Harrison's Practice: Muscular Dystrophies

Harrison's Practice

Muscular Dystrophies

Definition

A group of hereditary progressive myopathic diseases, each with unique phenotypic and genetic features
Clinical presentation is highly variable but always involves some form of progressive muscular weakness.
Most have onset of symptoms in childhood, although several can present in adulthood.
Duchenne muscular dystrophy
- Most common muscular dystrophy
- X-linked recessive disorder
- Onset before age 5
Becker muscular dystrophy
- Less-severe form of X-linked recessive muscular dystrophy
- Onset in early childhood or adulthood
Congenital muscular dystrophy
- A group of autosomal recessive disorders
- Symptoms present at birth or within first few months
  - Merosin deficiency
  - Fukutin-related protein deficiency
  - Fukuyama congenital muscular dystrophy (FCMD)
  - Muscle-eye-brain (MEB) disease
  - Walker-Warburg syndrome (WWS)
Limb-girdle muscular dystrophy (LGMD)
- Represents more than 1 genetic disorder
- Systematic classification is based on inheritance pattern
  - Autosomal dominant (LGMD1)
  - Autosomal recessive (LGMD2)
  - Classification employs a sequential alphabetical lettering system (LGMD1A, LGMD2A, etc.)
- Highly variable range of onset across disorders, although most present in first 3 decades of life
Emery-Dreifuss
- There are 2 genetically distinct forms: one is X-linked, and the other is autosomal dominant.
- Onset in childhood to early adulthood
Myotonic dystrophy
- Also called dystrophia myotonica (DM)
- Two autosomal dominant forms have been identified: DM1 and DM2.
- Onset of symptoms in second decade of life
Facioscapulohumeral (FSH) muscular dystrophy
- Autosomal dominant
- Onset of symptoms before age of 20
Oculopharyngeal dystrophy
- Autosomal dominant
- Onset of symptoms in fifth and sixth decades of life

Epidemiology

Duchenne
- Incidence
  - ~30 per 100,000 live-born males
- Age
  - Present at birth
  - Usually becomes apparent between ages 3 and 5
- Sex
  - Male (X-linked disorder)
Becker
- Incidence
  - 3 per 100,000 live-born males
  - ~10 times less frequent than Duchenne
- Age
  - Most patients experience symptoms between ages 5 and 15
  - Onset in the third or fourth decade or even later can occur
- Sex
  - Male (X-linked disorder)
LGMD
- Incidence
  - Data have not been systematically gathered for any large heterogeneous population.
  - Less common than dystrophinopathies
- Age
  - Onset ranging from late in the first decade to the fourth decade
- Sex
  - Affects both male and female
Emery-Dreifuss
- Age
  - Early childhood and teenage years
Congenital muscular dystrophy
- Age
  - Symptoms present at birth or within first few months
DM1 and DM2
- Age
  - Usually second decade
  - May be infancy if mother affected (DM1 only)
FSH
- Prevalence
  - ~5 in 100,000
- Age
  - Childhood or young adulthood
Oculopharyngeal
- Age
  - Onset in fifth and sixth decades
- Geographic and ethnic distribution
  - Incidence is high in French-Canadians and in Spanish-American families of the southwestern U.S.
  - Large kindreds of Italian and of eastern European Jewish descent have been reported.

