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Muscle Disease

David Roman Renner, MD

Department of Neurology

Reading Resources:

            Ptacek LJ, Johnson KJ, Griggs RC.  Mechanisms of Disease:  Genetics and

Physiology of the Myotonic Muscle Disorders; NEJM 1993;328:482-489.

            Mendell J, Griggs RC, Ptacek LJ.  Diseases of Muscle.  In:  Harrison’s Textbook

of Internal Medicine, ed 14.  New York, McGraw-Hill, 1998 pp. 2473-2483.

Dubowitz V.  The Muscular Dystrophies.  Postgrad Med J 1992 Jul;68(801):500-

506.

What you are responsible for:

            I will write all test questions for this lecture hour, the content of which is

addressed in this handout and/or the lecture hour.

Syllabus Contents:

            Introduction to Muscle Disease

                        Duchenne Muscular Dystrophy

                        Becker Muscular Dystrophy

                        Myotonic Dystrophy

                        Facioscapulohumeral Muscular Dystrophy

Objectives: 

The student should be able to:

1.      differentiate the 4 major muscular dystrophies by phenotype

2.      understand the genotype-phenotype correlation when appropriate

3.      describe tests which may be utilized to arrive at a diagnosis

4.      explain the genetics of inheritance of the muscular dystrophies

5.      illustrate the clinical hallmarks of the aforementioned disorders

Duchenne Muscular Dystrophy

I.                   Clinical Hallmark

·        Progressive symmetric weakness of proximal > distal skeletal muscles

·        Presents in childhood (usually age 3-5) in one of  3 ways:

·        with delay in motor milestones (delayed walking by 3-6 months) . . . most common

·        elevated serum levels of creatine kinase

·        malignant hyperthermia after exposure to halothane anesthesia

·        The most frequent presenting symptom is an abnormal gait (waddling)

·        There is a relentless progression of weakness

·        Gower’s sign from proximal/pelvic muscle weakness

·        Turns from supine to prone, then goes to the knees and elbows, extends knees and arms, moves the arms close to the trunk, and “marches up himself” with the hands on the legs

·        Trendellenberg’s sign

·        Lordosis results from weakness of hip extensors, producing a forward pelvic tilt

·        Gait becomes difficult, resulting in increasing numbers of falls

·        Heal cord contractures occur, producing “tip toe” walking

·        Doughy gastrocnemius pseudohypertrophy produces enlarged calves, which disappears when ambulation is lost

·        Over time, weakness progresses, limiting negotiation of stairs, running, and arising from the floor

·        Reflexes are often absent in the upper extremities and knees even in the early stages, while ankle reflexes are preserved up to the terminal stages

·        The ability to ambulate is lost usually around 7-13 years of age

·        Once boys take the wheel chair, they are at high risk for developing scoliosis (90% develop some degree)

·        Death usually occurs by age 15-25:  attributed to respiratory insufficiency (90%) or cardiac insufficiency (10%)

II.                Laboratory

·        CK (creatine kinase) is a marker of muscle breakdown, and is exceptionally high, on the order of thousands (5,000-150,000 IU/L) . . . when normal is <200 IU/L

·        Muscle biopsy findings vary with the stage of the disease:  classic myopathic findings on histology:

·        Endomysial fibrosis

·        Variable fiber size:  small and rounded

·        Hypercontracted opaque fibers

·        Muscle fiber degeneration and regeneration

·        Absence of distrophin stain

·        Replacement of myofibers with adipose

III.             Associated Features

·        Respiratory and accessory muscle: weakness allows hypoventilation and increases risks for pneumonia, usually in the late teen years

·        Dilated cardiomyopathy:  cardiac muscle is also affected), usually >15 yo

·        Intellectual impairment is seen in 30% of boys:  average IQ=88

·        This is not progressive

·        Not correlated with the severity or duration of the dystrophy

·        Verbal is worse than performance IQ

IV.              Diagnosis

·        Evaluate the pedigree for an X-linked inheritance pattern

·        At one time, the diagnosis was based upon a clinical exam:  males with weakness presenting by age 3, with progression, losing ambulation by age 13, with early death and possible cardiac involvement

·        When dystrophin staining was discovered, the diagnosis rested on the absence of dystrophin protein staining the perimetry of myocytes on biopsy . . . and this is still true today.

