Atormac
Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 1110  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Search
 
  » Next article
  » Previous article 
  » Table of Contents
  
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (1,308 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

 
  In this Article
 »  Abstract
 »  Introduction
 »  Materials and Me...
 »  Results
 »  Discussion
 »  Acknowledgment
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed5355    
    Printed185    
    Emailed8    
    PDF Downloaded61    
    Comments [Add]    
    Cited by others 5    

Recommend this journal

 


 
BRIEF REPORT
Year : 2010  |  Volume : 58  |  Issue : 5  |  Page : 747-751

Tubular aggregate myopathy: A phenotypic spectrum and morphological study


1 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India
2 Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India

Date of Acceptance08-Jul-2010
Date of Web Publication28-Oct-2010

Correspondence Address:
Gayathri Narayanappa
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore - 560 029
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.72166

Rights and Permissions

 » Abstract 

Tubular aggregates (TAs) are inclusions described in skeletal muscle in a variety of disorders. In a retrospective analysis, TAs were found in 18 (0.24%) cases and involved a spectrum of clinical phenotypes. Ultrastructurally, four distinct types of aggregates were noted. There was no correlation between the clinical phenotypes, duration of illness and types of TAs.


Keywords: Cramps, familial dementia, limb girdle myasthenia, lower motor neuron syndrome, myalgia, noncompressive myelopathy, periodic paralysis, tubular aggregates, ultrastructure


How to cite this article:
Ghosh A, Narayanappa G, Taly AB, Chickbasavaiya YT, Mahadevan A, Vani S, Atchayaram N, Mohapatra I, Susarala KS. Tubular aggregate myopathy: A phenotypic spectrum and morphological study. Neurol India 2010;58:747-51

How to cite this URL:
Ghosh A, Narayanappa G, Taly AB, Chickbasavaiya YT, Mahadevan A, Vani S, Atchayaram N, Mohapatra I, Susarala KS. Tubular aggregate myopathy: A phenotypic spectrum and morphological study. Neurol India [serial online] 2010 [cited 2019 Nov 18];58:747-51. Available from: http://www.neurologyindia.com/text.asp?2010/58/5/747/72166



 » Introduction Top


Tubular aggregates (TAs), inclusions in skeletal muscle derived from sarcoplasmic reticulum, are ultrastructurally characterized by accumulation of densely packed membranous tubules. They are uncommon but an important indicator of myopathies. Initially described by Engel [1] in a case of hypokalemic periodic paralysis and myotonia congenita, TAs are presently known to occur in a wide variety of conditions, [2],[3],[4],[5] and in male inbred mice during aging [6] and can be induced experimentally. [7] However, in several cases, TAs constitute the cardinal structural pathology indicating myopathy with TAs as a distinct entity. [8] In the present study, 18 cases with TAs seen over a period of 10 years were reviewed to determine the spectrum of clinical phenotypes associated with these distinctive inclusions and morphological types of TAs encountered. An attempt was made to correlate clinical phenotypes, duration of illness and ultrastructural types of TAs.


 » Materials and Methods Top


This is a retrospective analysis of 18 cases with TAs diagnosed during the period from January 2001 to April 2009. Case records were reviewed for clinical features, including onset of illness, pattern and distribution of weakness, presence of myalgia, cramps, myotonia; consanguinity; and family history. Biochemical, electrophysiological and radiological findings were also noted. Skeletal muscle biopsy was carried out with informed consent [biceps (n=13), quadriceps (n=5)]. Fresh frozen sections were stained for hematoxylin and eosin (H and E), modified Gomori trichrome (MGT) and enzyme stains [succinic dehydrogenase (SDH), succinic dehydrogenase with cytochrome c oxidase (SDH-COX), nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR), menadione- α glycerophosphate dehydrogenase (MAG), menadione- nitro BT (M-NBT), adenosine triphosphatase (ATPase) pH 9.4 and 4.6, acid phosphatase, myophosphorylase and periodic acid Schiff's (PAS)]. Tiny bits of muscle fixed in 3% buffered gluteraldehyde were processed for electron microscopy. Ultrathin sections contrasted with uranyl acetate and lead citrate were observed under FEI Tecnai electron microscope. Immunoperoxidase staining was carried out using monoclonal antibodies against ubiquitin, tau and S-100 in all the cases.


