have biochemical abnormalities

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• 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

Gets up climbing up his legs- Gower’s sign

• 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

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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

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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)

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EMG

• Electromyography (EMG) shows characteristic myopathic features but is not specific for Duchenne muscular dystrophy

• Nerve conduction velocity- normal, No evidence of denervation

• Diagnostic (Vastus lateralis/ Gastrocnemius)Myopathic changes – • endomysial connective tissue proliferation• Scattered degenerating and regenerating myofibers• Foci of mononuclear inflammatory cell infiltrates

Muscle biopsy –

Muscle biopsy

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Others

• Cardiac evaluation • CXR• ECG• ECHO• Molecular genetic diagnosis –

Immunohistochemical staining of section of muscle biopsy or by DNA analysis from peripheral blood -- absent dystrophin

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• Molecular genetic diagnosis - demonstrating deficient or defective dystrophin by immunohistochemical staining of sections of muscle biopsy

Treatment• No medical cure or a method of slowing its

progression.• To improve mobility:

– Physical therapy

– Surgery on tight joints

– Prednisone

– Non-steroidal medications

– Wheelchair

Management

Multidisciplinary approach:• Exercise – physical exercise, physiotherapy • Dietary – prevent obesity • Orthopedic • Psychological• Education • Genetic counselling

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• 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

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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

Dermatomyositis

Pathognomonic feature -Gottron's papules overlying the dorsal interphalangeal joints.

Gottron's sign:

Erythematous or violaceous atrophic macules and plaques overlying the dorsal interphalangeal joints and sparing the interphalangeal spaces

Heliotrope

Characteristic finding a violaceous eruption with periorbital edema.

Shawl sign. Poikilodermatous macules appear in a "shawl" distribution over the shoulder, arms and upper back

Mechanic's hand.

Fissured, scaly, hyperkeratotic and hyperpigmented hands are suggestive of manual labor

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