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Sem 1 Gatdula Monteclar Nepomuceno Salamanca Tiama Progressive Muscular Dystrophy Muscular dystrophy (MD) is a group of rare diseases that cause muscle fibers to weaken and break down. MD affects the skeletal or voluntary muscles that control movement in the arms, legs, and trunk. It also can affect the heart and other involuntary muscles, such as those in the gut. MD passes from parent to child (genetic) and worsens over time (progressive). Often beginning in childhood, which lead to progressive weakness and muscle wasting. The disease affects the muscles with definite fiber degeneration but without evidence of morphologic aberrations. Histologically, in advanced cases muscle fibers undergo degeneration and are replaced by fibrofatty tissue and collagen. This feature distinguishes dystrophies from myopathies, which also present with muscle weakness. Subdivided by mode of inheritance, age at onset, and clinical features, as shown in Table 1. All types of muscular dystrophy have in common progressive muscle weakness that tends to occur in a proximal-to-distal direction, although there are some rare distal myopathies that cause predominantly distal weakness. The decreasing muscle strength in those who are affected may compromise the patient's ambulation potential and, eventually, cardiopulmonary function. Electromyography may help confirm that weakness is myopathic rather than neurogenic. Histopathologic examination of a muscle biopsy specimen may help confirm that weakness is due to a primary disorder of muscle and to distinguish between various muscle diseases. There is no specific treatment for the muscular dystrophies, and management focuses on supportive care and rehabilitation therapy. There are nine major types of MD affecting people of all ages, from infancy to middle age or later. The two most common types of MD that affect children are Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Both DMD and BMD affect boys almost exclusively; girls are rarely affected.

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Table 1. The muscular dystrophies.

Disorder

Inheritance

Age at Onset (years) 15

Distribution

Prognosis

Genetic Locus

Duchenne type

X-linked recessive

Pelvic, then shoulder girdle; later, limb and respiratory muscles. Pelvic, then shoulder girdle. Pelvic or shoulder girdle initially, with later spread to the other.

Rapid progression. Xp21 Death within about 15 years after onset. Slow progression. Xp21 May have normal life span. Variable severity Multiple and rate of progression. Possible severe disability in middle life. Slow progression. 4q35 Minor disability. Usually normal life span. Variable. Xq28, 1q21.2

Becker

X-linked recessive Autosomal recessive (dominant or sporadic)

525

Limb-girdle (Erb)

1030

Facioscapulohumeral Autosomal dominant

Any age Face and shoulder girdle initially; later, pelvic girdle and legs. 510 Humeroperoneal or scapuloperoneal.

Emery-Dreifuss

X-linked recessive or autosomal dominant Autosomal dominant or recessive Autosomal dominant (may be recessive) Autosomal dominant

Distal

4060

Onset distally in extremities; proximal involvement later.

Slow progression. 2p13, 14q12

Ocular

Any age External ocular (usually muscles; may also be 530) mild weakness of face, neck, and arms. Any age As in the ocular form but with dysphagia Any age Face, neck, distal (usually limbs. 2040) 14q11.2 q13 Slow progression. 19q13.2q13.3; 3q13.3q24