 » Results Top


Clinical

Of the 7,441 muscle biopsies received (January 2001 to April 2009), 18 (0.24%) cases were diagnosed as having TAs based on morphological findings. The salient clinical features are provided in [Table 1]. Eighteen patients (15 men and 3 women) aged between 2 and 55 years, had onset of symptoms between1.5 and 50 years of age and duration of illness ranging from 6 months to 19 years. Weakness was the presenting symptom in the majority (n=15) of patients; while in three patients, myoclonus (n= 1) and stroke-like episode (n=2) were noted. Weakness was episodic in six,, progressive in another six and associated with hypotonia in two patients. An adult patient diagnosed to have noncompressive myelopathy of unknown etiology presented with tightness and weakness. Myalgia and cramps were present in two patients, while myalgia or cramps in isolation were noted in two patients each. Mental subnormality was present in three patients. There was history of seizure in three patients, one of whom was on antiepileptic drugs for 20 years. Consanguinity was recorded in four patients and a family history of similar illness in five instances.
Table 1: Summary of clinical profile

Click here to view


Examination revealed lower limb weakness (n=7), bilateral symmetrical weakness of upper and lower limbs (n=4), wasting (n=3), waddling gait (n=4), impaired tandem gait (n=1) and normal in the rest. Ptosis was present in two patients with congenital myopathy; and in one patient, with myasthenia. There was no evidence of myotonia either clinically or electrophysiologically in any of the patients. Radiological investigations [computed tomography (CT) or magnetic resonance imaging (MRI)] carried out in 11 patients revealed cerebral atrophy (n=2), deep white matter hyperintensities with cystic component (n=1), bilateral middle cerebellar artery MCA infarct (n=1) and were normal in the rest. Thymic hyperplasia was noted in one patient with myasthenia. Electro myography (EMG) was myopathic (n=4), neurogenic (n=1) or normal (n=3). Serum creatine kinase (CK) values ranged from 187 to 11,012 IU/L (normal range, 20-170 IU/L), with highest level recorded in a case of polymyositis (11,012 IU/L). Serum potassium was low in two cases and elevated in one patients. Serum sodium was within normal range in all the patients.

On the basis of clinical, electrophysiological and biochemical findings, the clinical diagnoses were: muscle cramp disease (n=2), congenital myopathy (n=3), dyskalemia [hypokalemic (n=2), hyperkalemic (n=1)], limb girdle myasthenia (n=2), recurrent stroke (n=2), polymyositis (n=1), metabolic myopathy (n=1), lower motor neuron syndrome (n=1), noncompressive myelopathy of unknown etiology (n=1), familial autosomal dominant dementia with myoclonus (n=1) and mitochondrial cytopathy (n=1).

Morphology

Light microscopy

Haematoxylin-eosin (H and E) sections revealed polygonal fibers with mild variation in diameter and basophilic granular material in subsarcolemmal region [Figure 1]a in all the biopsies. The percentage of fibers involved ranged from 2% to 80% [Table 2]. The material appeared bright red on MGT [Figure 1]b, stained intensely with NADH-TR [Figure 1]c, and remained unstained on SDH [Figure 1]d, MAG and ATPase reaction. In addition, type II fiber predominance (n=5), type II fiber grouping (n=1) and COX-deficient fibers (n=2) were noted. The other histological features included presence of atrophic fibers with clumped nuclei (n=1), myophagocytosis (n= 3), regenerating fibers and perivascular inflammation with transmural lymphocytic infiltration (n=1). The deposits were seen in type-II fibers in all the biopsies and also in type-I fibers in nine biopsies.. Immuostaining to monoclonal antibodies against ubiquitin showed subsarcolemmal positive labeling in ten biopsies, while antibodies against S-100 and tau did not label the TAs.
Figure 1: Transverse section of skeletal muscle tissue showing moderate variation in fiber size and basophilic granular material in the subsarcolemmal region (a: H and E ×400); bright red subsarcolemmal aggregates on modified Gomori trichrome stain (b: MGT ×400); intense blue on NADH-TR (c: NADH-TR, ×400) and unstained on SDH stains(d: SDH, ×400)

