PROBLEM-BASED LEARNING CASE
PENN STATE COLLEGE OF MEDICINE
PSUCOM 276
“ON TIPTOES”
Session 1:
Session 2:
Session 3:
Pages 1-5 (1 hour) *
Discuss previous learning objectives. (1.5 hours)
New Pages 6-7 (0.5 hour)
Receive page 8, finish discussion of case. (1 hour)
*If this case is to be done in 2 sessions:
Session 1: Pages 1-7 (1.5 hours)
Session 2: Discussion of all learning objectives (2 hours)
Receive page 8 at end
Figure 1- Patient CT
CC: The parents of a five-year-old boy, CT, bring him to you for an explanation of the
unusual way in which the child has begun to walk. The child is walking on his toes and
has difficulty walking up stairs.
WHAT ARE YOUR INITIAL HYPOTHESES?
WHAT WILL YOU ASK THE PARENTS ABOUT THE CHILD’S HISTORY?
1
HPI: CT’s parents tell you he began walking a little later than they expected, at the age
of fifteen months. He seemed to fall often, which at first was amusing to them,
but later became of concern. He always had a hard time keeping up with his
friends. Within the past six months, CT has begun to have difficulty walking up
and down stairs, and has developed the habit of walking on his toes.
FH:
CT has one older brother and two sisters, all healthy. His parents, aged 34 and 36
have had no medical problems. On the maternal side, one of the mother’s
brothers died at age 12 of heart failure after being wheelchair bound for several
years. On the paternal side, CT’s father does not remember any particular
problems occurring in his relatives.
SH:
CT and his family live in a well-kept two story house in an urban area. CT’s
father is a policeman, and his mother is a teacher, working in the local elementary
school. CT is watched by his grandmother during the day while his parents work
and the older siblings are in school.
HOW DOES THIS INFORMATION CHANGE YOUR INITIAL HYPOTHESES?
WHAT ADDITIONAL INFORMATION DO YOU WANT?
WHAT WILL YOU LOOK FOR ON PHYSICAL EXAM?
ON WHAT/WHERE WILL YOU FOCUS YOUR EXAM?
2
Physical examination reveals a child, 106 cm in height and 16 Kg in weight (normal for
5 years). There is noticeable lumbar lordosis when he stands.
HEENT: Head normocephalic, pupils equal, round, reactive to light and
accommodation. Tympanic membranes are intact, no thickening. Nasal mucosa
moist, pink and without discharge. Throat is moist and pink, without coating;
tonsils small with no exudate. The tongue seems unusually large.
CHEST: Heart rate 90 bpm, regular rate and rhythm. Lungs are clear to percussion and
auscultation.
ABDOMEN: Non-tender, without masses; normal bowel sounds.
EXTREMITIES: Calfs are noticeably increased in size and firm to palpation (see Figure
1, page 1). He has symmetrical equinus contractures. (Ankle dorsiflexion is 10
degrees short of neutral on both sides.)
GAIT AND MOVEMENT: The child walks on his toes, with a wide-based waddling
gait. In gait his spine is lordotic. When asked to lie down on the floor and then
get up as fast as possible, the child rolls over onto his knees, and then raises
himself using his arms to push against his shins, knees and thighs until he is
upright (see sequence of Figures 2 to 11 on pages 13-14).
NEUROLOGICAL: No deficits in cranial nerves. Peripheral reflexes +1/2 in both
lower limbs.
WHICH MUSCLE GROUPS MAY BE DYSFUNCTIONAL IN PRODUCING A
WADDLING GAIT, AN INCREASED LUMBAR LORDOSIS, AND
DIFFICULTY GETTING UP FROM THE FLOOR?
WHAT IS THE NAME AND SIGNIFICANCE OF THE RAISING MANEUVER
DESCRIBED ABOVE?
WHAT HYPOTHESES ARE AT THE TOP OF YOUR DIFFERENTIAL NOW?
WHAT LAB TESTS/DIAGNOSTIC TESTS WOULD YOU REQUEST AT THIS
POINT TO SUPPORT YOUR HYPOTHESES?