Risk Factors

Family history of muscular dystrophy

Etiology

Duchenne
- X-linked recessive
- Caused by a mutation of the gene that encodes dystrophin
  - Most common gene mutation is a deletion.
Becker
- X-linked recessive
- Results from allelic defects of same gene responsible for Duchenne
  - Deletions or duplications of the dystrophin gene in 65% of patients
LGMD
- Autosomal dominant (LGMD1)
  - Presently there are 6 autosomal dominant disorders identified.
- Autosomal recessive (LGMD2)
  - Presently there are 10 autosomal recessive disorders identified.
Emery-Dreifuss
- There are 2 genetically distinct forms.
  - X-linked
  - Autosomal dominant
    - Classified under rubric of LGMD1B, but clinical symptoms are closely related
Congenital
- Autosomal recessive
- There are 5 forms.
  - Merosin deficiency
  - Fukutin-related protein deficiency
  - FCMD
  - MEB disease
  - WWS
Myotonic
- There are at least 2 clinical disorders with overlapping phenotype.
  - DM1: autosomal dominant
  - DM2 [also called proximal myotonic myopathy (PROMM)]: autosomal dominant
FSH
- Autosomal dominant with almost complete penetrance
- Each family member should be examined for presence of disease, because ~30% of those affected are unaware of involvement.
- Caused by deletions of distal 4q
  - Mutation permits carrier detection and prenatal diagnosis.
  - Most sporadic cases represent new mutations.
Oculopharyngeal
- Autosomal dominant with complete penetrance
  - Molecular defect is a subtle expansion of a modest polyamine repeat tract in a poly-RNA binding protein (PABP2) in muscle.

Associated Conditions

In addition to progressive muscle weakness, many muscular dystrophy syndromes have multi-organ involvement that is associated with significant morbidity and mortality risk (see Symptoms & Signs).

Symptoms & Signs

Duchenne

Onset of symptoms typically begins before age 5.
Muscular manifestations
- Progressive loss of muscle strength
- Predilection for proximal limb muscles and neck flexors (girdle muscles)
- Involvement of legs is more marked than arms.
- Muscle weakness by age 5 is obvious by muscle testing.
- Common early signs and symptoms include:
  - Frequent falls
  - Difficulty keeping up with friends when playing
  - Abnormal running, jumping, and hopping
  - Use of hands to climb up (Gowers’ maneuver) when getting up from the floor
  - Contractures of the heel cords and iliotibial bands
  - Toe walking associated with a lordotic posture
  - Apparent by age 6
- Progressive kyphoscoliosis common
- Use of wheelchair typical by age 12
- Respiratory failure in second or third decade
Extramuscular manifestations
- Cardiomyopathy in almost all patients
  - Arrhythmias are rare.
- Intellectual impairment common
  - Average IQ approximately 1 standard deviation below mean
  - Appears to be nonprogressive
  - Verbal ability more affected than performance

Becker

Onset of symptoms occurs between ages 5 and 15.
Muscular manifestations
- Pattern of muscle wasting closely resembles Duchenne.
- Progressive weakness of girdle muscles, especially of lower extremities
- Weakness becomes generalized as disease progresses.
- Hypertrophy, particularly in calves, is an early and prominent finding.
- By definition, patients walk beyond age 15 (whereas patients with Duchenne dystrophy are typically in a wheelchair by the age of 12).
- Significant facial muscle weakness is not a feature.
- Respiratory failure may develop by fourth decade.
Extramuscular manifestations
- Cardiac
- May result in heart failure
- Mental retardation may occur.
  - Not as common as in Duchenne
Other less common presentations
- Asymptomatic hyper-CK-emia
- Myalgias without weakness
- Myoglobinuria

LGMD

Onset of symptoms varies widely across this group of diseases, usually in first three decades of life.
Muscular manifestations
- Slow, progressive weakness of pelvic and shoulder girdle musculature
- Respiratory insufficiency from weakness of the diaphragm may occur.
Extramuscular manifestations
- Cardiomyopathy may occur.
- Intellectual function is unaffected.

Emery-Dreifuss

Onset of symptoms occurs in early childhood or teenage years.
Muscular manifestations
- Muscle weakness
  - Affects humeral and peroneal muscles first
  - Later spreads to a limb-girdle distribution
- Prominent contractures in early childhood and teenage years
  - Often precede muscle weakness
  - Most commonly occur at the elbow and neck
  - Persist throughout course of disease
- Extramuscular manifestations
  - Cardiomyopathy
    - Potentially life threatening, may result in sudden cardiac death
    - Likely related to a spectrum of abnormal atrial rhythms and conduction defects (includes atrial fibrillation and atrioventricular heart block)
    - Some patients have a dilated cardiomyopathy.
    - Female carriers of the X-linked variant may have cardiac manifestations that become clinically significant.

