Muscular Dystrophies Lhedaven C. Santos R.N.

Muscular Dystrophies Progressive hereditary degenerative diseases of the skeletal muscle Intact spinal motor neurons, muscular nerves, and nerve endings in the presence of severe degenerative changes in muscle fibers General features: –symmetrical distribution of weakness and atrophy –intact sensation –preservation of reflexes –heredofamilial Classified by clinical types, pattern of inheritance and by the abnormal gene or it’s protein product

Etiology The abnormal gene and the gene product for Duchenne and Becker identified by Kunkel in 1986 Dystrophin is the protein encoded by the affected gene Dystrophin absent in Duchenne and structurally abnormal in Becker Dystrophin in normal skeletal and cardiac muscle is localized in the sarcolemma (cytoplasmic site) and interacts with F-actin of the cytoskeleton (reinforcing structure of muscle cell) Dystrophin also bound to a complex of sarcolemmal proteins known as dystrophin associated proteins (DAP)

Etiology Loss of dystrophin leads to disruption of the dystroglycan-protein complex rendering the sarcolemma susceptible to breaks during contraction These defects are shown to allow ingress of EC fluid and calcium which activate proteases and cause protein degradation Leakage of CK into serum is then seen

Duchenne MD Incidence rate per 100,000 male births annually X-linked recessive 30% of cases represent new mutations Females can present disease if only one chromosome is present (Turner) or due to inactivation of the normal paternal X chromosome in large proportion of embryonic cells (decreased expression of the normal dystrophin allele)

Clinical findings Recognized usually in third year of life due to delay in motor milestones or due to frequent falls Latter sway back and waddling gait (weak gluteus medius) as well as climbing stairs become more affected Elevated CK may be the first clue

Clinical findings Muscles mostly affected –early: illiopsoas, quadriceps, gluteal –latter: pretibial, pectoral girdle (serratus, pectorals, latissimus) and upper limbs (biceps, brachioradialis) Muscles pseudo-hypertrophied –gastronemius, lateral vastus and deltoid –have rubbery feel and are less strong and hypotonic than normals

Clinical findings Weakness of abdominal and paravertebral muscles - lordotic posture and protuberant abdomen when standing and rounded back when sitting Weak extensors of the knee and hip - difficult to climb stairs or from a chair Use of hands to compensate for weakness when rising from sitting position or from floor

Gower’s maneuver 4 point position Hands up to thigh alternately

Clinical Findings Ocular, facial and bulbar and hand muscles are usually spared Limbs later become flaccid but as disability progresses fibrous contractures appear due to immobility Early in the disease there is equinovarus due to weak pretibial and peroneal muscles; later knee contractures appear due to weak quadriceps Pelvic tilt also seen later due to contracture of hip flexors this is compensated with lordosis when standing

Clinical Findings Contractures contribute to eventual loss of ambulation Scoliosis appears due to unequal weakening of paravertebral muscles usually after walking is not possible As muscle atrophy progresses DTR’s are lost Bones are thin and demineralized Can have mild mental retardation Although smooth muscle is usually spared heart is usually affected

Clinical Findings Cardiac problems: –Arrhythmias –prominent R waves in right precordial leads and deep Q waves in left precordial and limb leads as result of replacement fibrosis of the basal part of the left ventricular wall Death is usually 2dary to pulmonary infection and respiratory failure or in some due to cardiac decompensation No more than 25% of patients survive beyond 25 years

Muscle biopsy In all dystrophies loss of muscle fibers, residual fibers of small and larger size in haphazard arrangement and increase in lipocytes and fibrosis Duchenne -Early: segmental degeneration, phagocytosis and evidence of regenerative activity –basophilia of sarcoplasm –hyperplasia and nucleolation of sarcolemmal nuclei –myotubes and myocytes Necrotic sarcoplasm and sarcolemma removed by mononuclear cells Hyalinization of the sarcoplasm of muscle fibers as marker of irritability of m fiber Fibers eventually degenerate and disappear due to exhaustion of regenerative capacity

Becker Muscular Dystrophy Incidence estimated to be 3-6 per 100,000 male births X-linked disorder Later onset than Duchenne (mean age 12 years but range 5-45 y/o) Affects same muscles as Duchenne’s MD Patient non-ambulatory at y/o Death in 5th decade in most Less frequent cardiac involvement Serum CK times normal EMG: fibrillations, positive waves, low amplitude polyphasic MUP

