Below are photos from a 6 month old child with Werdnig-Hoffman s disease.

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1 PBL 4 Sadie s story

2 Sadie s Story Objectives of PBL: 1) Review and be able to answer questions about normal skeletal muscle organization and structure. 2) Review and be able to answer questions about spinal motor neurons and neuromuscular junctions. 3) Understand the importance of the spinal motor neuron in muscle development 4) Understand the role of the extracellular matrix proteins in muscle development. 5) Understand the role of the satellite cells in muscle repair. 6) Give a working definition of frozen and paraffin sections and needle and full biopsies and the advantages and disadvantages of each. 7) Also, while you are doing it review the ultrastructure of muscle and the sarcomere, sarcoplasmic reticulum, T tubules, and understand the contractile machinery. This will be relevant for the NBME! Objectives 1 6 are relevant to the case. Adding Objective 7 will make a good exercise to use to review muscle for the NBME. I recommend you do this before the NBME!! You will be asked to look for photos and use information from your notes (Dr. Cave s lecture), Gartner and Hiatt, and Burns and Cave to answer the questions. You may work in small groups if you like. A quiz will be available to evaluate your understanding of the basic science issues behind this case, sometime this weekend. It will be based on the questions that are found in this exercise and answering the questions will help you with Objectives 1 6. Sadie Childs was born on October 9, 1989, 7 months premature. She was 6 lbs, 15 oz, a reasonable weight for a premature baby. However, as soon as she was born, her doctors realized that her arms and legs were very limp. She appeared unable to swallow, suck, and breathe simultaneously and needed a feeding tube. By October 15 th, she had grown stronger and could eat and breathe on her own. Her tubes and IV s were removed. But her limbs were still very hypotonic. When her mother was asked about her pregnancy, Cathy recalled that she did not feel as much movement during her pregnancy as she had with her first child, Sarah.. While Sadie s movements were detected by ultrasound, Cathy noted that she did not feel the same kicking or rippling movements that she had felt with her first child. A pediatric neurologist was consulted and diseases like cerebral palsy and Duchenne s muscular dystrophy were ruled out. A family history review showed that there were no cases that would lead them to assume a genetically transmitted disease. The physicians then ordered a needle biopsy of her muscle.

3 The results of the biopsy came back on October 17 th. The diagnosis on the basis of this biopsy was a form of Type I Spinal Motor Atrophy. The disease was otherwise known as Werdnig-Hoffman disease. Look up Werdnig Hoffman disease. 1.What cell types are involved? 2. What gene (s) are affected in these cells? 3. Is the hypotonia consistent with this diagnosis? 4. What would you have expected the muscle fibers to look like in Werdnig Hoffman disease? Below are photos from a 6 month old child with Werdnig-Hoffman s disease. Examples of biopsy from a 6 month old child with Werdnig-Hoffman disease. Note the small, uniform fibers in cross section. This shows other patches of fibers in longitudinal section. They are quite small and separated by connective tissue (blue) and adipose tissue. Note the central nuclei. Is this normal for skeletal muscle? 5. Draw the parts of a neuromuscular junction. Be able to identify the regions in a cartoon or electron micrograph. 6. Draw a cross-section of muscle and name the connective tissue layers dividing the muscle cells or bundles. 7. Where are the spinal motor neurons in the spinal cord and how would you distinguish their cell bodies? Sadie s physicians tell her parents (Cathy and Mike) that the prognosis is very poor. Sadie s disease is the earliest onset of Werdnig Hoffman, also known as a Type I Spinal Motor atrophy (SMA). Her spinal motor neurons had been degenerating since conception because of a mutation and would continue to do so. Her condition will progressively worsen. She would never sit up, hold her head up, crawl and would likely