Oculopharyngeal

Myotonic dystrophy Autosomal dominant

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History - The first historical account of MD was reported by Conte and Gioja in 1836. - In 1852, Meryon[ reported in vivid details a family with 4 boys, all of whom were affected by significant muscle changes but had no central nervous system abnormality when examined at necropsy. - Guillaume Duchenne was a French neurologist who was already famous for his application of faradism (the use of electric currents to stimulate muscles and nerves) in the treatment of neurologic disorders when he wrote about his first case of MD. In 1868, he gave a comprehensive account of 13 patients with the disease, which he called "paralysie musculaire pseudo-hypertrophique." Dystrophin - Dystrophin is located chiefly in muscles used for movement (skeletal muscles) and the muscles of the heart (cardiac muscles). Small amounts of the protein are present in nerve cells in the brain. - an important muscle protein that connects the cytoskeleton (a cell's scaffolding that provides structure and shape) of a muscle fibre to its surroundings. Deficiency of this protein causes muscular dystrophy - The dystrophin complex acts as an anchor, connecting each muscle cell's structural framework (cytoskeleton) with the lattice of proteins and other molecules outside the cell (extracellular matrix). - The dystrophin complex may also play a role in cell signaling by interacting with proteins that send and receive chemical signals. - In skeletal and cardiac muscles, dystrophin is part of a group of proteins that work together (a protein complex) that strengthens muscle fibers and protects them from injury as muscles contract and relax. - It appears that absence of dystrophin makes the muscle cell highly susceptible to mechanical stress, with eventual muscle fiber loss and replacement with fibrotic tissue - Dystrophin is associated with a large oligomeric complex of sarcolemmal glycoproteins, including dystroglycan, which provides a linkage to the extracellular matrix component laminin. - A large protein. - It appears that this dystrophin-glycoprotein complex provides structural support and strength to the muscle fibril and transmits the force generated by contraction to the cytoskeleton. It may well have additional functions. The complex is of special interest because congenital defects in it cause many of the different forms of muscular dystrophy. DMD gene - A gene that is located in the Xp21 region. - One of the largest human genes. - DMD gene provides instructions for making a protein called dystrophin. - Mutations of the dystrophin gene cause a frameshift, early termination, or deletion of the carboxyterminal or amino-terminal ends, resulting in a nonfunctional protein. Gatdula.Monteclar.Nepomuceno.Salamanca.Tiama092911

The dystrophin gene, which is one of the largest known genes, is also expressed in cardiac and smooth muscle and, in the brain.

Duchenne Muscular Dystrophy (DMD) - A.k.a. Pseudohypertrophic Mucular Dystrophy - Males are more likely to develop symptoms than women. - Most common and severe form of childhood muscular dystrophy. - Incidence of about 1 per 3500 live male births. - DMD can now be recognized early in pregnancy in about 95% of women by genetic studies. - Signs and Symptoms That starts at the lower extremities and the whole body. DMD becomes clinically manifest by the age of 5 years. It leads to wheelchair dependence by 10 to 12 years of age, and thereafter progresses relentlessly Typical initial symptoms include abnormal gait, frequent falls, and difficulty climbing steps. Hypotonia and delayed motor milestones occur in earlier onset cases, but in 75% to 80% of cases, onset is noted before age 4. The abnormal gait often is noted by toe-walking, which is a compensatory adaptation to knee extensor weakness, or increased lumbar lordosis as a compensation for hip extensor weakness. Another indication of pelvic girdle weakness is Gowers' sign, demonstrated as the child rises from the floor. The patient generally begins by assuming a four-point stance, then brings the knees into extension while leaning the upper limbs forward, and sequentially moves the hands up the thighs until upright stance is achieved. The earliest weakness is seen in the neck flexors, typically during the preschool years. Weakness of the proximal musculature of the shoulder and pelvic girdle is next, with steady progression, although the patient and family may feel that functional loss does not occur gradually, but rather quite suddenly. Quantitative strength testing shows greater than 40% to 50% loss of strength by age 6 years (4), with fairly linear progression from ages 5 to 13 measured by manual muscle testing. In patients not aggressively treated, the average age to wheelchair use is 10, with a range of 7 to 13 years of age. Prediction of wheelchair use may be helped by using timed motor performance. In one natural history study, all Duchenne muscular dystrophy subjects who took more than 9 seconds to ambulate 30 feet lost the ability to ambulate within 1 year Joint contractures are a major concern in DMD. Nearly all affected boys older than 13 years have contractures, and most commonly occur first in the ankle plantar flexors, iliotibial bands, and hip flexors, with subsequent involvement of the knee flexors, and elbow and wrist flexors.