Congenital

General

Symptoms are present at birth or within first few months of life.
Muscular manifestations
- Hypotonia and proximal or generalized muscle weakness
- Calf muscle hypertrophy in some patients
- Facial muscles may be weak.
  - Other cranial nerve–innervated muscles are spared (e.g., extraocular muscles are normal).
- Most have joint contractures of varying degrees at elbows, hips, knees, and ankles.
  - Contractures present at birth are referred to as arthrogryposis.
- Delayed milestones
- Respiratory failure may be seen.
Extramuscular manifestations
- Central nervous system is affected in some forms.
  - In merosin deficiency, cerebral hypomyelination is seen by MRI, yet only a small number of patients have mental retardation and seizures.
    - There is severe brain impairment in FCMD, MEB disease, and WWS.
    - Ocular abnormalities impair vision in MEB disease and WWS.

Merosin deficiency

Onset at birth with hypotonia
Joint contractures
Delayed milestones
Generalized muscle weakness
Cerebral hypomyelination, less often cortical dysplasia
Normal intelligence usually, some with mental retardation (~6%) and seizures (~8%)
Partial deficiency leads to milder phenotype (LGMD picture)

Fukutin-related protein deficiency

Onset at birth or shortly after
Hypotonia and feeding problems
Weakness of proximal muscles, especially shoulder girdles
Hypertrophy of leg muscles
Joint contractures
Cognition normal

FCMD

Onset at birth
Hypotonia, joint contractures
Generalized muscle weakness
Hypertrophy of calf muscles
Seizures
Mental retardation
Cardiomyopathy

MEB disease

Onset at birth, hypotonia
Eye abnormalities include: progressive myopia, cataracts, and optic nerve, glaucoma, retinal pigmentary changes
Progressive muscle weakness
Joint contractures
Seizures
Mental retardation

WWS

Onset at birth, hypotonia
Generalized muscle weakness
Joint contractures
Microphthalmos, retinal dysplasia, glaucoma, cataracts
Seizures
Mental retardation

DM1 and DM2

Onset of symptoms typically occurs in second decade of life.
Clinical expression varies widely.

Muscular manifestations

Slowly progressive weakness of face, neck, shoulder girdle, and distal extremities (hands and feet)
- Face and neck
  - Temporalis, masseter, and facial muscle atrophy and weakness
    - Result in typical "hatchet-faced" appearance
    - Less consistent in DM2
  - Palatal, pharyngeal, and tongue involvement
    - Produces dysarthric speech, nasal voice, and difficulty swallowing
  - Neck muscles, including flexors and sternocleidomastoids, involved early
- Distal extremities
  - Weakness of wrist extensors, finger extensors, and intrinsic hand muscles impairs function.
  - Ankle dorsiflexor weakness may cause footdrop.
Proximal muscles remain stronger throughout the course.
- Preferential atrophy and weakness of quadriceps may occur.
- DM2, or PROMM, has a distinct pattern of muscle weakness affecting mainly proximal muscles.
Some patients have diaphragm and intercostal muscle weakness.
- Results in respiratory insufficiency
Myotonia usually appears by age 5.
- Demonstrable by percussion of the thenar eminence, tongue, and wrist extensor muscles
- Causes a slow relaxation of hand grip after a forced voluntary closure
- Advanced muscle wasting makes myotonia more difficult to detect.

Extramuscular manifestations

Multi-organ involvement

Frontal baldness characteristic in men
- Less consistent in DM2

Cardiac disturbances common in DM1

Complete heart block and sudden death can occur.

Congestive heart failure occurs infrequently but may result from cor pulmonale secondary to respiratory failure.

Mitral valve prolapse is common.
Conduction defects are less common in DM2.

