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