Department of Pathology, University of Oklahoma Health Sciences Center

April 2004, Case 404-1. Quiz set! Click here to see.

Saud Khan, M.D.¹, Zahid F. Cheema, M.D.¹, Kar-Ming Fung, M.D., Ph.D.² Last update on May 28, 2004.

¹ Department of Neurology, ² Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma

A 52 year-old man with muscle weakness 

Clinical information:  The patient was a 52 year-old right handed male who presented with about 10-month history of weakness of the arm and legs, and occasional diplopia. The patient reported difficult in getting up from a squatting position. He also had difficulty in overhead movements such as combing his hair and painting. The patient described problem in gripping but not relaxation. He was unable to walk more than 150 feet before he has to stop because of leg wobbling. The patient also had constant numbness on both of his forearms and sometime find it difficult to tell where his feet are. His father had no history of muscle diseases. His mother had muscular dystrophy and also requires pacemaker. Multiple member of the family also have history of muscular symptoms similar to this patient.  His creatine kinase (CK) was 358 units.

    On physical examination, the patient had bilateral vertical and horizontal diplopia on sustained upward gaze. There was no diplopia on right or left gaze and no evidence of fatiguable ptosis. There was also hyperesthesia in the lower extremities. The patient walked with wide based gait with leg eversion and almost bow legged gait. He walked in stooped forward posture. There was no change in muscle strength or increased joint reflex. There was fatiguability of the full strength in bilateral upper and lower extremities. He had no problem on relaxation of muscle.

Pathology of the case: 

 Click thumbnails to see pictures.

Abbreviations:

Pathology:

     The salient feature of this case is the presence of centrally located fibers in over 95% of the fibers. There is also some replacement of muscle fibers by adipose tissue (Panel A and B). On longitudinal sections, there are short chains but not long chains of nuclei (Panel C). Frozen sections essentially show similar features except that perinuclear halo is present in many fibers. The variation in fiber diameter is also well appreciated. While some fibers contain only single nuclei, small clusters of nuclei are present in the rest of the fibers (Panel D and E). The modified Gomori's trichrome does not add much (Panel F). ATPase reaction shows a type I fiber predominance (Panel G). The centrally located nuclei produced a halo. The ATPase is perhaps the best way to detect centrally located nuclei. Similar halos are also seen in the NADH-TR reaction (Panel H). In addition, a thin rim of strongly reactive material is presence around the nuclei. The observations in succinate dehydrogenase and cytochrome oxidase are similar to that of NADH-TR reaction (Panel I and J). The centrally located nuclei also produced a halo in the phosphorylase reaction (Panel K). Under electron microscopy, there is some accumulation of mitochondria around the centrally located nuclei (Panel L). The morphology of the nuclei is within normal limits (Panel M and N). Rare concentric lamina body (Panel O) and crystal containing mitochondria (Panel P) are identified.

Discussion: General Information    Genetics    Pathogenesis    Clinical features    Pathology

General Information    

    Myopathy with substantial increase in centrally located nuclei as their salient features was first recognized in 1966 in a 12-year-old boy with weakness, including involvement of facial and extraocular muscles, and delayed motor development ¹. The authors suggested that the disease resulted from arrested maturation of embryonic muscle at the tubular stage and the term “myotubular myopathy” was used. The term “centronuclear myopathy” was introduced to describe the disease in two teenage sisters who had weakness, including involvement of the extraocular muscles, and impaired motor development ². Originally myotubular myopathy and centronuclear myopathy were thought to be different entities. Current studies, however, suggest that they have different clinical pathologic profile and represent different entities.

Genetics:

    No definitive gene associated with centronuclear myopathy has been identified to this date. In centronuclear myopathy, an autosomal dominant, male to male form of inheritance has been observed. Autosomal recessive inheritance has also been demonstrated in some families ³. Although X-linked myotubular myopathy shares the feature of centrally located nuclei with centronuclear myopathy,  X-linked myotubular myopathy is related to the MTM1 gene on chromosome Xq28 which codes for the myotubularin protein.