Intellectual impairment

Hypersomnia

Posterior subcapsular cataracts

Gonadal atrophy

Insulin resistance

Decreased esophageal and colonic motility

FSH

Onset of symptoms occurs in childhood or early adulthood.
Muscular manifestations
- Slowly progressive weakness of face, shoulder girdle, and foot dorsiflexion
- Facial weakness is typically the initial manifestation.
  - Inability to smile, whistle, or fully close the eyes
- Weakness of shoulder girdles usually brings patient to medical attention.
  - Loss of scapular stabilizer muscles makes arm elevation difficult.
  - Scapular winging is apparent with attempts at abduction and forward movement of the arms.
- Biceps and triceps muscles may be severely affected.
  - Relative sparing of the deltoid muscles
- Weakness is worse for wrist extension than for wrist flexion.
- Weakness of the anterior compartment muscles of the legs may lead to footdrop.
- In 20% of patients, weakness progresses to involve pelvic girdle muscles.
  - Results in severe functional impairment and possible wheelchair dependency
Extramuscular manifestations
- Characteristically, patients do not have involvement of other organ systems.
  - Labile hypertension common
  - Increased incidence of nerve deafness
  - Coats’ disease, a disorder consisting of telangiectasia, exudation, and retinal detachment

Oculopharyngeal

Onset of symptoms occurs in fifth and sixth decades of life.
Slowly progressive weakness of:
- Extraocular muscles
- Pharyngeal muscles
- Limb muscles
Progressive external ophthalmoplegia
- Slowly progressive ptosis
- Limitation of eye movements
- Sparing of pupillary reactions for light and accommodation
- Patients usually do not complain of diplopia.
Dysphagia
- May become debilitating
- May result in pooling of secretions and repeated episodes of aspiration
Mild weakness of neck and extremities may also occur.

Differential Diagnosis

Differential diagnosis is based on pattern of weakness on neurologic examination.
- Proximal > distal
  - Muscular dystrophies
  - Dermatomyositis
  - Polymyositis
- Ptosis/extraocular muscles
  - Oculopharyngeal muscular dystrophy
  - Mitochondrial myopathy
  - Myotubular myopathy
- Facial and scapular winging
  - FSH muscular dystrophy
- Facial, distal, quadriceps; hand grip myotonia
  - DM
- Proximal and distal (hand grip) and quadriceps
  - Inclusion body myositis
- Distal
  - Distal myopathy
  - Neuropathy
- Head Drop

Diagnostic Approach

Careful history and physical examination with particular attention to family history and age of onset of muscle weakness
Diagnostic evaluation of persistent muscle weakness (See Figure 1.)
- Define the pattern of weakness on neurologic examination (see Differential Diagnosis).
- Myopathic electromyogram (EMG) confirms muscle disease and excludes ALS.
- Repetitive nerve stimulation indicates myasthenia gravis.
- Creatine phosphokinase (CK) elevation supports myopathy.
- Muscle biopsy will help distinguish many disorders.
- Patient may need DNA testing for further distinction of inherited myopathies.

Laboratory Tests

Serum CK
- Duchenne
  - Elevated to between 20 and 100 times normal
  - Abnormal at birth but declines late in the disease because of inactivity and loss of muscle mass
- Becker
  - Closely resembles findings in Duchenne dystrophy
- LGMD
  - As the syndrome represents multiple disorders, CK levels are highly variable.
- Emery-Dreifuss
  - May be elevated 2- to 10-fold
- Congenital
  - Markedly elevated
    - Merosin deficiency: 5–35 times normal
    - Fukutin-related protein deficiency: 10–50 times normal
    - FCMD: 10–50 times normal
    - MEB disease: 5–20 times normal
    - WWS: 5–20 times normal
- DM
  - May be normal or mildly elevated
- FSH
  - May be normal or mildly elevated
- Oculopharyngeal
  - May be 2–3 times normal
Mutation analysis on peripheral blood leukocytes
- Duchenne
  - Identification of a specific mutation in dystrophin gene
    - Allows for unequivocal diagnosis
    - Makes possible accurate testing of potential carriers
    - Is useful for prenatal diagnosis
- Becker
  - Reveals deletions or duplications of dystrophin gene
- Other dystrophies
  - Availability of commercial genetic testing for other dystrophies continues to evolve.

