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72 Cards in this Set
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Differential diagnosis of inherited myopathies is broad. They include (5) |
1. Muscular dystrophies 2. Congenital myopathies 3. Metabolic myopathies 4. Channelopathies 5. Mitochondrial myopathies |
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Congenital myopathies often present with (5) |
1. At birth 2. Hypotonia 3. Poor respiratory effort 4. Reduced feeding ability 5. Slow or non-progressive course |
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Dystrophinopathies are caused by |
mutations in the largest human gene, dystrophin, located on chromosome Xp21 |
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Most severe form of muscular dystrophy? |
Duchenne, and is the most common with an incidence of 1 in 3,500 newborn males |
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What is dystrophin? |
A sarcolemmal protein and a component of the dystrophin-glycoprotein complex, which links the cytoskeleton to the extracellular matrix stabilizing the sarcolemma and protecting the muscle fibers from contraction-induced damage |
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Clinical features of DMD (4) |
1. Progressive proximal muscle weakness 2. Calf muscle enlargement (pseudohypertrophy) 3. Lose the ability to ambulate around age 13 4. Die of cardiac and respiratory causes in their 20s, if untreated |
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Diagnosis of muscular dystrophies is based on (4) |
1. Clinical features 2. Elevated CK (50-100 times normal levels) 3. Muscle biosy 4. Molecular analysis shows deletions in the dystrophin gene in approximately 70% of patients, duplications in 7% and point mutations in 20% |
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Treatment of muscle dystrophies |
1. Corticosteroids prolong ambulation, maintain pulmonary function, and delay ventricular dysfunction 2. Effective treatments are prednisone 0.75mg/kg a day or deflazacort 0.9 mg/kg a day 3. Continuation of corticosteroid treatment after ambulation is lost, is aimed at preserving arm strength and slowing respiratory and cardiac impairment, but remains controversial 4. ACEi or ACEi+BB to delay cardiomyopathy 5. BiPAP for children with respiratory insufficiency 6. Spinal fusion if scoliosis is more than 35 degrees |
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Promising new treatments for muscular dystrophies? |
Gene therapy, such as the delivery of minidystrophin and exon skipping |
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Third most common muscular dystrophy? |
Facioscapulohumeral muscular dystrophy; incidence of 1 in 15,000 to 20,000 |
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Pathophysiology of facioscapulohumeral muscular dystrophy |
More than 95% carry a contraction of D4Z4 repeats array on chromosome 4q24, resulting in DNA hypomethylation and chromatin relaxation. Incomplete suppression of DUX4 retrogene in skeletal muscle, which in turn leads to release of inappropriate gene expression in muscle |
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Clinical features of facioscapulohumeral muscular dystrophy? (5) |
1. Asymmetric weakness of the facial muscles and scapular stabilizer muscles 2. Scapular winging 3. Weakness may progress to involve the tibialis anterior, axial, or pelvic muscles 4. Slowly progressive weakness, sometimes stepwise 5. Normal life-expectancy |
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Extramuscular manifestations of facioscapulohumeral muscular dystrophy? (3) |
1. High-frequency hearing loss 2. Asymptomatic retinal telangiectasias seldom resulting in retinal exudates and detachment (Coats disease) 3. Very rarely atrial arrhythmias |
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Diagnosis of facioscapulohumeral muscular dystrophy? |
1. Clinical phenotype 2. Confirmed by genetic testing |
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Treatment of facioscapulohumeral muscular dystrophy? (2) |
1. Supportive with physical therapy 2. Ankle-foot orthotics if foot drop is present |
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Screening for what is important in patients with limb girdle muscular dystrophies? |
Cardiac involvement, because cardiomyopathy or cardiac conduction defects accompany several forms of LGMD |
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Diagnosis of LGMD is made on the basis of (3) |
1. Elevated CK 2. Muscle biopsy (shows signs of muscle degeneration and regeneration) 3. Gene analysis may be necessary |
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Treatment of LGMD? |
No definitive treatment is available; physical therapy is helpful for avoiding development of contractures |
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The most common congenital muscular dystrophy is due to |
recessive mutations in merosin, an extracellular matrix protein |
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Clinical features of merosin-deficient congenital muscular dystrophy? (2) |
