Case Study 38

1. Case Study 38 Henry Armah, M.D., M.Phil.

2. Question 1 Clinical history: 4-week-old male with severe hypotonia at birth. He was a product of vaginal delivery at 39 weeks of gestation, and weighed 6Ib 2oz at birth. His mother had hypoglycemic episodes and complained of decreased fetal movements during pregnancy. He had a positive maternal family history of Congenital Fiber Type Disproportion (CFTD) and Nemaline Myopathy (NM). He had a positive paternal family history of Depression and Type 1 Diabetes Mellitus (DM). His four half siblings and one full brother were unaffected. Serum Creatine Kinase (CK) and Electromyography (EMG) findings are not available. A left lateral thigh muscle biopsy was performed. Describe the microscopic findings on the H&E and histochemical slides? Click here to view the slides.

3. Answer H&E section shows increased myofiber size variability with some internalized nuclei and many fibers with central clearing (vacuoles). No degenerating or regenerating fibers are identified. Some hyaline fibers are seen. Multifocal perivascular and perimysial mononuclear inflammatory infiltrates are present. Gomori trichrome section is negative for ragged red fibers, rimmed vacuoles, or definite nemaline rods. NADH-TR section shows central clearing without central cores. Oil red O and PAS sections show no abnormal accumulations of lipid and glycogen material, respectively. The central clearing (vacuoles) do not react with PAS. Some fibers show centrally prominent PAS reactivity.

4. Answer ATPase sections show a normal checkerboard pattern with a Type 1 to Type 2 fiber ratio of 2:1. Esterase section shows increased reactivity in hyaline fibers only. Succinic dehydrogenase (SDH) section shows no SDH-rich fibers. Cytochrome oxidase (COX) section shows no COX-negative fibers.

5. Question 2 What additional immunostains would you need to rule out other important differential diagnoses and confirm the final diagnosis in this case?

6. Answer Merosin should be performed for possible merosin-deficient congential muscular dystrophy especially it the creatine kinase is elevated. Immunostains for other dystrophies could be performed but are less likely to present with neonatal hypotonia. In this case, immunostains for Dystrophin 1 (mid-rod), Dystrophin 2 (carboxy terminus), Merosin, Adhalin (alpha-sarcoglycan), and Dysferlin were performed.

7. Question 3 What do you see on this Dystrophin 1 (mid-rod) immunostain slide? Click here to view slide.

8. Answer Dystrophin 1 (mid-rod) section show normal sarcolemmal labelling of all fibers.

9. Question 4 What do you see on this Dystrophin 2 (carboxy terminus) immunostain slide? Click hereto view slide.

10. Answer Dystrophin 2 (carboxy terminus) section show normal sarcolemmal labelling of all fibers.

11. Question 5 What do you see on this Merosin immunostain slide? Click hereto view slide.

12. Answer Merosin section show normal subsarcolemmal labelling of all fibers.

13. Question 6 What do you see on this Adhalin (alpha-sarcoglycan) immunostain slide? Click here to view slide.

14. Answer Adhalin (alpha-sarcoglycan) section show normal subsarcolemmal labelling of all fibers.

15. Question 7 What do you see on this Dysferlin immunostain slide? Click hereto view slide.

16. Answer Dysferlin section show normal subsarcolemmal labelling of all fibers, with occasional cytoplasmic reactivity.

17. Question 8 What is your final diagnosis in this case?

18. Answer Centronuclear Myopathy The inflammation is a non-specific finding in this case.

19. Question 9 What is the mode of inheritance of the severe neonatal, often fatal, form of centronuclear myopathy (myotubular myopathy)? • Autosomal Recessive • Autosomal Dominant • X-linked Recessive • X-linked Dominant

20. Answer C. X-linked Recessive