Click here to view
Table 2: Summary of morphological features

Click here to view


Electron microscopy

Ultrastructural studies in 17 patients revealed large aggregates of tubules predominantly in the subsarcolemmal regions and to a lesser extent in the intermyofibrillar zones. The following morphologic types of tubular aggregates were encountered in decreasing order of frequency: (1) Vesicular membrane collections (VMC) (n=15): Clusters of closely set round-to-oval dilated vesicular structures bound by single membrane containing moderately dense flocculent material. The diameter of these vesicular structures varied greatly (60-300 nm) within the cluster [Figure 2]a; (2) Single-walled tubules (SWT) (n=10): Bundles of parallel dilated single-walled tubules traversing in different directions without any particular orientation to the long axis of the myofibers. These tubules were placed in regular hexagonal arrangement, well defined in both longitudinal and transverse plane. The diameter (60 nm) was fairly constant and uniform throughout the length. The individual tubules were either empty or contained pale to moderately dense granular or flocculent material [Figure 2]b; (3) Double-walled tubules (DWT) (n=7): Large assemblies of tightly packed long membranous double-walled straight tubules arranged in parallel bundles, which on transverse plane appeared as closely packed hexagonal arrays. The outer tubule had a diameter of 60 nm, with a single smaller inner tubule of diameter 30 nm separated by a clear space. The inner core either contained electron-dense material or was empty [Figure 2]c; (4) Dilated tubules with inner tubules (DTT) (n=2): These had much wider and shorter tubules containing numerous smaller inner tubules regularly spaced, giving a sieve-like appearance [Figure 2]d.
Figure 2: Electronmicrograph showing various types of tubular aggregates: (a) closely packed dilated vesicular membranous collections (VMC), either empty or containing moderately electron-dense flocculent material, ×23,000; (b) parallel bundles of single-walled dilated tubules (SWT) traversing in different directions, constant and uniform diameter throughout the length, containing flocculent material, ×64,000; (c) large assemblies of tightly packed long membranous double-walled straight tubules (DWT) arranged in parallel and closely packed hexagonal array, ×30,000; and (d) dilated tubules (DTT) with several inner smaller tubules giving a sieve-like appearance, ×40,000

Click here to view


The types of TAs present in various disease entities and the frequency of occurrence are presented in [Table 2]. All four types of TAs were present in one case of congenital myopathy. One case (Case 17), in addition, showed central crisscross arrangement of thin filaments embedded in granular material. These areas on MGT appeared greenish and showed intense reaction to NADH-TR. The nature of these filaments is unclear. There was no correlation between morphologic type of TAs, duration of illness and clinical phenotype.


 » Discussion Top


TAs, a distinctive histochemical feature, have been the major, if not the sole, pathological abnormality in skeletal muscle of patients, with four rare but distinctive clinical conditions, which occur either sporadically or may show evidence of genetic transmission, referred to as myopathy with TAs. Several families with autosomal dominant and autosomal recessive inheritance have been described in Caucasian population. [9],[10] The four major clinical phenotypes primarily associated with TAs are: (i) weakness with exercise-induced cramps, pain and stiffness; (ii) isolated slowly progressive proximal muscles weakness; (iii) limb girdle myasthenia (LGM); (iv) gyrate atrophy of retina and choroids.

In the present series, TAs were noted in the commonly described disease entities, in addition to their presence in the following unusual clinical phenotype: familial dementia with myoclonus, lower motor neuron syndrome, noncompressive myelopathy of unknown etiology and suspected case of mitochondrial cytopathy, thus expanding the spectrum of clinical conditions with TAs. This study describes a large series from south India. Jain et al.,[11] from north India, describe four patients (muscle pain and cramps, secondary to alcoholism and /or hyperparathyroidism and pituitary adenoma) with TAs and ultrastructure evidence of only DWT.

The common morphological abnormality seen in all these diverse neuromuscular disorders was the presence of tubular aggregates reacting intensely to NADH-Tr predominantly in type-II fibers. In addition, its presence in type-I fibers was seen in nine patients. It has been reported that in periodic paralysis and the disorder characterized by muscle cramps and stiffness, the changes are confined to type-II fibers; while in inherited myopathies, they occur in both fiber types. [2],[12] However, in our series, TAs were observed in both fiber types in familial (familial myopathy with tubular aggregates and familial LGM) and nonfamilial forms (motor neuron syndrome, recurrent ischemic stroke, noncompressive myelopathy of unknown etiology and 1 case of muscle cramp disease).