1 .Facial and limb weakness 2. Often contractures |
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Diagnosis of congenital muscular dystrophies |
Confirmed by gene analysis; biopsy may be helpful before the results of gene analysis are ready |
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Treatment of congenital muscular dystrophies? |
Supportive |
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What is EMD? |
Emery-Dreifus muscular dystrophy; of which there are two types |
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Clinical features of EMD (4) |
1. Presentation in early to middle childhood 2. Predominant scapulohumeroperoneal (limb-girdle) distribution 3. In type 1 - early onset of joint contractures, in type 2 - contractures follow onset of weakness 4. Cardiomyopathy with conduction abnormalities can occur in the 20s to 30s |
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Diagnosis of EMD is made by |
muscle biopsy |
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Progressive ptosis and dysphagia in the fifth to sixth decade of life |
Oculopharyngeal dystrophy |
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Inheritance pattern of oculopharyngeal dystrophy? |
AD; expanded GCG repeat in the PABPN1 gene on chromosome 14 |
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Diagnosis of oculopharyngeal dystrophy |
1. Normal CK level 2. EMG shows typical myopathic motor units 3. Muscle biopsy - dystrophic changed and rimmed vacuoles and intranuclear inclusions |
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Treatment of oculopharyngeal muscular dystrophy? |
Aimed at preventing medical complications such as nutritional issues; surgery for ptosis |
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Other name for Steinert disease |
Myotonic dystrophy type 1 (DM1) |
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Most common adult-onset muscular dystrophy? |
DM1; also the second most common muscular dystrophy after dystrophinopathy |
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Incidence of DM1 |
13.5 per 100,000 live births |
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Highest prevalence of DM is seen where? |
Germany and Poland, and in subjects with German or Polish ancestry |
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Main symptoms of DM1 (4) |
1. Distal muscle weakness 2. Myotonia 3. Prominent in the hands 4. Ptosis, facial muscle weakness, and temporalis muscle wasting are common |
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DM2 manifests in the ___ decade of life and is characterized by |
third; proximal muscle weakness, myalgia, and less prominent myotonia |
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Genetic basis of myotonic muscular dystrophies |
Unstable CTG repeats in the 3' UTR of the dystrophia myotonica protein kinase (DMPK) gene on chromosome 19q13.2 |
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Treatment of myotonia treatment in DM1 and DM2? |
Mexiletine 150 to 200mg 3 times daily is an effective and safe antimyotonia treatment |
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Most common inherited metabolic muscle disorders? (3) |
1. McArdle disease 2. Pompe disease 3. CPT deficiency 2 |
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Epidemiology of Pompe disease (3) |
1. Lysosomal storage disease 2. Inherited with AR trait 3. Prevalence varies from 1 in 35,000 to 1 in 138,000 for the early-onset form and 1 in 57,000 for the adult-onset form |
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Pathophysiology of Pompe disease |
GAA is a lysosomal enzyme that catalyzes the breakdown of glycogen into glucose; results in glycogen accummulation and autophagic vacuoles |
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Clinical spectrum of Pompe disease (3) |
1. Infantile form - hypotonia, cardiomegaly, macroglossia, possible hepatomegaly, and death before age 2 2. Juvenile form - predominant muscle weakness 3. Adult form - third or fourth decade, proximal muscle weakness, respiratory weakness |
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Diagnosis of Pompe disease |
1. Elevated CK 2. EMG shows myopathic motor unit potentials, fibrillation potentials, myotonic discharges, and often complex repetitive discharges 3. GAA deficiency in dried blood spot, muscle tissue, and skin fibroblasts |
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Treatment of Pompe disease |
Enzyme replacement therapy with alglucosidase alfa before age 6 months and before the need for ventilatory assistance |
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Defect in McArdle |
Myophosphorylase deficiency |
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Clinical features of McArdle (5) |
1. Exercise intolerance 2. Premature exertional fatigue and myalgia 3. Exercise-induced muscle contractures 4. Myoglobinuria 5. Improves with rest |
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Diagnosis of McArdle (5) |