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Scoliosis is a major clinical concern in DMD, and prevalence is strongly related to age. Factors such as the adolescent growth spurt and progressive involvement of the trunk musculature may be responsible for progression of scoliosis during the adolescent years. Symptomatic respiratory failure in Duchenne muscular dystrophy typically manifests in later adolescence. Cardiac function is affected in DMD, because the dystrophin protein has been shown to be present in both the myocardium and Purkinje fibers. Progressive congestive heart failure is the more frequent sequelae, and some investigators estimate 40% to 50% of DMD patients die from this complication Cardiomyopathy is usually noted after 10 years of age and occurs in nearly all patients by age 18. Considering the presence of a dystrophin isoform in brain tissue (27), it is not surprising that DMD patients show mildly decreased IQ scores compared with their peers and normative data. There may be a specific deficit with tasks requiring attention to complex verbal information, regardless of IQ Obesity from reduced physical activity is a major concern in DMD, particularly at the onset of wheelchair dependence. However, at later stages of the disease (ages 17 to 21), significant weight loss becomes the predominant nutritional concern. This probably results from nutritional compromise along with increased protein and calorie requirements during the later stages of DMD, partially as a result of the increased work of breathing from restrictive lung disease. Proximal weakness of the leg begins during early childhood, although histologic evidence indicates that abnormalities already exist at birth. The child normally attains initial developmental milestones such as raising the head or sitting upright. Early difficulty in standing or walking may give an erroneous impression of clumsiness. Weakness becomes apparent by age 3 or 4 years, with inability to run or to climb stairs. Patients tend to walk on their toes with their feet externally rotated and, on standing up from the floor, show Gower's sign or climbing up legs to stand. In advanced stages, the patient develops severe kyphoscoliosis, cardiomyopathy and respiratory distress as the result of intercostal and diaphragm involvement. Cardiomyopathy may result from abnormal baseline myocardial blood flow. Severe spine deformities may cause upper motor neuron abnormalities, which in turn lead to urinary dysfunction. The calf muscle, although initially strong, develops pseudohypertrophy, as do the deltoid, quadricep, and gluteal muscles. With a steady, downhill course, frequent falls force 90-95 percent of children into a wheelchair before age 12 years, contractures of the joints prevent limb movement, and the patients eventually die usually by age 20. Weakness begins in the pelvic girdle muscles and then extends to the shoulder girdle. Enlargement of the muscles of the lower leg associated with weakness, a phenomenon termed pseudohypertrophy, is an important clinical finding. The increased muscle bulk is caused initially by an increase in the size of the muscle fibers and then, as the muscle atrophies, by an increase in fat and connective tissue.

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No well-established structural abnormalities of the central nervous system, cognitive impairment is a component of the disease and is sometimes severe enough to be considered a form of mental retardation. Death results from respiratory insufficiency, pulmonary infection, and cardiac decompensation. Many children with DMD lose their ability to walk by late childhood and require wheelchairs. As muscles continue to weaken in the back and chest, most children develop curvature of the spine (scoliosis). By adolescence, DMD usually progresses to weaken the heart and respiratory muscles. Laboratory and Diagnostic Studies they are clinically asymptomatic but often have elevated serum creatine kinase (10-fold increase) and show minimal histologic abnormalities on muscle biopsy. Muscle biopsy specimens from individuals with DMD show little or no dystrophin by both staining and western blot analysis Most DMD patients older than age 13 demonstrate electrocardiogram (ECG) abnormalities Cardiomyopathy is typically followed clinically with echocardiography, and the onset of systolic dysfunction is associated with a poor short-term prognosis. Once patients with DMD reach adolescence, regular screening with ECG, echocardiography, and Holter monitoring is prudent. Mild impairments are noted on neuropsychological testing as well (4), without a specific area of strength or weakness. A markedly elevated serum CK during the first year often heralds the clinical onset of illness. The values then fall gradually as the disease advances but never return to normal. Cardiac involvement results in typical electrocardiographic changes that consist of a tall, right precordial R wave and a deep limb and precordial Q wave in conjunction with characteristic abnormalities seen by cardiac echo and positron emission tomography. Muscle biopsy material usually reveals variations in muscle fiber size, necrotic fibers, phagocytosis, regenerating basophilic fibers, and vesicular nuclei. Diagnosis is based on clinical presentation, a 100700-fold elevation in CK, the appearance of fatty degeneration in muscle biopsy tissue, direct measure of dystrophin protein by immunohistochemistry or Western protein blotting, and antibody detection in muscle biopsy specimens. Treatment Prednisone produces a rapid increase in muscle strength, with maximal effect at a dosage of 0.75 mg/kg or less. Alternate day prednisone therapy effectively increases strength but does not sustain the improvement to the same extent as daily therapy or mitigate the side effects. Deflazacort, 0.9 mg/kg/day, a new corticosteroid with potentially fewer side effects. Dantrolene, which inhibits calcium release from the sarcoplasmic reticulum, reduced serum CK associated with a lessening trend in motor function deterioration. Long-term low-frequency electrical stimulation of affected muscles also improved strength compared with the non-stimulated control side.