Ultrastructurally, the various morphological forms were classified as described previously. [13] All four morphological forms (VMC, SWT, DWT and DDTA) were encountered. However, a definite pattern of association between clinical phenotypes, duration of illness and type of TAs could not be elucidated. Coexistence of tubular aggregates and tubulofilamentous inclusions of inclusion body myositis (IBM) type in a case of congenital myopathy with progressive proximal muscle weakness, lumbar hyperlordosis and bilateral Achilles tendon contractures has been reported. [14] Mass of intermediate filaments organized in a crisscross pattern was noted in the center of the fiber in one of our patients who presented with tightness and weakness of lower limb (Case 17). The filaments were negative for desmin, ubiquitin, tau and S-100. The nature of these filaments and its association with disease process are unclear.

The occurrence of TAs in such diverse and unrelated conditions has made it difficult to evaluate and predict their functional significance and identify the factors involved in their evolution. On the other hand, remarkable consistency of their ultrastructural features suggests their origin from a single subcellular organelle. In their study of skinned muscle fibers from affected members of a family with a dominantly inherited tubular aggregate myopathy, Salviati et al.[15] demonstrated presence of TAs potentiated the calcium-loading capacity of slow muscle fibers, and hypothesized that TAs are functional equivalents to the hypertrophied terminal cisterns of the sarcoplasmic reticulum; while rearrangement of preexisting sarcoplasmic reticulum (SR) or neo-formation from the SR due to various insults to skeletal muscle fiber as an adaptive response to increased calcium influx was suggested by Chevessier et al.[13] There is prevailing and widely accepted evidence for the origin of TAs from terminal cisterns of SR, [13],[16] as seen ultrastructurally in our cases. Presence of SR proteins like RyR, triadin, calsequestrin, sarcalumenin and sarcoplasmic/ endoplasmic calcium ATPase (SERCA1, 2) necessary for storage and release of calcium by the SR; and dihydropyridine receptor (DHPR), which is specifically located in the T-tubule, suggests that TAs represent a tubular arrangement of all endoplasmic and sarcoplasmic reticulum proteins and are functionally competent. [13] Up-regulation of glucose-regulated proteins (GRPs), necessary for tertiary folding of proteins and epitopes of heat shock proteins found in the area of TAs, suggests their role in modulation of the tertiary structure of proteins. [17]

The pathophysiological process that is widely accepted is a disturbance in sarcoplasmic calcium homeostasis. TAs identical to those seen in human diseases are noted in congenic mice (MRL +/+ sub-strain), [18] which are age related and gender specific. Castration of male mutants early in life, before TAs have developed, completely abolishes their occurrence, suggesting hormonal and gonadal influences, in addition to genetic factors involved in pathogenesis.


 » Acknowledgment Top


The authors thank Mrs. Nangina, Mrs. Hemavathy, Mr. Ramesh and Mrs. Mary Kasi for their untiring technical help.

 
 » References Top

1.Engel WK. Mitochondrial aggregates in muscle disease. J Histochem Cytochem 1964;12:46-8.  Back to cited text no. 1
[PUBMED]  [FULLTEXT]  
2.North K. Congenital myopathies. In: Engel AG, Franzini-Armstrong C, editors. Myology. New York: McGraw Hill; 2004. p. 1505-7.   Back to cited text no. 2
    
3.Niakan E, Harati Y, Danont MJ. Tubular aggregates: Their association with myalgia. J Neurol Neurosurg Psychiatry 1985;48:882-6.  Back to cited text no. 3
    
4.Shahrizaila N, Lowe J, Wills A. Familial myopathy with tubular aggregates associated with abnormal pupils. Neurology 2004;63:1111-3.  Back to cited text no. 4
[PUBMED]  [FULLTEXT]  
5.Shahrizaila N, Lim WS, Robson DK, Kinnear WJ, Wills AJ. Tubular aggregate myopathy presenting with acute type II respiratory failure and severe orthopnea. Thorax 2006;61:89-90.  Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Chevessier F, Marty I, Paturneau-Jouas M, Hantaο D, Verdiθre-Sahuquι M. Tubular aggregates are from whole sarcoplasmic reticulum origin: Alterations in calcium binding protein expression in mouse skeletal muscle during aging. Neuromuscul Disord 2004;14:208-16.   Back to cited text no. 6
    