Pathogenesis:

    In the absence of an known associated gene and/or protein to centronuclear myopathy, the pathogenesis can only be speculative. In fact, it is not impossible that the spectrum may represent more then one etiology similar to Emery-Drefuss muscular dystrophy. Identification of both autosomal dominant and recessive families supports this speculation. During the myotubular stage of development, the nuclei are centrally located. Migration occur as the muscle fiber mature. It is not clear whether the centrally located nuclei are residue of nuclear that fail to migrate during maturation or they represent migration from the periphery to center as a result of myopathic process. Cases that do not contain centrally located nuclei at the initial biopsy but display centrally located nuclei as in cetronuclear myopathy has been described ^{4, 5}.

Clinical Features:

    A childhood-onset form and a adult-onset form are recognized. The childhood-onset form is far less severe than the x-linked myotubular myopathy which also typically present at this age and have centrally located nuclei. Similar to many congenital myopathy with infantile onset, there may be hypotonia, reduced activity, weak sucking and crying. The childhood or adolescence has more insidious onset and manifest with hypotonia, proximal limb weakness, and weakness of other skeletal muscles such as axial weakness, weak in mastication, facial weakness, ptosis, and ophthalmoplegia. In the adult-onset patients, the clinical is usually that of a lim-girdle weakness and lack ophthalmoplegia and bulba signs. Unless associated with rhabdomyolysis, serum creatine kinase is normal.As a general trend, those that have later onset are not as severe as those with infantile onset.  The age of presentation can be quite variable and spans from the second to as late as 6^th decade as in the patient in this case. Patient may have periods of improvement in strength. High-arched palate and a long, thin, triangular face have been described in some patients ⁶. Association of cardiomyopathy with centronuclear myopathy has been extremely rare ⁷.

Pathology    

    The most distinct histologic feature is nuclei located at the geographical center of the muscle fiber. In older patients, clusters of nuclei can be present as illustrated in this case. A perinuclear halo is often present. The proportion of fibers with centrally located nuclei is variable but the diagnosis of centronuclear myopathy should be questioned if less then 20% of the fibers are affected. Centrally located nuclei can also be seen in many chronic myopathies. Necrotic fiber and regenerating fibers are almost never present. The centrally located nuclei will appear as a halo in ATPase reaction. The type I fibers tend to be smaller. Clumps of reaction products may be seen around the nuclei with oxidative enzymes such as NADH-TR, succinate dehydrogenase, and cytochrom C oxidase prepartions.

    Ultrastructure of the central nuclei is normal. Accumulation of glycogen and mitochondria may be seen around the nuclei. They correspond to the reactive material on oxidative enzyme reactions. A variety of abnormal organelle may be present as illustrated by the presence of concentric lamina body in this case. Occasional mitochondria containing crystalloid bodies an also be identified as illustrated in this case. These ultrastructural changes, however, are non-specific.

Reference: 

1. Spiro AJ, Shy GM, Gonatas NK. Myotubular myoptahy: Persistence of fetal muscle in an adolescent boy. Arch Neurol 14:1-14, 1966

2. Sher JH, Rimalovski AB, Athanassiades TJ, Aronson SM. Familial centronuclear myopathy: A clinical and pathological study. Neurology 17:727-742, 1967

3. Wallgren-Pettersson C, Clarke A, Samson F, Fardeau M, Dubowitz V, Moser H, Grimm T, Barohn RJ, Barth PG. The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies. J Med Genet. 1995 32:673-9.

4. van der Ven PF, Jap PH, Wetzels RH, ter Laak HJ, Ramaekers FC, Stadhouders AM, Sengers RC. Postnatal centralization of muscle fibre nuclei in centronuclear myopathy. Neuromuscul Disord. 1991;1:211-20.

5. Danon MJ, Giometti CS, Manaligod JR, Swisher C. Sequential muscle biopsy changes in a case of congenital myopathy. Muscle Nerve. 1997 20:561-9.

6. Zanoteli E, Oliveira AS, Schmidt B, Gabbai AA. Centronuclear myopathy: clinical aspects of ten Brazilian patients with childhood onset. J Neurol Sci. 1998 11;158:76-82.

7. Al-Ruwaishid A, Vajsar J, Tein I, Benson L, Jay V. Centronuclear myopathy and cardiomyopathy requiring heart transplant. Brain Dev. 2003 25:62-6.

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