4 die of respiratory disease or pneumonia before she reaches a year old. They said that she had inherited two recessive genes for this mutation, one from both parents. The family is devastated, but rallied around Cathy, Mike and Sadie, praying for a miracle, and planning what time they had with her. It was easy to bond with her and everyone chose not to hold back and simply made the days and moments count. Sadie was transferred to a hospital in Longview, closer to their home. On October 25, 2004, not knowing if she would ever be able to come home, they arranged for a christening ceremony at the hospital. However, she continued to grow stronger and was taken off the monitor. They decided she could go home that week right after the christening. Nervous parents watched her night and day, waiting for signs of deterioration. However with time, she began to move her hands. In her lower limbs, movement was confined to her ankles and toes. The physicians told the parents that this progress would not continue. She would never be able to raise her arms or shoulders. 8. What do the doctors predictions say about the importance of spinal motor neurons to the continued and full development of muscle fibers? What symptoms of SMA do you see in photos of muscle above or elsewhere? 9. In normal muscle, what cells give rise to new muscle fibers, if the muscle is damaged? Why would these same cells not be able to compensate for the defect in Type I SMA? Sadie was kept quarantined from anyone with a cold or flu. She continued to seem frail and weak, but there were no further signs of deterioration. They put her crib rail down to its lowest level, knowing that she would never raise her head, let alone be able to move enough to fall out. This allowed them to see her from multiple angles. On Thanksgiving when she was 6 weeks old, they traveled to be with grandparents and one night Cathy awakened Mike with the news that Sadie is sucking her thumb. By 4 months of age, Sadie could raise her arms further. At 5 months, they discovered that they could no longer lay her down on the couch. Instead of passively lying on the couch as she had been doing, she rolled off. By 6 months, she showed some more leg movements. She was taken to her pediatrician who was very surprised at her progress. As he laid her down, almost on cue, she rolled over. Her parents discovered with amazement one morning, she had raised her head and was peaking at them over the crib railing. The railing was then raised to its proper position to prevent her from rolling over and falling out. One day, while reclining in her infant carrier, she seemed to strain and try to pull up. Cathy said, Why, I think Sadie is trying to sit up. Sure enough, they elevated the infant seat and she was able to support a sitting position and enjoy the view. Obviously they felt encouraged to stimulate these efforts, propping her up with pillows and watching what might be possible, hardly daring to believe that she was getting better and yet wishing for a miracle.

5 Clearly, her physicians agreed that this progress was not predicted from the diagnosis and with that encouragement Cathy and Mike began to look for physicians who could give a second opinion. The family contacted expert researchers at the Texas Children s Hospital in Houston and arranged for a trip to have Sadie evaluated in June, when she was 8 months old. By the time she was examined, she could sit up and move all limbs. The physicians at Texas Children s Hospital examined her and immediately told them that she had no symptoms of Werdnig-Hoffman. They did a complete muscle biopsy during surgery this time and a complete series of paraffin sections and electron microscopic views were used for the diagnosis by experts in Montreal. After some time, the complete series of biopsies resulted in a diagnosis of merosinpositive Congenital Muscular Dystrophy (CMD). The physicians reported that this was not fatal; she would continue to improve and likely walk before she was 4 years old. They advised physical therapy and regular consultations with orthopedics and other therapists because of continuing muscle weakness. However, with therapy, they counseled that she would lead a relatively normal life although would have continued muscle weakness. 10. Use your text, or the internet and understand basic techniques used to produce frozen sections and paraffin sections. What are the advantages of each type of section? What are the disadvantages? Why would one want to do electron microscopy? 11.Compare and contrast techniques involved with a needle biopsy done when Sadie was 1 week old, with the muscle biopsy taken when Sadie was 8 months old. What information might be obtained with each? How might the type of biopsy have led to the misdiagnosis? 12. What is merosin-positive congenital muscular dystrophy? How does it differ from merosin negative congenital muscular dystrophy? In answering this question, approach the following subtopics: 12a. What does it mean when a muscle is dystrophic? How would this differ from myopathy? What would you expect to see in a biopsy? 12b. What is merosin (a type of laminin) and where does it act? Why is merosin positive CMD a more favorable diagnosis for Sadie? Do they know the source of the defect in the merosin-positive form? 13. The pathologists doing the second diagnosis reviewed the slides from the first muscle biopsy. They did not agree with the original findings. What might they have seen that led them to disagree? (Note: in answering this, you need to be able to differentiate CMD from Werdnig Hoffman and understand the reason for the difference.)

6 14. Would you advise genetic counseling for Sadie and her family? What would you tell the family about the inheritance pattern? Sadie s story today: Sadie did progress as predicted and began to walk when she was 3 years old. She walked then and now with an abnormal gait because her hips were dislocated during the prolonged period when she had low mobility during her infancy. She also is developing scoliosis and corrective surgery may be required. They were unable to do surgery to correct the hip dislocation by the time they had diagnosed it. (When you learn about the lower limb, these concepts will become clearer.) Below are some photos of Sadie at 1 year and this year. We remain grateful to this day that the first diagnosis was wrong. Newspaper photos of Sadie and family (upper) or her Mom (right) at 1 year old, taken before the full and final diagnosis was completed. All they knew was that she was misdiagnosed and did not have Werdnig-Hoffman disease. Today, Sadie is in the mainstream of her classes and excels academically. She is a lovely teenager, a freshman in high school. We thank her for allowing us to share her story. We hope that this makes you think about the types of biopsies you might order when you practice medicine and the importance of knowing histopathology well enough to differentiate the diseases.