Myotubular Myopathy

Abstract

FOR SEVERAL WEEKS prior to the formation of mature muscle cells, the process of which is virtually completed by the fifth fetal month in humans,1 the cell exists as a myotube. Similar muscle cells were seen in the biopsy of an adolescent boy with a muscle-wasting disorder.Since this unusual pathological occurrence appears to be unique, it is the purpose of this report to present the clinical, pathological, cytochemical, and electron microscopic studies of this disease. An attempt will also be made to correlate these findings with previously reported studies in myogenesis. MethodsBiopsy specimens of gastrocnemius muscle were removed on two separate occasions (September 1962 and January 1965) after infiltration of the overlying skin with a local anesthetic. The initial specimen was removed with sutures and fixed in Zenker's solution; the second specimen was removed with a C-shaped clamp designed for that purpose, and fixed in Bouin's solution. Both specimens were oriented in a manner whereby both cross and longitudinal sections could be made. The fixed sections from the first biopsy were stained with hematoxylin and eosin. In addition to this, the sections from the second biopsy were stained with the hematoxylin-van Gieson, Gomori trichrome, periodic acid-Schiff (PAS) and Lillie allochrome techniques.2 During the second biopsy, a muscle specimen was frozen in isopentane cooled to \p=m-\160 C by liquid nitrogen. Thin sections cut in a cryostat were stained unfixed for histochemical and cytochemical studies. Sections were stained with the modified Gomori trichrome technique for morphological de¬ tail.3 Mitochondrial oxidative enzymatic activity and enzymes involved in electron transport were studied with the cytochrome oxidase,1 nicotinamide adenine nucleotide dehydrogenase (NADH),5 and succinic dehydrogenase (SDH) reactions." Myofibrillary activity was sudied using adenosine triphosphatase (ATPase).7 Individual sarcoplasmic contents were studied utilizing amylophosphorylase and the periodic acid-Schiff stain.Lipids were stained using scharlach-R and Sudan black. Sections were also stained for acid phosphatase.8 Immunofluorescence studies were done using rabbit anti-human myosin and fluorescein labelled anti-rabbit globulin.8 Electron Microscopy.-For electron microscopy, tissue immediately frozen at -160 C in liquid nitrogen and stored at -4 C for four weeks was thawed at room temperature and fixed in 1'% osmium tetroxide in barbital (Veronal) acetate buffer10 for two hours. Dehydration was carried on in ascending solutions of acetone, and English Araldite * was used for embedding. A microtome was used for sectioning of the blocks. The sections were examined in an electron microscope.A 12-year-old white boy was admitted to Chil¬ dren's Hospital of Philadelphia in January 1965 for evaluation of muscle weakness and repeat muscle biopsy. This was prompted by uniquely abnormal fibers found in routine review of the patient's muscle biopsy done in 1962.This boy (Fig 1) was the product of his then 30-year-old mother's fifth...

Clinical heterogeneity and treatment response in inclusion body myositis

“…Filamentous inclusions may appear to be released from a ruptured nucleus (4,13). Myelin figures, which are also referred to as myeloid bodies or membranous whorls, are common in this disease, but have also been reported in chloroquine myopathy (22), colchicine myopathy (231, adult-onset acid-maltase deficiency (24), and occasionally in myotonic and limb girdle dystrophies (25). Large mitochondria with unusual crystalline lamellae may also be associated with the filamentous inclusions (3-5,7).…”

The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice

“…Histopathological studies of the skeletal muscle in these patients reveal the presence of small rounded muscle fibers that contain centrally located nuclei surrounded by a halo devoid of myofibrils where mitochondria accumulate (5,6). These fibers resemble fetal myotubes, and it was suggested that the disease may result from an arrest in the normal development of muscle fibers at the myotubular stage (7,8). The gene responsible for XLMTM, MTM1, was isolated by positional cloning (9).…”

Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase

“…The MTM1 gene on chromosome Xq28 is mutated in X-linked myotubular myopathy, a severe congenital muscular disorder characterized by hypotonia and generalized muscle weakness in newborn males (18,19). Myogenesis in affected individuals is arrested at a late stage of differentiation͞ maturation following myotube formation, and the muscle cells have characteristically large centrally located nuclei (20). Mutations in a second MTM gene MTMR2, on chromosome 11q22, have been shown recently to cause the neurodegenerative disorder, type 4B1 Charcot-Marie-Tooth disease (21,22).…”