Final Diagnosis -- Severe X-linked myotubular myopathy (XLMTM)


Severe X-linked myotubular myopathy (XLMTM)


Internal nuclei in a muscle biopsy is defined by displacement of nuclei from normal subsarcolemmal region to anywhere in the muscle fibers more than 3% of the fibers in a transverse section (2). It is a common nonspecific feature that can present in myopathic, neurogenic, or dystrophic conditions (4). Presence of nuclei at the center of fibers, central nuclei, in the other hand, is a characteristic feature of centronuclear/myotubular myopathies and congenital myotonic dystrophies. In centronuclear/myotubular myopathies, central nuclei are regularly found in 30 to nearly 100% of the muscle fibers (4). Making the diagnosis of these conditions requires phenotypic-genotypic correlation. Thus, it is important to precisely describe the proportion of nuclear positions in a muscle biopsy as it can be a useful marker for further genetic workups. Severe X-linked myotubular myopathy (XLMTM) is caused by mutations in myotubularin 1 gene (MTM1) on Xq28 encoding for 3'-phosphoinositides lipid phosphatase. XLMTM is a member of centronuclear/myotubular myopathies, a group of congenital myopathies defined by the presence of abnormally high number of fibers with central nuclei. While "centronuclear" is the general term for the entities in this group, "myotubular" is reserved for severe neonatal X-linked recessive disease that contains myotubule-like muscle fibers. In addition to genetic coding, centronuclear /myotubular myopathies are classified by their clinical, histological, immunohistochemical, and ultrastructural differences. To date, although there are additional candidate disorders awaiting genetic resolutions, the entities in this group include severe XLMTM, MTM1-related centronuclear myopathy (CNM) with necklace fibers, autosomal dominant dynamin-2 gene (DNM2)-related CNM, autosomal recessive amphiphysin 2 gene (BIN1)-related CNM, and autosomal recessive ryanodine receptor gene (RYR1)-related CNM (4, 7).

Typically, male neonates affected by MTM1 mutations will show severe hypotonia, and generalized muscle weakness, usually associated with respiratory insufficiency. External ophthalmoplegia and ptosis are typically present later in the disease course. Female patients with early clinical presentation and female carriers with mild symptoms caused by X chromosome inactivation have been described (6). Most XLMTM patients died during first month of life. Small number of atypical cases has survived into childhood or early adulthood but require ambulatory and respiratory supports (4). Muscle biopsy in severe neonatal XLMTM shows small fiber size with prominent central nuclei resembling immature myotubes, hence the term "myotubular myopathy". The PAS stain and oxidative enzyme reactions show peripheral halo and central dark region. By ultrastructural study, the central areas contain nuclei (sometimes with prominent nucleoli), mitochondrial aggregates, glycogen granules, and a reduction in myofilaments. The myofibrils are well-arranged and confined to the periphery of the fibers (4, 7). Recent studies suggest that mutations in MTM1 associate with unbalanced regulation between autophagy and ubiquitin-proteosome pathways and lead to histologic changes in XLMTM (1, 3). Interestingly, in addition to fiber size variations and fatty infiltration, the muscle histopathology in female patients/carriers and atypical male patients with mild clinical presentation are different from typical cases as the presence of "necklace fibers" (i.e. fibers with basophilic ring following the contour of the cells that align with the internal nuclei) (4, 6). A case of young child with MTM1-related CNM with abundant necklace fibers has also been reported (5). Ultrastructurally, the necklace fibers show smaller size myofibrils align with the nucleus in the necklace area.

Besides nuclear centralization, the other types of centronuclear/myotubular myopathies also have other characteristic histologic and ultrastructural features. In autosomal dominant DNM2-related CNM the biopsy shows predominant small type 1 muscle fibers and radial arrangement of sarcoplasmic strands in oxidative enzyme reactions. In ultrastructural study, the central nuclei are within normal limits (with occasional prominent nucleoli) and surrounded by radial sarcoplasmic strands arrangement. The sizes of radially arranged myofibrillar bundles are smaller toward the center. Central internuclear spaces contain mitochondria, rough endoplasmic reticulum, Golgi complex, and glycogen particles. Muscle biopsy in autosomal recessive BIN1-related CNM show uniformity of small type 1 fibers with central nuclei and small package of nuclei in muscle fibers. The ultrastructural study show one or more nuclei occupying the center of the fibers. The nuclei are surrounded by filamentous and amorphous material containing mitochondria, tubules, and glycogen. Abnormal myofibrillar organization resembling radial sarcoplasmic strands are also noted (4, 7). In autosomal recessive RYR1-related CNM the muscle fibers show nuclear internalization and centralization with variable oxidative staining abnormalities. Myofibrillar/sarcomeric disorganization is noted in the ultrastructural study (7, 8).

Congenital myotonic dystrophy (CDM) shows similar clinical and histopathologic features as present in XLMTM in the neonatal period. The prognosis in CDM is more favorable that the patient can survive into early adulthood but many patients suffer from psychomotor retardations. CDM inheritance is autosomal dominant and almost always maternal. Hence, clinical examination including electromyography of the mother is essential. The definite diagnosis for CDM requires gene analysis for expansion of CTG repeats in dystrophia myotonica-protein kinase gene (DMPK) gene (4).

In conclusion, this is a typical case of XLMTM. The main differential diagnoses include entities in the group of centronuclear/myotubular myopathies and CDM. The definite diagnosis requires clinical-pathological correlation and genetic confirmation.


  1. Al-Qusairi L, Prokic I, Amoasii L, Kretz C, Messaddeq N, Mandel JL, Laporte J (2013) Lack of myotubularin (MTM1) leads to muscle hypotrophy through unbalanced regulation of the autophagy and ubiquitin-proteasome pathways. FASEB J 27: 3384-3394.
  2. Dubowitz V, Sewry CA, Oldfors A (2013) Muscle biopsy: a practical approach. 4th Edition, Saunders Elsevier: China.
  3. Fetalvero KM, Yu Y, Goetschkes M, Liang G, Valdez RA, Gould T, Triantafellow E, Bergling S, Loureiro J, Eash J, Lin V, Porter JA, Finan PM, Walsh K, Yang Y, Mao X, Murphy LO (2013) Defective autophagy and mTORC1 signaling in myotubularin null mice. Mol Cell Biol 33: 98-110.
  4. Goebel HH, Sewry CA,Weller RO (2013) Muscle disease: pathology and genetics. 2nd Edition, Wiley Blackwell: Singapore.
  5. Gurgel-Giannetti J, Zanoteli E, de Castro Concentino EL, Abath Neto O, Pesquero JB, Reed UC, Vainzof M (2012) Necklace fibers as histopathological marker in a patient with severe form of X-linked myotubular myopathy. Neuromuscul Disord 22: 541-545.
  6. Hedberg C, Lindberg C, Mathe G, Moslemi AR, Oldfors A (2012) Myopathy in a woman and her daughter associated with a novel splice site MTM1 mutation. Neuromuscul Disord 22: 244-251.
  7. Jungbluth H, Wallgren-Pettersson C, Laporte JF; Centronuclear (Myotubular) myopathy Consortium (2013) 198th ENMC International Workshop: 7th Workshop on Centronuclear (Myotubular) myopathies, 31st May - 2nd June 2013, Naarden, The Netherlands. Neuromuscul Disord 23:1033-1043.
  8. Romero NB (2010) Centronuclear myopathies: a widening concept. Neuromuscul Disord 20: 223-228.

Contributed by Jantima Tanboon, Sorawit Viravan, Yukiko K. Hayashi, Ichizo Nishino, Tumtip Sangruchi

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