Imaging

Overall, imaging of the neuroaxis is not usually necessary in the evaluation of myopathies and muscular dystrophies.
MRI of the brain can help distinguish amongst the congenital muscular dystrophies, as some have central nervous system involvement and others do not (see Symptoms & Signs).
- FCMD
  - Hydrocephalus
  - Periventricular and frontal hypomyelination
- MEB disease
  - Hydrocephalus
  - Cobblestone lissencephaly
  - Corpus callosum and cerebellar hypoplasia
  - Cerebral hypomyelination
- WWS
  - Cobblestone lissencephaly
  - Hydrocephalus
  - Encephalocoele
  - Absent corpus callosum

Diagnostic Procedures

EMG
- Can confirm underlying myopathic process, characterize distribution/pattern of muscle involvement, exclude other cause (e.g., neuropathy, motor neuron disease), and evaluate for coexisting myotonia
- Duchenne
  - Myopathic
- Becker
  - Myopathic
- LGMD
  - Myopathic, with mixed myopathy/neuropathy in LGMD1A (autosomal dominant limb-girdle muscular dystrophy type A)
- Emery-Dreifuss
  - Myopathic
- Congenital
  - Myopathic
- DM
  - Evidence of myotonia is present in most cases of DM1 but may be more patchy in DM2.
- FSH
  - Usually indicates a myopathic pattern
- Oculopharyngeal
  - Myopathic
Muscle biopsy
- Duchenne
  - Muscle fibers of varying size
  - Small groups of necrotic and regenerating fibers
  - Connective tissue and fat replace lost muscle fibers.
  - Definitive diagnosis is established on the basis of dystrophin deficiency.
  - Diagnosis can also be made by Western blot analysis of muscle biopsy specimens.
    - Abnormalities on the quantity and molecular weight of dystrophin protein
  - Immunocytochemical staining of muscle with dystrophin antibodies
    - Can be used to demonstrate absence or deficiency of dystrophin localizing to the sarcolemmal membrane
    - Possible mosaic pattern in carriers of the disease
    - Dystrophin analysis of muscle biopsy specimens for carrier detection not reliable
- Becker
  - Results closely resemble those in Duchenne dystrophy.
  - Diagnosis requires Western blot analysis of muscle biopsy samples demonstrating a reduced amount or abnormal size of dystrophin.
- Emery-Dreifuss
  - Nonspecific dystrophic features
  - Immunohistochemistry reveals absent emerin staining of myonuclei in X-lined Emery-Dreifuss.
- Congenital
  - Nonspecific dystrophic features
  - In merosin deficiency, merosin, or laminin α2 chain (a basal lamina protein), is deficient surrounding muscle fibers.
  - In other disorders (fukutin-related protein deficiency, FCMD, MEB disease, WWS), abnormal dystroglycan staining in muscle.
- DM
  - Muscle atrophy
    - Selectively involves type 1 fibers in 50% of cases
    - Ringed fibers in DM1 but not in DM2
  - Typically, numerous internalized nuclei can be seen in individual muscle fibers as well as atrophic fibers with pyknotic nuclear clumps in both DM1 and DM2.
  - Necrosis of muscle fibers and increased connective tissue not common
- FSH
  - Nonspecific features of a myopathy
  - A prominent inflammatory infiltrate present in some biopsy samples
  - Often multifocal in distribution
- Oculopharyngeal
  - Muscle fibers contain vacuoles.
  - Electron microscopy shows membranous whorls, accumulation of glycogen, and other nonspecific debris related to lysosomes.
  - A distinct feature is the presence of tubular filaments, 8.5 nm in diameter, in muscle cell nuclei.
Electrocardiogram
- Duchenne
  - Increase net RS in lead V₁
  - Deep, narrow Q waves in the precordial leads
  - Tall right precordial R waves in V₁
- Emery-Dreifuss
  - Atrial and atrioventricular rhythm disturbances
- DM
  - Abnormalities include first-degree heart block and more extensive conduction system involvement.

Treatment Approach

Currently there is no cure for the muscular dystrophies.
Treatment is aimed at slowing progression.
Supportive care is used to relieve symptoms as disease progresses and to treat complications.

Specific Treatments

Duchenne

Prednisone in a dose of 0.75 mg/kg per d
- Significantly slows progression for up to 3 years
- Some patients cannot tolerate glucocorticoid therapy.
  - Weight gain is significant deterrent.
- Complications of long-term use often outweigh the benefits.