·        The gold standard is genetic testing:  evaluation for deletions in one or more exons in the dystrophin gene

·        Immunofluorescence to determine the levels of dystrophin expression in frozen biopsy specimens  (no fluorescence is seen around the perimetry of cells in patients with DMD)

V.                 Genetics

·        Affects 1:3500 live male births

·        X-linked inheritance

·        The disease is most often transmitted to male offspring by asymptomatic female carriers

·        Chromosome Xp21

·        The gene occupies 2.5 million base pairs of DNA . . . 10x larger than the next gene identified to date

·        The gene produces a protein called dystrophin, which localizes to the plasma membrane inside all myocytes (and some neurons)

·        The role of dystrophin is to form part of a link between the intracellular cytoskeleton and the extracellular matrix, and may help stabilize the membrane during contraction and relaxation

·        Deletions, duplications, or small mutations

·        96%:  frameshift mutations

·        30%:  new mutations

·        10-20%:  gonadal mosaics

·        genetic testing is 96% sensitive . . . in the remaining 4%, one must utilize muscle biopsy for diagnosis

VI.              Treatment

·        The goal of treatment is to prolong ambulation, which is partly accomplished through the use of prednisone 0.75 mg/kg/day

·        Deflazacort is a new steroid, equally effective in slowing progression, with fewer side effects

·        Prolongs walking by 2-3 years

·        Physical therapy with heal cord stretches

·        Bracing with knee-foot orthoses (KFO)

·        Night-time bracing to prevent contractures

·        Electric wheel chairs

·        Continuous positive pressure ventilation at night

·        Harrington rod placement if vital capacity is limited

·        Screening others with creatine kinase

·        Genetic counseling to unsuspecting parents

·        Mom’s future sons may be at risk for Duchenne MD

·        Sisters of the proband may be carriers of the gene

Becker Muscular Dystrophy

I.                   Clinical Hallmark

·        Progressive symmetric proximal > distal weakness of the skeletal muscles in the appendices (limb-girdle) similar to that of DMD, but with a course later in onset and slower in progression

·        Presents later than DMD, usually after 7 yo

·        There is significant variability as to when these patients present with weakness

·        Can present in infancy, though this is rare

·        Similarly, individuals in their 50’s have presented for the first time with weakness from BMD

·        The rule is this:  Infants are usually normal, and the disease manifests somewhere thereafter.

·        Weakness is in the same distribution of DMD, though not nearly as severe

·        Most prominent in the quadriceps or hamstrings

·        Other unusual presentations may include:

·        Myoglobinuria may call attention to the disorder, with persistent elevation of CK between myoglobinuric attacks

·        Muscle cramping and myalgias with exercise

·        Isolated cognitive impairment

·        Muscle hypertrophy of gastrocnemius

·        Muscle atrophy

·        Like DMD patients, gait and negotiating stairs becomes problematic first

·        May manifest Gower’s, Trendellenberg’s signs, and develop lordosis, though often their weakness is not nearly as bad

·        Many will lose ambulation after age 16, requiring a wheel chair

II.                Laboratory

·        CK is not as high as that of DMD, though can get as high as 10,000 IU/L

·        Muscle biopsy findings vary with the stage of the disease:  classic myopathic findings on histology:

·        Endomysial fibrosis

·        Variable fiber size:  small and rounded

·        Hypercontracted opaque fibers

·        Muscle fiber degeneration and regeneration

·        Reduced distrophin staining

·        Replacement of myofibers with adipose

 III.             Associated Features

·        Dilated cardiomyopathy may be the presenting symptom

·        This should raise suspicion for BMD

·        Intellectual impairment is associated with deletion of the Dp140 transcription unit

·        Not progressive

IV.              Diagnosis

·        Evaluate the pedigree for an X-linked inheritance pattern

·        When dystrophin staining was discovered, the diagnosis rested on the reduction of dystrophin protein staining the perimetry of myocytes on biopsy . . . and this is still true today.