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Surgical stabilization by spinal fusion prevents progressive deformity for relative ease and comfort of wheelchair seating, although the vital capacity primarily related to muscle weakness continues to decline. Many patients do well on longterm ventilation, but some choose to discontinue this method of life prolongation. Physical therapy, bracing, orthoses, and orthopedic surgery are often required. Rehabilitation concerns in DMD: o Maintaining mobility, range of motion, and strength during childhood o Progressive scoliosis o Progressive restrictive lung disease o Cardiac dysrhythmias and cardiomyopathy o Obesity (early adolescence) and cachexia (late adolescence) o Psychosocial adjustment and social interaction Etiology DMD is caused by abnormalities in DMD gene. A genetic defect on the short arm of the X chromosome has been identified in DMD. The affected gene codes for the protein dystrophin, which is markedly reduced or absent from the muscle of patients with the disease. The main pathologic sequence of events in the early stages consists of repeated episodes of muscle fiber necrosis and regeneration. Incomplete regeneration reduces the number of muscle cells, rendering some fibers hypertrophic. Progressive accumulation of collagen finally replaces the muscle cells. Becker Muscular Dystrophy (BMD) - This disorder is a milder allelic form of dystrophinopathy, with decreased or altered dystrophin rather than absence. - Dystrophin levels are generally normal in the Becker variety, but the protein is qualitatively altered. - The Becker type of muscular dystrophy is a benign, X-linked recessive dystrophy that affects male offspring. - BMD is less common than DMD, with an overall prevalence recently estimated as 24 per million. - The first type, age of onset averages 7.7, and most patients have difficulty climbing stairs by age 20. - In the more common milder form, age of onset averages 12, and there is no problem climbing stairs at age 20. - It also results from a mutation in the dystrophin gene, leading to relatively mild clinical features. - BMD has a later onset and considerably longer and milder clinical course with survival into middle adulthood. - Signs and Symptoms BMD and DMD has a similar pattern of muscle weakness, but generally presents with a later onset and a slower rate of progression. The neck flexors and proximal lower limb muscles are affected early, particularly the hip and knee extensors There is gradual involvement of the proximal upper-limb muscles Gatdula.Monteclar.Nepomuceno.Salamanca.Tiama092911