Becker

Use of glucocorticoids has not been adequately studied.
Endurance training may be helpful.[1]

LGMD and Emery-Dreifuss

Supportive care, including ambulatory aids if necessary, should be offered for neuromuscular disability.
Stretching of contractures is difficult.
Management of cardiomyopathy and arrhythmias can save lives.

Congenital

No specific treatment is available.
Proper wheelchair seating is important.
Management of epilepsy and cardiac manifestations is necessary for some patients.

DM

Myotonia in DM1 rarely warrants treatment.
Some patients with DM2 experience significant discomfort related to the associated muscle stiffness.
- Phenytoin and mexiletine are preferred agents for the occasional patient who requires an anti-myotonia drug.
  - Other agents, particularly quinine and procainamide, may worsen cardiac conduction.
Cardiac pacemaker insertion should be considered for patients with:
- Unexplained syncope
- Advanced conduction system abnormalities with evidence of second-degree heart block
- Trifascicular conduction disturbances with marked prolongation of the PR interval
Molded ankle-foot orthoses
- Help prevent footdrop in patients with distal lower extremity weakness
Excessive daytime somnolence with or without sleep apnea: not uncommon, and patient may benefit from:
- Sleep studies
- Noninvasive respiratory support (BiPAP)
- Modafinil

FSH

No specific treatment is available.
Ankle-foot orthoses are helpful for footdrop.
Scapular stabilization procedures
- Improve scapular winging but may not improve function

Oculopharyngeal

Cricopharyngeal myotomy
- May improve swallowing
- Does not prevent aspiration
Eyelid crutches
- Can improve vision when ptosis obstructs vision
- Candidates for ptosis surgery must be carefully selected.
- Those with severe facial weakness are usually not suitable.

Monitoring

Monitor for disease progression and complications.
Monitor for treatment complications.

Complications

Duchenne

Tendon and muscle contractures
Progressive kyphoscoliosis
Impaired pulmonary function
Cardiomyopathy
Intellectual impairment

Becker

Mental retardation: not as common as in Duchenne
Heart failure
Respiratory failure

LGMD

Complications (e.g., cardiac, respiratory) vary with the specific subtype of disease.

Emery-Dreifuss

Contractures
Cardiomyopathy
A spectrum of atrial rhythm and conduction defects
- Includes atrial fibrillation and paralysis and atrioventricular heart block
Sudden death

Congenital

Contractures
Respiratory failure
Central nervous system is affected in some forms.
- Mental retardation
- Seizures
- Ocular abnormalities impairing vision

DM

Posterior subcapsular cataracts
Gonadal atrophy
Respiratory problems including chronic hypoxemia leading to cor pulmonale
Cardiac problems including complete heart block
Endocrine abnormalities
Intellectual impairment
Hypersomnia

FSH

Labile hypertension
Hearing loss

Oculopharyngeal dystrophy

Recurrent aspiration

Prognosis

Duchenne

Between ages 8 and 10
- Walking may require use of braces.
- Joint contractures and limitations of hip flexion, knee, elbow, and wrist extension are worsened by prolonged sitting.
By age 12
- Most patients are wheelchair-dependent.
- Contractures become fixed.
- Progressive scoliosis often develops.
  - May be associated with pain
- Chest deformity occurs with scoliosis.
  - Impairs pulmonary function, already diminished by muscle weakness
By age 16–18
- Predisposition to serious pulmonary infections
Respiratory failure in second or third decade
Causes of death include:
- Pulmonary infections
- Aspiration
- Acute gastric dilation
- A cardiac cause of death is uncommon.

Becker

Patients have reduced life expectancy.
Most survive into the fourth or fifth decade.
Respiratory failure may develop by fourth decade.

Congenital

WWS is the most severe, causing death by 1 year of age.

Prevention

Prevention
- There are no known preventive strategies.
Screening
- Genetic testing, including prenatal testing, is available for some of the muscular dystrophies.

ICD-9-CM

359.0 Congenital hereditary muscular dystrophy
359.1 Hereditary progressive muscular dystrophy
359.2 Myotonic disorders (includes myotonic muscular dystrophy)