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Table of Contents    
Year : 2013  |  Volume : 61  |  Issue : 3  |  Page : 254-259

Spectrum of congenital myopathies: A single centre experience

1 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Andhra Pradesh, India
2 Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, Andhra Pradesh, India

Date of Submission16-Mar-2013
Date of Decision15-May-2013
Date of Acceptance31-May-2013
Date of Web Publication16-Jul-2013

Correspondence Address:
Challa Sundaram
Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad - 500 082, Andhra Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.115064

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 » Abstract 

Background: Congenital myopathies (CMs) are rare and they are clinically and genetically heterogeneous. Muscle biopsy is characterized by structural abnormality that is diagnostic. There are few studies from India. Materials and Methods: This is a retrospective study of 12 years. The demographic data, clinical features and laboratory data of patients diagnosed as CMs on muscle biopsy were retrieved from medical records. The slides were reviewed for morphological and structural abnormalities using the following stains hematoxylin and eosin, modified Gomori trichrome, masson trichrome, periodic acid schiff, adenosine triphosphatase preincubated at pH 9.4, 4.6 and 4.3, nicotinamide adenine dinucleotide tetrazolium reductase, succinic dehydrogenase and cytochrome c oxidase. Immunohistochemistry was performed with dystrophin, sarcoglycans and desmin wherever necessary. Results: There were 50 patients with CMs: Centronuclear myopathy (23), myotubular myopathy (3) and central core disease (CCD) (8), nemaline myopathy (5), congenital fiber type proportion (10) and desmin related myopathy with arrythmogenic right ventricular cardiomyopathy (ARVD) (1). Of the 50 patients, 30 (60%) presented in the first decade of life. Proximal muscle weakness and hypotonia were the common presenting features. Type 1 atrophy and predominance were seen in most cases on muscle biopsy. CCD had one patient with high creatine phosphokinase levels, biopsy in one patient showed both rods and cores, in the other limb girdle muscular dystrophy like picture and one biopsy showed uniform type 1 fibers. There was one desmin related myopathy with ARVD, who had cardiac transplantation and both skeletal and cardiac muscle showed characteristic rimmed vacuoles and inclusions positive for desmin. Conclusion: CMs are rare and the diagnosis can only be established on muscle biopsy. Defining the specific CMs helps the clinician in counseling the patient and family.

Keywords: Central core disease, centronuclear myopathy, congenital fiber type disproportion, congenital myopathy, desmin related myopathy, muscle biopsy, myotubular myopathy, nemaline myopathy

How to cite this article:
Uppin MS, Meena A K, Sundaram C. Spectrum of congenital myopathies: A single centre experience. Neurol India 2013;61:254-9

How to cite this URL:
Uppin MS, Meena A K, Sundaram C. Spectrum of congenital myopathies: A single centre experience. Neurol India [serial online] 2013 [cited 2020 Aug 4];61:254-9. Available from:

 » Introduction Top

Congenital myopathies (CMs) are rare heterogeneous group of inherited muscle diseases with usually slow or non-progressive course and characterized by structural abnormalities in the muscle. Based on clinical features alone, they cannot be distinguished from other muscle diseases. [1] Muscle biopsy with detailed histochemical studies, supplemented by immunohistochemistry (IHC) and electron microscopy is essential for establishing the diagnosis of CMs. [2] In India, there are limited reports on CMs, mostly case reports [3],[4],[5],[6],[7] and very few large series. [8],[9] This is mostly due to few laboratories with facilities to work-up such cases. This report presents series of 50 cases of biopsy confirmed CMs, probably the largest series from India, seen over a period of 12 years in a tertiary care University Teaching Hospital.