3
LABORATORY RESULTS*
RBCs
HBG
Sodium
Potassium
Chloride
Bicarbonate
BUN
Calcium, total
Glucose
Creatinine
Creatine kinase
Patient Values
4.5 x 1012/L
12.5 g/dL
140 mEq/L
4.0 mEq/L
98 mEq/L
24 mEq/L
10 mg/dL
9 mg/dL
80 mg/dL
0.3 mg/dL
1900 IU/L
Normal Range
3.8-5.2 x 1012/L
9.9-14.5 g/dL
135-145 mEq/L
3.5-5.0 mEq/L
96-109 mEq/L
22-26 mEq/L
5-25 mg/dL
8.0-10.4 mg/dL
60-105 mg/dL
0.3-0.7 mg/dL
0-180 IU/L
*Units: L (liter)
g/dL (grams/deciliter)
mg/dL (milligrams/deciliter)
mEq/L (milliequivalents/liter)
IU/L (International Units/liter)
Muscle biopsy: A biopsy of quadriceps muscle was done, and sent to a commercial lab
for analysis. Results will take several days.
WHAT DO THE ABOVE LAB RESULTS INDICATE?
DO YOU THINK THE BIOPSY WAS NECESSARY?
WHAT WILL THE BIOPSY SHOW, AND WHAT WILL BE ASSAYED?
WHAT IS YOUR DIAGNOSIS NOW?
4
BIOPSY RESULTS:
Histological sections show necrotic fibers, areas of fibrofatty tissue in greater volume
than the fibers it replaces, central nuclei, contraction bands, and disorganized and
split fibers. Remaining fibers show inequality of fiber diameter. See Figures 12
and 14 on page 15.
Immunoperoxidase assay for the protein dystrophin showed absence of staining around
the periphery of fibers. See Figure 13 and 15, on page 15.
Polymerase chain reaction identified a deletion in the dystrophin gene near the 5’ end.
WHAT WILL YOU TELL THE PARENTS AT THIS POINT?
HOW WILL YOU EXPLAIN THIS DISEASE IN TERMS THAT THEY CAN
UNDERSTAND?
DRAW A POTENTIAL PEDIGREE OF THIS FAMILY. WHAT IS THE
CHANCE OF A SISTER OF THE PATIENT HAVING A SON WHO HAS
MD?
5
MEDICAL MANAGEMENT
CT was started on alternate-day prednisone (1.0 mg/kg), with continued follow up for
side effects. His parents were told what to look for while he is on this medication. He is
to return for biannual evaluations of pulmonary and cardiac function. The parents were
advised to encourage CT to be active but never to exercise to the point of exhaustion.
Exercises aimed at strength building (pumping iron) are contraindicated. CT is signed up
for physical therapy sessions to teach his parents stretching exercises to retard
progression of his contractures.
EPILOG
CT has two normal sisters. Should they be screened now to determine if they are
carriers? Should they be screened early in pregnancy if they do conceive at a later time?
THE END
6
MINI-CASE SCENARIO
A 14 year-old-boy is brought to you for evaluation.
CC:
Recent difficulty walking up stairs; fatigue and muscle cramps.
Laboratory Results:
Plasma CK 9,000 IU/L
Muscle biopsy:
Immunocytochemical staining for dystrophin is present, but
discontinuous. See Figure 16 on page 16.
HOW DOES THIS DISEASE DIFFER FROM DUCHENNE’S MUSCULAR
DYSTROPHY?
HOW DO THE DNA DEFECTS DIFFER IN THESE DISEASES?
7
LEARNING OBJECTIVES
After the discussions of pages 1-5 in session 2, a student finishing this case should be
able to:
1. Describe the pathogenesis and pathology of Duchenne’s and Becker’s
muscular dystrophies, and the role of dystrophin.
2. Describe the genetics of X-linked recessive mutations and be able to draw a
pedigree of a family with such a mutation.
3. List and explain other clinical abnormalities that are associated with this
disease in addition to the progressive muscular weakness.
4. Discuss heterogeneity in genetic diseases and how this influences diagnostic
issues.
5. Explain the principles of PCR, and how it is used diagnostically.
6. Explain the principles of immunohistochemical analysis.
7. Discuss the natural history of this disease, including prognosis.
After the discussions of pages 6-7 in session 3, a student finishing this case should
be able to:
8. Describe the ethical considerations of chorionic villous sampling and
amniocentesis for prenatal testing.
9. Evaluate the potential end of life decisions that may have to be made by the
family, physician, and patient.
10. Describe the rationale for use of prednisone, and list and explain the side
effects in a pediatric patient.
11. Contrast Becker’s and Duchenne muscular dystrophies, including pathology,
pathophysiology, genetics and management.