Facioscapulohumeral MD Slowly progressive or nearly complete arrest Usually autosomal dominant 4 q35 Subvariety w/o facial weakness Onset usually 6-20 y/o Difficulty raising arms above head and winging of the scapulae first manifestations Invariably weakness of lower trapezius and sternal part of pectoralis Deltoids unusually large and strong Weak orbicularis oculi and oris, zygomaticus

Facioscapulohumeral MD Eventually atrophy involves sternomastoid, serratus, rhomboid, erector spinae, latissimus and deltoids Winged and elevated scapulae, prominent clavicles Popeye arm: upper arm thinner than forearm Pelvic muscles involved later and milder Can be asymmetrical CPK can be normal or mildly elevated Rare cardiac involvement

Scapular winging Weak (serratus, lower trapezius, rhomboids) stabilizers of scapula cause winging Scapular angles can be seen when facing the patient

Facioscapulohumeral MD Foot drop might be seen Early in the disease weakness can be asymmetrical Rare cardiac involvement CPK normal or slightly elevated

Scapuloperoneal MD Autosomal dominant, Chromosome 12 Typically involves muscles of the neck, shoulder, upper arms, anterior tibial and peroneal groups Onset usually in early or middle adulthood Walking becomes difficult due to foot drop Symptoms in arms and shoulders usually seen later Progression slow in most cases

Limb-girdle MD Heterogeneous group Children of both sexes affected No hypertrophy (besides SCARMD) Adults can have weakness in either pelvic or shoulder girdle or both, if later onset more benign course Most commonly heredited as autosomal recessive (2A-2J), Also AD (1A-1E) forms, AD good prognosis EMG myopathic, CK normal or only moderately elevated, cardiac involvement infrequent

AD Limb Girdle Dystrophies LGMD 1 Onset is varied from 4-38 years CPK is slightly or moderately increased Can have flexion contractures of elbows, ankles, and IPJ but non-disabling Slow progression with long periods of arrest Normal longevity Some with facial and cardiac involvement Includes defects in proteins located in myofibril, cell membrane and EC (collagen proteins)

AR Limb Girdle Dystrophies LGMD 2 Affects males and females equally Shoulder and pelvic girdles affected Defects in proteins located on cell membranes but also on myofibril+nucleus (calpain 3) SCARMD (2C-2F)- clinically similar to DMB, from 3-12 y/o onset, CPK times normal, hypertrophy and joint contractures, rare cardio involvement Some have involvement of distal lower extremities (dysferlinopathy)

Severe Childhood AR Muscular Dystrophy (SCARMD) LGMD 2C -2E Calf hypertrophy Cardiac involvement marked elevations of CPK early Defect is in one of the 3 dystrophin associated glycoproteins –γ sarcoglycan, chr 13q –α sarcoglycan is called adhalin, chr 17q21 –ß sarcoglycan also called hetarosin, chr 4q12

AD Limb-Girdle Dystrophy with cardiac conduction involvement Mild proximal limb/girdle dystrophy In half cases cardiac conduction disorders being the major threat to life Begins in Lext then shoulders CK normal or moderately elevated All patients retain ambulation Mild contratures infrequent Pacemaker required in some old patients

Emery- Dreifuss Muscular Dystrophy X-linked, chromosome Xq28 -emerin Age of onset: childhood- adulthood Weakness first upper arm and pectoral girdle; later pelvic girdle and distal muscles in Lexts Early appearance of contractures in elbow flexors, extensors of the neck and posterior calf muscles No pseudohypertrophy Usually accompanied by severe cardiomyopathy with variable s/a and a/v conduction defects Death secondary to cardiac problems although general course is benign in most

Oculopharyngeal Dystrophy Autosomal dominant; chr 14q q13 Usually late onset (after 45th y/o) Bilateral ptosis and dysphagia noticed as progressive difficulty in swallowing and change in voice, can progress to cachexia External ocular muscles, shoulder and pelvic muscles can later become weak CK and aldolase might be normal EMG only altered in the affected muscle

LGMD