 » Materials and Methods Top

All cases of CMs diagnosed on muscle biopsy between January 2000 and December 2012 were retrieved from the histopathology records of the Department of Pathology. The demographic data, clinical details regarding age at presentation, muscle weakness, progression of disease, family history, investigations including creatine phosphokinase (CK) and electromyogram findings were noted. The muscle biopsy slides were reviewed by two pathologists. Muscle biopsy was performed from left vastus lateralis in all patients and cryosections were processed for routine and enzyme histochemical studies. The histochemical stains included hematoxylin and eosin (H and E), modified Gomori trichrome (MGT), Masson trichrome, periodic acid Schiff (PAS), adenosine triphosphatase (ATPase) pre-incubated at pH 9.4, 4.6 and 4.3, nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR), succinic dehydrogenase (SDH) and cytochrome c oxidase (COX). The diagnosis of various types of CMs was essentially based on the morphologic appearance in routine and enzyme histochemical stains. IHC was performed with dystrophin (Novocastra, dilution 1:10), sarcoglycans (Novocastra, dilution alpha and delta 1:100, beta 1:200, delta 1:20), desmin wherever it was felt necessary.

 » Results Top

During the study period, 3420 muscle biopsies were performed and in 50 (1.46%) cases the diagnosis was CM [Table 1]. Out of 50 patients, 30 (60%) patients were presented in the first decade. Proximal muscle weakness and hypotonia were the presenting features in most of the patients. Positive family history was present in four patients. The clinical features of the various CMs are given in [Table 2]. The muscle biopsy showed type 1 atrophy and predominance in most of the cases.
Table 1: Distribution of various types of congenital myopathies

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Table 2: Clinical and demographic details of patients of various congenital myopathies

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Centronuclear myopathy

There were 23 (46%) patients in this group. Muscle biopsy showed central nuclei ranging from 15% to 85%. The central nuclei were large, vesicular with perinuclear halo. Twelve biopsies showed moderate degree of interstitial adipose tissue infiltration. PAS stain showed perinuclear aggregation of glycogen with radiating pattern. NADH-TR and SDH showed perinuclear aggregation of oxidative enzyme activity. NADH-TR showed radiating strands of sarcoplasm from the central nucleus in 10 biopsies [Figure 1].
Figure 1: (a) H and E showing central nuclei in most of the fibers, (b) nicotinamide adenine dinucleotide tetrazolium reductase showing radiating strands of sarcoplasm from central nucleus, (c) adenosine triphosphatase at pH 9.4 showing type 1 fiber predominance and atrophy

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Myotubular myopathy

There were three patients in this group. Muscle biopsy showed small round fibers with 20-40% of fibers showing centrally placed nuclei and peripheral halo. The central nuclei were seen in both type 1 and type 2 fibers, which showed increased oxidative enzyme activity [Figure 1].

Central core disease

There were eight patients in this group. Muscle biopsy showed fiber size variation. Central nuclei were seen in four and adipose tissue infiltration in three biopsies. One biopsy showed features of limb-girdle muscular dystrophy (LGMD), marked fiber size variation, splitting, and adipose tissue infiltration [Figure 2]. Though there were cores, IHC was performed with dystrophin and sarcoglycans, which showed positivity along sarcolemma. All biopsies on NADH-TR, SDH and COX showed central to eccentric areas devoid of oxidative enzyme reaction predominantly in type 1 fibers. The cores were structured and did not show myofibrillar disruption on ATPase. The cores extended 3-4 sarcomeres on longitudinal section. One biopsy showed uniform type 1 fibers with central cores [Figure 3].
Figure 2: Central core disease mimicking limb‑girdle muscular dystrophy. (a) H and E, showing hypertrophic, split fibers and adipose tissue infiltration, (b) adenosine triphosphatase at pH 9.4 showing type 1 fiber predominance, (c and d) nicotinamide adenine dinucleotide and succinic dehydrogenase showing absence of oxidative enzyme activity in most of the fibers

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Figure 3: (a) H and E, showing mild fiber size variation, (b) adenosine triphosphatase at pH 4.6 showing all type 1 fibers, (c and d) nicotinamide adenine dinucleotide tetrazolium reductase and succinic dehydrogenase showing cores in most of the fibers

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Nemaline myopathy

There were five patients in this group. The H and E, stain was normal on histology. The rods were identified on MGT; most were clustered in bundles in the subsarcolemmal area, but also seen in the cytoplasm and near the nuclei [Figure 4]. The number of rods per fiber and number of fibers involved was variable. None of the biopsies showed rods in the nuclei. In one biopsy, there were cores on NADH-TR and SDH and rods in the same biopsy were identified on MGT indicating core-rod myopathy [Figure 5].
Figure 4: (a) H and E, showing fiber size variation, (b) nicotinamide adenine dinucleotide tetrazolium reductase showing cores in few fibers, (c) modified Gomori trichrome showing nemaline rods in the subsarcolemmal, perinuclear region

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Figure 5: (a) Marked fiber size variation on H and E, (b) nemaline rods on modified Gomori trichrome

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Congenital fiber type disproportion

There were 10 patients in this group. Muscle biopsy showed fiber size variation. There were no abnormalities on NADH-TR, SDH and MGT. ATPase showed type 1 atrophy and predominance.