Extensors are generally weaker than flexors Calf enlargement occurs, and presence of Gowers' sign is indicative of the proximal muscle weakness. On standing, there is increased lumbar lordosis, and hip abductor weakness results in a waddling gait with trunk lean over the weight-bearing limb. Pulmonary dysfunction is not a hallmark of BMD. There are no consistent abnormalities on cognitive and neuropsychological testing in BMD. The clinical course is lengthened compared with DMD, with ambulation maintained into the twenties and survival to the forties. The initial symptoms at ages 5 to 20 years consist of weakness of the pelvic girdle and legs and muscle cramps after exercise. Physical examination shows hypertrophied calves, shortening of the Achilles tendon, flexion contractures, and depressed stretch reflexes. The patient's difficulty involves climbing stairs and rising from the floor. Unlike DMD, patients with the Becker type usually walk for 25 to 30 years after onset, and many may reach an advanced age. Patients eventually develop contractures and skeletal deformities, but not as severely as in DMD. Early myocardial disease and myalgia may develop as a primary feature, unrelated to the severity of skeletal muscle damage. Patients may develop cardiac failure as a late complication but usually live into the sixth or seventh decade. Swallowing-related complications, from difficulties with mastication to problems in the pharyngeal phases, may arise with progressive weakness of the swallow mechanism. Recurrent aspiration pneumonias from progressive dysphagia may eventually cause mortality. Laboratory and Diagnostic Studies Without dystrophin analysis, it may be difficult to clinically discriminate between DMD and BMD. The most useful diagnostic discriminator is the ability to ambulate into adolescence. It is unusual for a patient with BMD to be wheelchair dependent before late adolescence, whereas even DMD outliers are dependent on the wheelchair for mobility by age 16. ECG abnormalities can be detected in about 75% of Becker muscular dystrophy patients. Electromyography shows nearly symmetric abnormalities in the proximal muscles. Serum creatine kinase shows moderate-to-severe elevation (that is, 5-100 times the normal level). Muscle biopsy with dystrophin antibody staining demonstrates the presence of dystrophin in variable percentages. An electrocardiogram/echocardiogram may show cardiomyopathy and/or arrhythmia. Dilated cardiomyopathy manifests after age 20 years; the risk progressively increases with age. Histologic changes specifically, findings of degenerating muscle fibers, a variation in fiber size, focal necrosis, regeneration, and a proliferation of connective tissue, as well as fatty replacement of degenerated muscles point to a muscular dystrophy.

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Treatment Physical therapy services is to address the functional needs of the patient as the disease progresses. Early interventions may focus on stretching tight muscles. As the patient's weakness progresses, appropriate equipment and assistive devices will be required to enable the individual to maintain functional mobility and independence in daily living activities. Educational objectives include teaching the patient techniques for energy conservation, joint protection, and the prevention of overuse fatigue. Spinal fusion to correct scoliosis may be scheduled based on the progression of spinal deformity and the age of the patient. Etiology Like DMD, the disorder has an abnormality in the gene location (Xp21) coding for the protein dystrophin. However, in this case, dystrophin levels are usually 20% to 80% of normal, or have the presence of the protein with an abnormal molecular weight.

Facioscapulohumeral Muscular Dystrophy (FSHD) - Facioscapulohumeral dystrophy was identified as a distinctive muscular dystrophy because of the predilection for slowly progressive muscular weakness in the facial and shoulder girdle musculature. - It is nearly always inherited as an autosomal-dominant disorder, with the chromosomal abnormality identified at the 4q35 gene locus. - Also known as Landouzy-Dejerine type, affects both genders equally. - The specific genomic sequence and gene function have not yet been expounded. - Is has an estimated prevalence of 1 case in 20,000 people. - Life span of FSHD patients does not appear to be affected. - Presentation is often in adolescent or early adult years. - Signs and Symptoms The distinctive clinical feature of facioscapulohumeral dystrophy is the presence of facial weakness, primarily involving the orbicularis oris, zygomaticus, and orbicularis oculi. These manifest as difficulty with eye closure (but not ptosis) and expressionless face The patient will typically have difficulty burying the lashes and pursing the lips, drinking through a straw, or whistling. Extraocular and pharyngeal muscles are spared. Onset of symptoms is typically in adolescence or early adulthood. In the shoulder girdle, the scapulae are typically displaced laterally and superiorly, resulting from combined weakness of the serratus anterior, rhomboids, latissimus dorsi, and lower trapezius Profound winging of the medial border of the scapula is common. Asymmetry of muscular involvement is common In the lower extremities, the proximal musculature of the hip girdle is typically affected. However, there also appears to be a predilection for early involvement of the ankle dorsiflexors. Gatdula.Monteclar.Nepomuceno.Salamanca.Tiama092911

