Mayo Clinic 2 - 43 - Inherited Muscle Disorders

Front 1

Differential diagnosis of inherited myopathies is broad. They include (5)

Back 1

1. Muscular dystrophies

2. Congenital myopathies

3. Metabolic myopathies

4. Channelopathies

5. Mitochondrial myopathies

Front 2

Congenital myopathies often present with (5)

Back 2

1. At birth

2. Hypotonia

3. Poor respiratory effort

4. Reduced feeding ability

5. Slow or non-progressive course

Front 3

Dystrophinopathies are caused by

Back 3

mutations in the largest human gene, dystrophin, located on chromosome Xp21

Front 4

Most severe form of muscular dystrophy?

Back 4

Duchenne, and is the most common with an incidence of 1 in 3,500 newborn males

Front 5

What is dystrophin?

Back 5

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

Front 6

Clinical features of DMD (4)

Back 6

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

Front 7

Diagnosis of muscular dystrophies is based on (4)

Back 7

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%

Front 8

Treatment of muscle dystrophies

Back 8

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

Front 9

Promising new treatments for muscular dystrophies?

Back 9

Gene therapy, such as the delivery of minidystrophin and exon skipping

Front 10

Third most common muscular dystrophy?

Back 10

Facioscapulohumeral muscular dystrophy; incidence of 1 in 15,000 to 20,000

Front 11

Pathophysiology of facioscapulohumeral muscular dystrophy

Back 11

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

Front 12

Clinical features of facioscapulohumeral muscular dystrophy? (5)

Back 12

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

Front 13

Extramuscular manifestations of facioscapulohumeral muscular dystrophy? (3)

Back 13

1. High-frequency hearing loss

2. Asymptomatic retinal telangiectasias seldom resulting in retinal exudates and detachment (Coats disease)

3. Very rarely atrial arrhythmias

Front 14

Diagnosis of facioscapulohumeral muscular dystrophy?

Back 14

1. Clinical phenotype

2. Confirmed by genetic testing

Front 15

Treatment of facioscapulohumeral muscular dystrophy? (2)

Back 15

1. Supportive with physical therapy

2. Ankle-foot orthotics if foot drop is present

Front 16

Screening for what is important in patients with limb girdle muscular dystrophies?

Back 16

Cardiac involvement, because cardiomyopathy or cardiac conduction defects accompany several forms of LGMD

Front 17

Diagnosis of LGMD is made on the basis of (3)

Back 17

1. Elevated CK

2. Muscle biopsy (shows signs of muscle degeneration and regeneration)

3. Gene analysis may be necessary

Front 18

Treatment of LGMD?

Back 18

No definitive treatment is available; physical therapy is helpful for avoiding development of contractures

Front 19

The most common congenital muscular dystrophy is due to

Back 19

recessive mutations in merosin, an extracellular matrix protein

Front 20

Clinical features of merosin-deficient congenital muscular dystrophy? (2)

Back 20

1 .Facial and limb weakness

2. Often contractures

Front 21

Diagnosis of congenital muscular dystrophies

Back 21

Confirmed by gene analysis; biopsy may be helpful before the results of gene analysis are ready

Front 22

Treatment of congenital muscular dystrophies?

Back 22

Supportive

Front 23

What is EMD?

Back 23

Emery-Dreifus muscular dystrophy; of which there are two types

Front 24

Clinical features of EMD (4)

Back 24

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

Front 25

Diagnosis of EMD is made by

Back 25

muscle biopsy

Front 26

Progressive ptosis and dysphagia in the fifth to sixth decade of life

Back 26

Oculopharyngeal dystrophy

Front 27

Inheritance pattern of oculopharyngeal dystrophy?

Back 27

AD; expanded GCG repeat in the PABPN1 gene on chromosome 14

Front 28

Diagnosis of oculopharyngeal dystrophy

Back 28

1. Normal CK level

2. EMG shows typical myopathic motor units

3. Muscle biopsy - dystrophic changed and rimmed vacuoles and intranuclear inclusions

Front 29

Treatment of oculopharyngeal muscular dystrophy?

Back 29

Aimed at preventing medical complications such as nutritional issues; surgery for ptosis

Front 30

Other name for Steinert disease

Back 30

Myotonic dystrophy type 1 (DM1)

Front 31

Most common adult-onset muscular dystrophy?

Back 31

DM1; also the second most common muscular dystrophy after dystrophinopathy

Front 32

Incidence of DM1

Back 32

13.5 per 100,000 live births

Front 33

Highest prevalence of DM is seen where?

Back 33

Germany and Poland, and in subjects with German or Polish ancestry

Front 34

Main symptoms of DM1 (4)

Back 34

1. Distal muscle weakness

2. Myotonia

3. Prominent in the hands

4. Ptosis, facial muscle weakness, and temporalis muscle wasting are common

Front 35

DM2 manifests in the ___ decade of life and is characterized by

Back 35

third; proximal muscle weakness, myalgia, and less prominent myotonia

Front 36

Genetic basis of myotonic muscular dystrophies

Back 36

Unstable CTG repeats in the 3' UTR of the dystrophia myotonica protein kinase (DMPK) gene on chromosome 19q13.2

Front 37

Treatment of myotonia treatment in DM1 and DM2?