References:
1. Emery, Alan E. H., The Muscular Dystrophies, Lancet 359(9307): 687-95, 2002
2. Principles of PCR http://users.ugent.be/~avierstr/principles/pcr.html (good
diagrams, also has sections for sequencing and alignment)
3. Griffiths, A.J.F., Introduction to Genetic Analysis, 8th ed., 2005. WH Freeman &
Co., New York, NY. ISBN 0716749394.
8
Case Authors: Carol F. Whitfield, Ph.D. and Edwards P. Schwentker, M.D.
Penn State College of Medicine, Hershey, PA 17033
May 31, 2006
FACILITATOR’S GUIDE
This case is a classical example of Duchenne muscular dystrophy, with a following minicase scenario of Becker muscular dystrophy. Duchenne MD and Becker MD together
constitute the dystrophinopathies, X-linked recessive disorders associated with mutations
of the gene coding for the protein dystrophin. In the more severe Duchenne variety no
dystrophin is produced or the amount produced is ineffective. The clinical course in
Duchenne MD is remarkably consistent. In the Becker varieties the amount of effective
dystrophin is reduced, and depending on the extent of the reduction the clinical course
varies. The gene for dystrophin, found on Xp21, most commonly has deletions near the
5’ end or middle, but other mutations also occur (point mutations, microdeletions and
duplications).
Dystrophin, a 427 kDa protein, functions as a component of a large protein-glycoprotein
complex underlying the sarcolemma, that gives stability to the membrane. Dystrophin
binds to f-actin and to beta-dystroglycan in the complex. Deficiency of dystrophin or any
of the other components allows the membrane to break, leading to necrosis of the muscle
fibers. Identification of the other components in the complex and their function is not
well understood as yet.
Identification of mutations can be done by PCR, Southern Blotting, or modifications of
the PCR technique. Detection of dystrophin in biopsy samples can be done by
immunostaining, Western Blots, or fluorescent antibody staining.
Patients with Duchenne MD present with difficulty in ambulation in the first few years of
life. Walking becomes progressively more difficult and the ability is finally lost at an
average of 10 years of age. The weakness is relentlessly progressive. As they enter the
adolescent growth spurt the majority develop a collapsing scoliosis. Smooth muscle is
spared but cardiac muscle is not and death generally occurs in the late teens or early 20s
secondary to loss of pulmonary function and/or a cardiomyopathy. Survival and quality
of life may be significantly increased with the use of nighttime respiratory support, e.g.
BiPAP, early operative stabilization of spinal deformities, and corticosteroids to retard
muscle deterioration.
The dystrophin molecule is also found in the brain and the dystrophinopathies appear to
affect cognitive function. The bell-shaped IQ curve in DMD is shifted to the left with an
average IQ of 83.
9
Patients with Becker MD usually present with significant symptoms between 10 and 20
years of age. They do not develop the spinal deformities seen with Duchenne MD, but
otherwise experience a similar sequence of muscle deterioration but at a much slower
rate. Most patients with Becker MD will survive into the 5th decade, but survival into the
7th or even the 8th decade is not uncommon.
Because of the X-linked recessive inheritance pattern DMD and BMD affect males
almost exclusively. Two thirds of female carriers will have mildly elevated CK levels,
and a few may exhibit mild signs and symptoms, particularly a cardiomyopathy
manifesting in adult life.
Page Director
Page 1. Students should focus on the toe walking. Although this is such a classical sign
of MD, students should also consider possible neuromuscular defects in their
differential. DMD usually begins before 4 years, but can present from 1-10 yrs.
Page 2. Half of DMD patients have a history of delayed walking and repeated falls. The
peculiar walking patterns and difficulty climbing stairs should prompt the
students to think about muscle weakness. They may or may not associate toe
walking with shortening of the Achilles tendon. His family history is significant
for a maternal uncle who used a wheelchair and died at age 12.
Page 3. The facilitator should make sure the students pick up on the physical findings of
hypertrophy of the tongue, increased girth of the calfs, and the strange way of
rising from the floor (Gowers maneuver). When muscle degenerates, it is
replaced by fat and fibrous tissue, which is the reason for pseudohypertrophy,
an apparent increase in calf and tongue size. Other muscles may also manifest
pseudohypertrophy. The increase in size is deceptive as muscle strength is
diminished.
Among the first muscles to lose function are the hip extensors. Their loss causes
the pelvis to fall into flexion. The lumbar lordosis is a necessary compensation
to bring the head over the pelvis. With the Gowers maneuver the patient
compensates for hip extensor weakness by using his upper extremities to “climb
up” legs and thighs into an upright position. While an excessive contracture of
the Achilles tendon can become dysfunctional, mild toe-walking actually helps
provide stability by generating an extension moment at the knee which
compensates for weakness of the quadriceps.