1. Serum CK is increased at rest 2. Forearm ischemic exercise test causes no increase in lactate and a normal increase in ammonia (increase in both occurs in normal muscles) 3. EMG results are often normal 4. Muscle contractures are electrically silent 5. Muscle biopsy confirms the diagnosis |
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Treatment of McArdle (3) |
1. Maximal aerobic and isometric exercise should be avoided 2. high-protein and low-carbohydrate diet 3. Creatine monohydrate may improve symptoms |
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Defect in Pompe disease |
acid a-glucosidase deficiency (acid maltase) |
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Most common disorder of lipid metabolism involving the skeletal muscle? |
Carnitine palmitoyltransferase II (CPTII) deficiency |
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Phenotypes of CPTII deficiency |
1. Lethal neonatal 2. Severe infantile hepatocardiomuscular form 3. Myopathic form |
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Treatment of CPTII deficiency |
1. High-carbohydrate and low-fat diet 2. Administration of glucose in the setting of infections, frequent meals, and avoidance of fasting and prolonged exercise |
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Which drugs should be avoided in CPTII deficiency? (3) |
1. Valproic acid 2. General anesthesia 3. Diazepam in high doses |
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Diagnosis of CPTII deficiency? |
Enzyme assay in muscle tissue |
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The myopathic form of CPTII deficiency presents how? |
In the first or second decade of life with myalgia and paroxysmal myoglobinuria on prolonged exercise |
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What is myotonia congenita? |
Nondystrophic skeletal muscle disorder due to abnormal muscle excitability; it can be inherited as AD (Thomsen myotonia) or recessive (Becker myotonia) trait |
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Mutations in muscle ___ channel can lead to AD or AR myotonia congenita |
chloride channel (CLCN1) |
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Myotonia congenita manifests how? (5) |
1. Muscle stiffness 2. Inability of the muscle to relax after voluntary contraction 3. Warm-up phenomenon 4. Muscle hypertrophy 5. Exacerbation of symptoms when cold |
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Diagnosis of myotonia congenita? (2) |
1. EMG shows myotonic discharges 2. Genetic testing confirms the diagnosis |
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Treatment of myotonia congenita? |
Mexiletine prevents involuntary repetitive firing of muscle action potentials and alleviates the symptoms ,however, most patients do not require pharmacologic treatment |
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Attacks of flaccid weakness associated with reduced serum potassium level |
Familial periodic paralysis (hypokalemic PP, hypoKPP) |
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Increased serum potassium levels and attacks of flaccid weakness? |
Periodic paralysis (hyperkalemic PP, hyperKPP) |
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Pathophysiology of hypoKPP |
Mutations in the alpha 1 subunit of the skeletal muscle calcium channel (CACNA1S) or less frequently the alpha subunit of the skeletal muscle sodium channel (SCN4A) |
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Pathophysiology of hyperKPP? |
Mutations in the SCN4A gene |
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Clinical features of hypoKPP? (2) |
1. Paralytic attacks manifest in the first 2 decades of life 2. Rest after exercise and carbohydrate-rich meals trigger the attacks |
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Clinical features of hyperKPP? |
1. Manifests in the first decade of life 2. Duration is shorter (usually less than 2 hours) 3. Attack frequency often decreases after age 35 |
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Andersen-Tawil syndrome is characterized by? (3) |
1. Periodic paralysis 2. Cardiac arrhythmias 3. Dysmoprhic features |
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Diagnosis of familial periodic paralysis (3) |
1. Clinical history 2. Potassium levels during attack 3. Genetic testing |
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Treatment of hyperKPP (3) |
1. High-carbohydrate diet 2. Preventive fasting 3. Acetazolamide and dichlorphenamide |
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Treatment of hypoKPP |
1. Avoidance of high-carbohydrate food and intense exertion 2. Potassium salts 3. Acetazolamide and dichlorphenamide may reduce frequency of the paralytic attacks |
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Main treatment of Andersen-Tawil syndrome (2) |
1. Antiarrhythmics or pacemaker implantation 2. Acetazolamide |
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Patients with the CACNA1S mutation are at increased risk of |
malignant hyperthermia |
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Common pathologic findings among mitochondrial myopathies is |
the finding of ragged red fibers |