Back 37

Mexiletine 150 to 200mg 3 times daily is an effective and safe antimyotonia treatment

Front 38

Most common inherited metabolic muscle disorders? (3)

Back 38

1. McArdle disease

2. Pompe disease

3. CPT deficiency 2

Front 39

Epidemiology of Pompe disease (3)

Back 39

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

Front 40

Pathophysiology of Pompe disease

Back 40

GAA is a lysosomal enzyme that catalyzes the breakdown of glycogen into glucose; results in glycogen accummulation and autophagic vacuoles

Front 41

Clinical spectrum of Pompe disease (3)

Back 41

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

Front 42

Diagnosis of Pompe disease

Back 42

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

Front 43

Treatment of Pompe disease

Back 43

Enzyme replacement therapy with alglucosidase alfa before age 6 months and before the need for ventilatory assistance

Front 44

Defect in McArdle

Back 44

Myophosphorylase deficiency

Front 45

Clinical features of McArdle (5)

Back 45

1. Exercise intolerance

2. Premature exertional fatigue and myalgia

3. Exercise-induced muscle contractures

4. Myoglobinuria

5. Improves with rest

Front 46

Diagnosis of McArdle (5)

Back 46

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

Front 47

Treatment of McArdle (3)

Back 47

1. Maximal aerobic and isometric exercise should be avoided

2. high-protein and low-carbohydrate diet

3. Creatine monohydrate may improve symptoms

Front 48

Defect in Pompe disease

Back 48

acid a-glucosidase deficiency (acid maltase)

Front 49

Most common disorder of lipid metabolism involving the skeletal muscle?

Back 49

Carnitine palmitoyltransferase II (CPTII) deficiency

Front 50

Phenotypes of CPTII deficiency

Back 50

1. Lethal neonatal

2. Severe infantile hepatocardiomuscular form

3. Myopathic form

Front 51

Treatment of CPTII deficiency

Back 51

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

Front 52

Which drugs should be avoided in CPTII deficiency? (3)

Back 52

1. Valproic acid

2. General anesthesia

3. Diazepam in high doses

Front 53

Diagnosis of CPTII deficiency?

Back 53

Enzyme assay in muscle tissue

Front 54

The myopathic form of CPTII deficiency presents how?

Back 54

In the first or second decade of life with myalgia and paroxysmal myoglobinuria on prolonged exercise

Front 55

What is myotonia congenita?

Back 55

Nondystrophic skeletal muscle disorder due to abnormal muscle excitability; it can be inherited as AD (Thomsen myotonia) or recessive (Becker myotonia) trait

Front 56

Mutations in muscle ___ channel can lead to AD or AR myotonia congenita

Back 56

chloride channel (CLCN1)

Front 57

Myotonia congenita manifests how? (5)

Back 57

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

Front 58

Diagnosis of myotonia congenita? (2)

Back 58

1. EMG shows myotonic discharges

2. Genetic testing confirms the diagnosis

Front 59

Treatment of myotonia congenita?

Back 59

Mexiletine prevents involuntary repetitive firing of muscle action potentials and alleviates the symptoms ,however, most patients do not require pharmacologic treatment

Front 60

Attacks of flaccid weakness associated with reduced serum potassium level

Back 60

Familial periodic paralysis (hypokalemic PP, hypoKPP)

Front 61

Increased serum potassium levels and attacks of flaccid weakness?

Back 61

Periodic paralysis (hyperkalemic PP, hyperKPP)

Front 62

Pathophysiology of hypoKPP

Back 62

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)

Front 63

Pathophysiology of hyperKPP?

Back 63

Mutations in the SCN4A gene

Front 64

Clinical features of hypoKPP? (2)

Back 64

1. Paralytic attacks manifest in the first 2 decades of life

2. Rest after exercise and carbohydrate-rich meals trigger the attacks

Front 65

Clinical features of hyperKPP?

Back 65

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

Front 66

Andersen-Tawil syndrome is characterized by? (3)

Back 66

1. Periodic paralysis

2. Cardiac arrhythmias

3. Dysmoprhic features

Front 67

Diagnosis of familial periodic paralysis (3)

Back 67

1. Clinical history

2. Potassium levels during attack

3. Genetic testing

Front 68

Treatment of hyperKPP (3)

Back 68

1. High-carbohydrate diet

2. Preventive fasting

3. Acetazolamide and dichlorphenamide

Front 69

Treatment of hypoKPP

Back 69

1. Avoidance of high-carbohydrate food and intense exertion

2. Potassium salts

3. Acetazolamide and dichlorphenamide may reduce frequency of the paralytic attacks

Front 70

Main treatment of Andersen-Tawil syndrome (2)

Back 70

1. Antiarrhythmics or pacemaker implantation

2. Acetazolamide

Front 71

Patients with the CACNA1S mutation are at increased risk of

Back 71

malignant hyperthermia

Front 72

Common pathologic findings among mitochondrial myopathies is

Back 72

the finding of ragged red fibers