·        The gold standard is genetic testing (evaluation for deletions in one or more exons in the dystrophin gene)

·        Immunofluorescence to determine the levels of dystrophin expression in frozen biopsy specimens  (there should be reduced fluorescence around the perimetry in patients with BMD)

V.                 Genetics

·        Affects 1:3500 live male births

·        X-linked inheritance

·        The disease is most often transmitted to male offspring by asymptomatic female carriers

·        Chromosome Xp21

·        The gene occupies 2.5 million base pairs of DNA . . . 10x larger than the next gene identified to date

·        The gene produces a protein called dystrophin, which localizes to the plasma membrane inside all myocytes (and some neurons)

·        The role of dystrophin is to form part of a link between the intracellular cytoskeleton and the extracellular matrix, and may help stabilize the membrane during contraction and relaxation

·        There is a lack of correlation between the size of the dystrophin gene deletion and the clinical phenotype.  Patients with DMD may have small deletions, and those with BMD may have large deletions.  The salient feature of deletions seems to be whether they allow translation of a dystrophin protein with some degree of function. 

VI.              Treatment

·        Prednisone is not used like in DMD

·        Physical therapy with heal cord stretches

·        Bracing with knee-foot orthoses (KFO)

·        Electric wheel chairs

·        Continuous positive pressure ventilation at night

·        Screening others with creatine kinase

·        Genetic counseling to unsuspecting parents

·        Mom’s future sons may be at risk for Beckers MD

·        Sisters of the proband may be carriers of the gene

Myotonic Dystrophy

I.                   Clinical Hallmark

·        The most common adult form of muscular dystrophy

·        The disease was named for its principal manifestations in skeletal muscle:

·        Myotonia:  the sustained contraction of muscle in response to electrical or percussive stimuli

·        Dystrophy:  the progressive loss of skeletal muscle with fibrosis and fatty infiltration

·        Spans a continuum from mild to severe

·        Affects both skeletal and smooth muscle

·        3 phenotypes

·        mild:  cataracts, myotonia, normal life span

·        classical:  muscle weakness, atrophy, myotonia, cataracts, cardiac conduction abnormalities, possibly shortened life span

·        congenital:  hypotonia, severe generalized weakness at birth, often respiratory insufficiency, early death, mental retardation, facial diplegia

·        inherited by either sex but only through their mother

·        in general, the earlier the onset, the more rapid and severe the muscle involvement

·        Onset may vary; the earlier the age of onset, the longer the CTG repeat

·        Childhood:  mental retardation, motor delay

·        Adult:  weakness

·        Older adult:  cataract formation

·        Pattern of weakness:

·        Distal weakness progresses for years before proximal weakness occurs

·        Usually begins in the hands and feet:  weak grip and progressive footdrop

II.                Laboratory

·        Muscle biopsy:  fatty infiltration, fibrosis, variation in fiber size, increase in central nuclei, ring fibers

·        Serum CK is usually not helpful, as it is often normal or mildly elevated

III.             Associated Features

·        Cardiac Conduction System fibrosis:  sinus bradycardia, may progress to heart block

·        Eye cataracts:  punctate, multicolored, posterior flecks that gradually worsen to become mature cataracts

·        Endocrine:  insulin insensitivity renders patients resistant to hypoglycemia

·        Smooth muscle involvement:  bowel hypomotility with dilation and megacolon

·        CNS:  patients have been described as hostile, reticent, uncooperative, suspicious, stubborn, superficial, hypersomnolence

·        Other:  narrow face, poorly developed chin, prominent forehead, temporal muscle wasting, male pattern baldness

IV.              Diagnosis

·        Clinical features give the diagnosis away in DM type 1

·        EMG (electromyography) reveals myotonia

·        The diagnosis is established by a DNA diagnostic procedure that measures the size of the unstable CTG repeat in blood or tissue DNA

V.                 Treatment

·        EKG:  watch for gradual widening of the P-R interval to evaluate for impending heart block

·        Demand pacemakers

·        Ritalin and caffeine for hypersomnolence

VI.              Genetics

·        Two types of myotonic dystrophy have been described, based upon genotype:

·        DM1:  chromosome 19

·        DM2:  chromosome 3

·        (clinically, they look similar, though the degree of facial and limb weakness and ptosis in DM2 are more like that of mild (rather than severe) DM1