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Coats' syndrome is an early-onset variant of FSHD associated with sensorineural hearing loss. Muscle weakness typically begins in infancy, with progressive weakness and wheelchair dependence by late second or third decade There is also an associated progressive exudative telangiectasia of the retina, requiring early recognition to prevent permanent visual loss. Hearing loss in more common forms of FSHD patients. Spinal deformity typically presents as hyperlordosis, scoliosis, or a combination Facial weakness often precedes shoulder girdle weakness. Associated abnormalities include high- (and rarely, low-) frequency hearing loss and retinal abnormalities (telangiectasia, microaneurysms) in up to 75%. There are no cardiac abnormalities, and cognition is preserved. Patients usually have protruded lips, a transverse smile, weak eye closure, and an inability to wrinkle the forehead. The loss of the ability to use the arms, a common initially recognized symptom, results from weakness of the pectoralis major, latissimus dorsi, biceps, triceps, and brachioradialis muscles. Attempted abduction of the arm elevates the weak trapezius, giving rise to the typical appearance called trapezius hump. Weakness of the tibialis anterior may cause foot drop as an early sign, but otherwise the disease affects the lower limbs later than the upper limbs. Beevor's sign is a prelude to functional weakness of abdominal wall muscles. The patient has bilateral foot-drop as the presenting sign in a variety known as scapuloperoneal dystrophy. In advanced stages, patients develop lordosis and pelvic girdle muscle weakness but no cardiac myopathies. The infantile variant seen in the first 2 years of life has a rapid progression and poor prognosis. The devastating combination of this entity with Charcot-Marie-Tooth disease resulted in severe generalized weakness and early death. Respiratory insufficiency is rare, and most patients have a normal life expectancy. Laboratory and Diagnostic Studies CK levels in FSHD tend to remain normal or mildly elevated. EMG shows myopathic features. Muscle biopsy evidence is nonspecific, with myopathic changes and variable inflammation. Genetic testing to confirm the diagnosis is available. Treatment No definitive therapy is available for FSHD. Treatment is symptomatic, consisting of orthotic devices, braces, walking aids that may include a wheelchair, and physical therapy. Scapular fixation surgery may be beneficial. The goals of pharmacotherapy are to reduce morbidity and prevent complications.

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Etiology An abnormal genetic locus has been found at the 4q35 site.

Myotonic Dystrophy - It is the most prevalent form of muscular dystrophy in adults. - Autosomal dominant inheritance - An incidence of 1 per 8,000 - A multisystem disorder affecting skeletal muscle, smooth muscle, myocardium, brain, and ocular structures. - The genetic and clinical abnormalities tend to increase in severity with successive generations (termed genetic anticipation). - An abnormal genetic locus on the long arm of chromosome 19 (19q13.3) results in a trinucleotide repeating sequence - Signs and Symptoms A distinctive feature of myotonic muscular dystrophy among the dystrophies is the presence of myotonia, a state of delayed relaxation or prolonged contraction of muscle. Variable onset from infancy to adult life Onset of disease may occur in any decade, including the neonatal period. Weakness of facial, bulbar, and distal greater than proximal muscles. This may manifest clinically with cataracts, cardiac conduction defects, swallowing dysfunction, and skeletal muscle weakness and myotonia. Slowly progressive weakness of facial and sternocleidomastoid muscles occurs in association with frontal balding and ptosis, producing a hatchet-face appearance. The distal muscles may be affected to a greater extent, particularly early in the disease. This manifests as foot drop that is due to involvement of the ankle dorsiflexors, ankle invertors, and evertors, and grip weakness from affected hand muscles Eventually, the neck, shoulder, and hip girdle muscles become weak Cardiac abnormalities are common in myotonic muscular dystrophy. Approximately 70% to 75% of patients demonstrate ECG and echocardiographic abnormalities When myotonic muscular dystrophy manifests in infancy as congenital myotonic muscular dystrophy, involvement of the respiratory musculature may cause significant respiratory distress. In noncongenital myotonic muscular dystrophy, restrictive lung disease causes significant morbidity later in life for many patients with myotonic muscular dystrophy Nocturnal hypoventilation and sleep apnea may occur, and clinicians should take a careful history to elicit symptoms common to these disorders: morning headache, frequent nightmares, excessive snoring, difficulty sleeping, and daytime somnolence. Smooth muscle involvement most frequently manifests as difficulty swallowing and constipation, particularly in congenital myotonic muscular dystrophy. Cognitive deficits are most profound in the congenital myotonic muscular dystrophy population, with a reduced IQ often in the mentally retarded range. Multisystem disease consisting of frontal baldness, cataracts, testicular atrophy in boys, smooth muscle and cardiac muscle dysfunction, all typical of the adult form of myotonic