Towards the end of the ambulatory stage of DMD ambulation becomes a finely
tuned balancing act. Falls are frequent but serious injuries are surprisingly rare.
Page 4. Lab values are all normal except for the highly elevated creatine kinase, which
is released from degenerating muscle fibers. Compared to other conditions that
10
are associated with CK elevations, the elevations seen in the dystrophinopathies
are astronomical. Decreased functional muscle mass accounts for low
creatinine, a product of muscle metabolism. CK is already elevated by the time
of birth.
Page 5. Diagnosis is made by the clinical features, muscle biopsy showing necrotic
fibers with fibrofatty infiltration, and immunofluorescent assay for dystrophin
which will be absent. In normal muscle, the staining is around the periphery of
fibers, coincident with sub-membrane location of dystrophin. The facilitator
should prompt the students to compare the patient’s and normal muscle (Figs.
12 and 14) and identify that there is variation of fiber size, central rather than
peripheral nuclei in the fibers, fibrous tissue and fatty tissue replacement of
muscle fibers. Although not always necessary, the deletion can often be
identified by PCR, except point mutations or microdeletions can be difficult to
detect.
Students may find it difficult to give the parents the prognosis for CT. Almost
all children with DMD will be wheelchair dependent by age 12. Death often
occurs by late teens and 20’s, usually from impaired pulmonary function (weak
muscle action, infection) or, less commonly, from cardiac myopathy. Students
should be encouraged to discuss end-of-life decisions.
It can never be easy for parents or physicians to talk about a disease as serious
as DMD, but the information need not destroy hope. In the past few decades
there has been enormous progress in neuromuscular research. If CT is not
treated we can predict his death in approximately 20 years. That may well be
time enough to find an effective treatment. The physician’s chief responsibility
is to wisely manage his/her patient to minimize deterioration, not only to
maximize the quality of life, but to preserve function so that the patient may
optimally benefit from any treatment that is developed.
Page 6. Treatment with prednisone can delay muscle degeneration, muscle contracture
and increase muscle strength and function and pulmonary function, but the side
effects, including moon face, weight gain, and immunosuppression can be
intolerable in some. Physical therapy helps slow the progression of function
robbing contractures. When patients reach the wheelchair stage they should be
provided power mobility. A power wheelchair not only enhances function but
helps maintain self esteem. Teenagers must be closely monitored for signs of
spinal deformity. Early operative stabilization is critical to preserving sitting and
pulmonary function.
Follow up should include immunizations for influenza and pneumococcus,
ECGs, and echocardiograms (beginning at age 10).
CT’s sisters are at risk for being carriers. Genetic testing can detect the carrier
state and should be combined with genetic counseling to thoroughly acquaint
11
affected individuals with the implications of being a carrier and the options
available to avoid passing this disease on to another generation. The physician’s
responsibility is to fully inform.
Page 7. The mini-case scenario describes Becker’s muscular dystrophy. It is a milder
form of MD, with onset usually in the teens to 30’s, and death usually in the 3rd
to 5th decades. In this mutation of the dystrophin gene, deletions do not cause a
frame-shift of the coding sequence, but results in shortened dystrophin
molecules that are partially functional but more quickly degraded. Other
mutations can be duplications that yield larger dystrophin molecules.
Immunostaining of biopsies show spotty staining.
12
Figure 2
Figure 5
Figure 3
Figure 6
Figure 4
Figure 7
13
Figure 8
Figure 11
Figure 9
Figure 10
Photo’s obtained with consent.
14
Figure 12. H&E stained section of
patient’s skeletal muscle biopsy.
Magnification 20X.
Figure 14. H&E stained section of
normal skeletal muscle.
Magnification 40X.
Figure 13- Immunoperoxidase
staining for localization of dystrophin
in patient’s skeletal muscle biopsy.
Magnification 40X.
Figure 15. Immunoperoxidase
staining for localization of dystrophin
in normal skeletal muscle.
Magnification 40X.
15
Figure 16. Immunoperoxidase
staining for localization of dystrophin
in skeletal muscle biopsy of patient
with Becker’s muscular dystrophy.
Magnification 40X.
Histological images kindly provided
by Javad Towfighi, MD, Department
of Pathology, Penn State Hershey
Medical Center.
16