7.Klomkleaw W, Kasashima Y, Kobayashi A, Fuller GA, Morimoto M, Nakade T, et al. Tubular aggregates observed in spindle muscle fiber of horse lumbrical muscle. Acta Neuropathol 2001;101:509-17.  Back to cited text no. 7
[PUBMED]  [FULLTEXT]  
8.Morgan-Hughes JA. Tubular aggregates in skeletal muscle: Their functional significance and mechanisms of pathogenesis. Curr Opin Neurol 1998;11:439-42.  Back to cited text no. 8
[PUBMED]  [FULLTEXT]  
9.de Groot JG, Arts WF. Familial myopathy with tubular aggregates. J Neurol 1982;227:35-41.  Back to cited text no. 9
[PUBMED]    
10.Kim NR, Suh YL. Tubular aggregate myopathy: A case report. J Korean Med Sci 2003;18:135-40.  Back to cited text no. 10
[PUBMED]  [FULLTEXT]  
11.Jain D, Sharma MC, Sarkar C, Suri V, Sharma SK, Singh S, et al. Tubular aggregate myopathy: A rare form of myopathy. J Clin Neurosci 2008;15:1222-6.  Back to cited text no. 11
[PUBMED]  [FULLTEXT]  
12.Martin JJ, Ceuterick C, Van Goethem G. On a dominantly inherited myopathy with tubular aggregates. Neuromuscul Disord 1997;7:512-20.   Back to cited text no. 12
[PUBMED]  [FULLTEXT]  
13.Chevessier F, Bauchι-Godard S, Leroy JP, Koenig J, Paturneau-Jouas M, Eymard B, et al. The origin of tubular aggregates in human myopathies. J Pathol 2005;207:313-23.  Back to cited text no. 13
    
14.Fidzianska A, Kaminska A, Ryniewicz B. Congenital myopathy with tubular aggregates and tubulofilamentous IBM-type inclusions. Neuropediatrics 2005;36:35-9.  Back to cited text no. 14
    
15.Salviati G, Pierobon-Bormioli S, Betto R, Damiani E, Angelini C, Ringel SP, et al. Tubular aggregates: Sarcoplasmic reticulum origin, calcium storage ability, and functional implications. Muscle Nerve 1985;8:299-306.  Back to cited text no. 15
[PUBMED]    
16.Narayanappa G, Nalini A, Thaha F. Congenital myopathy with tubular aggregates: Report on two siblings from India. J Child Neurol 2009;24:874-8.  Back to cited text no. 16
[PUBMED]  [FULLTEXT]  
17.Martin JE, Mather K, Swash M, Gray AB. Expression of heat-shock protein epitopes in tubular aggregates. Muscle Nerve 1991;14:219-25.   Back to cited text no. 17
[PUBMED]    
18.Kuncel RW, Pestronk A, Lane J, Alexander E. The MRL +/+ mouse: A new model of tubular aggregates which are gender- and age-related. Acta Neuropathol 1989;78:615-20.  Back to cited text no. 18
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]

This article has been cited by
1 Calcium Dyshomeostasis in Tubular Aggregate Myopathy
Jong-Mok Lee,Satoru Noguchi
International Journal of Molecular Sciences. 2016; 17(12): 1952
[Pubmed] | [DOI]
2 When tubules aggregate
Hans H. Goebel
Neuromuscular Disorders. 2012; 22(3): 208
[Pubmed] | [DOI]
3 Tubular aggregates in skeletal muscle: Just a special type of protein aggregates?
Stefano Schiaffino
Neuromuscular Disorders. 2012; 22(3): 199
[Pubmed] | [DOI]
4 When tubules aggregate
Goebel, H.H.
Neuromuscular Disorders. 2012; 22(3): 208-210
[Pubmed]
5 Tubular aggregates in skeletal muscle: Just a special type of protein aggregates?
Schiaffino, S.
Neuromuscular Disorders. 2012; 22(3): 199-207
[Pubmed]



 

Top
Print this article  Email this article
Previous article Next article
Online since 20th March '04
Published by Wolters Kluwer - Medknow