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dystrophy, is seen in adults with congenital myotonic dystrophy and leads to a typically shortened life span, with death most commonly due to cardiac dysrhythmias. Congenital Myotonic Dystrophy Is an autosomal dominant disorder transmitted from an affected mother. Typical features include severe hypotonia at birth with respiratory distress often requiring prolonged ventilator support. Facial diplegia with a characteristic triangular-shaped mouth), equinovarus contractures, and mental retardation are also seen. Clinical diagnosis is confirmed by examining the mother, who invariably has the adult form of the disease. Laboratory and Diagnostic Studies EMG evidence of myotonia Genetic testing provides definitive diagnosis. Serum CK level may be normal or mildly elevated. Slit-lamp examinations may be required to detect cataracts. Treatment No specific treatement is available other than for the management of complicating systemic disease. Orthotic devices are helpful as are drugs to suppress myotonia, such as phenytion, 300 mg/day. Phenytion is preferred to quinine and procainamide in treatment of myotonic dystrophy because it has fewer adverse effects on cardiac conduction. Rehbilitation Concerns in Myotonic Muscular Dystrophy o Progressive weakness, often in a distal > proximal distribution o Clinical myotonia, with difficulty in releasing grip o Cardiac conduction defects o Swallowing dysfunction o Cataracts o Nocturnal hypoventilation/sleep apnea Etiology The abnormal gene has been localized to chromosome 19q13.3 coding for a protein kinase.

Emery-Dreifuss Muscular Dystrophy (EDMD) - This entity is also known as scapuloperoneal muscular dystrophy, scapulohumerodistal muscular atrophy, and humero peroneal neuromuscular disease. - Most pedigrees show an X-linked inheritance, but rare kindred have autosomal dominant transmission. - The genetic defects in both the X-linked recessive form and the autosomal dominant form of EDMD have been determined.