·        This disorder results from a trinucleotide repeat expansion (CTG)

·        Normal:  5-38 repeats

·        Affected individuals:  50 to several thousand repeats

·        The gene codes for myotonin protein kinase

·        The role of the myotonin protein kinase protein is unknown

·        The mechanism by which the genetic mutation causes symptoms and signs is unknown

·        Autosomal dominant with extremely variable penetrance

·        Anticipation:  apparent worsening of the disease in subsequent generations

Facioscapulohumeral Muscular Dystrophy

I.                   Clinical Hallmark

·        Weakness in a striking distribution of the face, upper arms, shoulders

·        Winging of the scapulae

·        Difficulty raising arms above the head

·        Unable to whistle or suck through a straw

·        May not be able to close eyes completely

·        Poorly developed chest muscles give the appearance of pectus excavatum

·        Begins asymmetric in late childhood or adolescence

·        Progresses to involve the forearms, pelvic girdle, peroneal muscles

·        Symptoms can be extremely variable

II.                Laboratory

·        Serum CK are usually normal, though may be elevated up to 5 times normal, though this varies by sex

·        Elevated in 73% of affected males

·        Elevated in 43% of affected females

·        Muscle biopsy may reveal minimal myopathic changes or severe dystrophic changes, depending upon which muscle is biopsied

·        EMG:  myopathic findings

III.             Associated Features

·        Hearing loss

·        Retinopathy

IV.              Diagnosis

·        DNA analysis for linkage to chromosome 4q35

V.                 Treatment

·        Wheel chairs for the 10% who need them

·        For those with severe limitation of arm functions, the scapulae may be wired to the chest to give better purchase for shoulder girdle muscles

VI.              Genetics

·        Autosomal dominant with sporadic de novo mutations

·        Chromosome 4q

·        There may be evidence of anticipation:  onset at earlier age in successive generations

·        Penetrance is almost complete

·        The pathogenesis of this disorder is obscure

·        There is no evidence that the deleted region is transcribed or even functions as a gene

·        One hypothesis is that the FSH deletion affects expression of nearby genes by position effect

·    Transcription of genes near the centromere or telomere might be altered when mutations occur in proximity to heterochromatin, the tightly packed DNA found in these regions

·        Genetic testing via Southern blot analysis for detection of the 4q deletion

Other Muscular Dystrophies  (you will not b e tested on the following disorders)

Occulopharyngeal Muscular Dystrophy

·        Clinical Hallmark

·        Presents usually in early middle age

·        Initial findings of ptosis

·        Progressive involvement of extraocular muscles

·        Spared pupillary reactions

·        Dysphagia, facial weakness, proximal limb weakness develop later

·        Laboratory

·        Hyper-CK-emia (5X upper limits of normal)

·        Muscle biopsy:  characteristic filamentous inclusions in muscle fibers

·        Treatment

·        Supportive

·        Death eventually from intercurrent infection

·        Dysphagia may necessitate cricopharyngeal myotomy

·        Genetics

·        AD

Limb-Girdle Muscular Dystrophy

·        Clinical Hallmark

·        Onset may be delayed into middle life

·        Muscle involvement is asymmetric

·        Muscles first involved are usually in the pelvic girdle

·        Progression is slow

·        Disease may arrest

·        Some patients experience muscle hypertrophy (calves)

·        Laboratory

·        CK is moderately elevated

·        Cardiac involvement usually does not occur

·        EMG:  nonspecific myopathic features

·        Muscle biopsy:  confirms myopathy with connective tissue proliferation

·        Treatment

·        Symptomatic

·        Genetic counseling is difficult because of the high frequency of sporadic cases, variable inheritance, and absence of hyper-CK-emia in carrier states.

·        Genetics

·        AD or AR

Emery Deifuss Muscular Dystrophy

·        Clinical Hallmark

·        Contractures of the elbows and neck are associated with periscapular and biceps weakness

·        Spared deltoids

·        Laboratory

·        Muscle biopsy is non-specifically abnormal

·        Associated Features

·        Cardiomyopathy with conduction abnormalities can be life threatening

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                                              Last updated:  10/05/2002                                                          © 2000-2002 John Rose, MD  University of Utah School of Medicine