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The classic triad of symptoms consists of prominent early contractures (elbows, fingers, knees, ankles, and spine), weakness and atrophy of humeral and peroneal muscles, and cardiac conduction defects that can lead to syncope or sudden death. The major cause of mortality and morbidity in EDMD is cardiac disease, which is consistently present. The most common disturbances are a result of atrial conduction defects (eg, bradycardia, atrial arrhythmias, atrioventricular [AV] block, atrial paralysis). Males are affected in X-linked EDMD. In autosomal dominant EDMD, males and females are affected in equal numbers. The mean age of onset is in the teenaged years. Signs and Symptoms Patients develop a triad of slowly progressive humeroperoneal weakness, early contracture, and early conduction defects. Weakness and wasting confined to the muscles of the shoulder girdle and the anterior compartment muscles of the lower limb. Clinical manifestations begin in the second decade, primarily involving deltoids, pectorals, muscles of the arms, extensors of the hands, fingers, and feet, and occasionally muscles of the face, relatively sparing the muscles of the pelvic girdle. Patients also develop cardiopathy with atrioventricular block, atrial fibrillation, decreased ventricular rate, and exertional dyspnea, often dying suddenly from cardiac arrest. A variant of this syndrome has an onset at ages 3-11 years, with initial symptoms and signs of shortening of the Achilles tendon, flexion contractures of the elbows, weak shoulder girdle muscles, normal CK, and death eventually by cardiac arrest. Prominent early contractures Laboratory and Diagnostic Studies The serum CK level may be elevated Muscle biopsy specimens show nonspecific dystrophic changes. DNA or gene product (emerin) analysis is needed for precise diagnosis. In EDMD, EMG shows small amplitude narrow duration motor unit potentials (MUPs) with early recruitment (as is typical for myopathies). ECG should be obtained in all patients with EDMD. Confirmation of the diagnosis is obtained by demonstration of a lack of all electrical and mechanical activity of the atria and an inability to pace the atria confirming that the myocardium, not the conduction system, is affected. Treatment No specific treatment for EDMD exists, but aggressive supportive care is essential to preserve muscle activity, to provide for maximal functional ability, and to prolong life expectancy. Cardiac surveillance and timely pacemaker insertion is an essential part of disease management. Aggressive use of passive stretching, bracing, and orthopedic procedures allows the patient to remain independent for as long as possible.

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Etiology Mutation of the responsible gene results in loss or reduction of emerin, which serves as a membrane anchor. X-linked recessive EDMD is caused by a mutation on the X chromosome in the gene encoding emerin (EMD Emerin is a protein that belongs to a family of nuclear proteins that bind a variety DNA regulatory molecules and to molecules thought to be important in maintaining nuclear membrane structure. Autosomal dominant EDMD is caused by a mutation on chromosome 1 in the gene that codes for lamin A/C (LMNA).

Limb-Girdle Muscular Dystrophy (LGMD) - The term limb-girdle muscular dystrophy is reserved for noncongenital muscular dystrophies with progressive proximal weakness not due to dystrophin deficiency. - Autosomal-dominant (LGDM-1) and autosomal recessive (LGDM-2) forms exist, and increasing numbers of distinct forms continue to be descrived. - These disorders are caused by different protein deficiencies, such as the sarcoglycans (dystrophin-associated proteins), calpain, dysferlin, and caveolin. - A slowly progressive pattern of proximal greater than distal muscular weakness with either autosomal-recessive (more common) or -dominant inheritance were termed limb-girdle muscular dystrophies. - Occurs equally in males and females, and has a slower progression. - The illness often begins during the second or third decade of life - The patient usually has normal life span. - Signs and Symptoms Loss of ambulation generally occurs between 10 and 20 years. Progressive weakness mainly affects the proximal muscles of the shoulders, pelvic girdles, and upper and lower limbs. Symptoms and signs vary, usually leading to severe disability by midlife. Weakness soon spreads to the shoulder girdle, typically but not always sparing the facial muscles. The disease process usually runs a more rapid course in the tibialis anterior than in the plantar flexor muscles. Pseudohypertrophy may or may not occur in the calves and deltoid. - Laboratory and Diagnostic Studies Highly elevated serum CK level Muscle biopsy with special staining for sarcoglycan, calpain, dysferlin, and caveolin may help distinguish these disorders. - Treatment Treatment is symptomatic Gatdula.Monteclar.Nepomuceno.Salamanca.Tiama092911

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Sources: - Robbins and Coltran. Pathologic Basis of Disease. 8TH Ed. - Lange. Review of Medical Physiology. Ganong - Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice. Kimura - Physical Medicine & Rehabilitation. Principles and Practice. Fourth Edition. Joel A. Delisa - The McGraw-Hill Companies. Current Medical Diagnosis & Treatment 2011, Fiftieth Edition. - www.ghr.nlm.nih.gov/gene/DMD - www.ncbi.nlm.nih.gov/books/NBK22263/ - www.nlm.nih.gov/medlineplus/musculardystrophy.html - www.ninds.nih.gov/disorders/md/md.htm

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