Desmin related myopathy-Case report

A 28-year-old male was diagnosed arrythmogenic right ventricular cardiomyopathy (ARVD) and had intracardiac device implantation and on treatment with amiodarone. He presented with recurrent attacks of ventricular tachycardia and fibrillation. During the evaluation, he was found to have wasting of all four limbs with significant distal muscle wasting and weakness and CK was 112 IU/L. Muscle biopsy showed rimmed vacuoles with basophilic granular inclusions on H and E, which stained red on MGT. There were few fibers showing subsarcolemmal and perinuclear basophilic spheroid bodies. NADH-TR, SDH and COX showed a lack of staining in the areas corresponding to the granular material and inclusions. IHC with desmin was strongly positive in the spheroid inclusions and granular material. Dystrophin showed positive staining of sarcolemma and periphery of the vacuoles [Figure 6]. Patient underwent orthotopic heart transplantation; however, patient succumbed to recurrent respiratory infections on 45 th post-operative day. The explanted heart showed marked fatty replacement of the right ventricle and the myocardium showed rimmed vacuoles on H and E and MGT, which stained positively with desmin.
Figure 6: (a) Rimmed vacuoles on muscle biopsy, (b) desmin positivity within the vacuole, (c) rimmed vacuoles in myocardial fibers, (d) showing positivity for desmin

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 » Discussion Top

CMs are rare. In a large series of 10,332 muscle biopsies, in 597 (5.8%) biopsies the diagnosis was CMs. [1] The reported series of CMs differ in the patient characteristics and also in the indications for muscle biopsy [Table 3]. [8],[9],[10] The true incidence of CMs is difficult to estimate. Nonaka, [10] estimated the incidence of CMs at 6/100,000 live births or one-tenth of all neuromuscular disorders.
Table 3: Comparison of various studies

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Though genetically heterogeneous, hypotonia is the clinical hallmark of most of the CMs and present in early life with hypotonia, hyporeflexia and generalized weakness that is more often proximal. Dysmorphic facies, external opthalmoplegia, contractures are other features. Scoliosis and contractures are seen in childhood onset form, whereas muscle weakness is usual presentation during adult hood. [1] In this series, 30% of patients presented in the first decade and majority presented with proximal muscle weakness followed by hypotonia.

Myotubular mypopathies can have X-linked or autosomal dominant and recessive inheritance. [11],[12] Respiratory insufficiency is the frequent cause of death. [12] All patients in this series presented as floppy infants. Pierson et al. correlated the myofiber size with prognosis and opined that patients with small calibered fibers continue to be ventilator dependent and have a poor prognosis. [13] All the three biopsies in our study had small caliber myofibers; however, the follow-up details were not available in our patients.

Facial weakness, ptosis and opthalmoplegia are common in CNM. [1] Delayed milestones, facial weakness, ptosis, opthalmoplegia, contractures were seen apart from muscle weakness and hypotonia in patients in this series. Muscle biopsy features were characteristic with a variable number of central nuclei. Radially arranged sarcoplasmic strands as seen in 10 of our cases were described in DNM2 related CNM on NADH-TR. [14] Similar morphological observations were made by Thaha et al. [9]

Proximal muscle weakness was the most common presentation in our patients with CCD, similar to the earlier observations. [8] Definite diagnosis of CCD depends on the histopathological features on muscle biopsy. In our sereis, all the biopsies showed well defined cores, predominantly involving type 1 fibers. Serum CK levels are usually normal or only mildly elevated. However, in rare cases, it can be elevated to 6-14 times normal as seen in one of our patients. [15]

Core like areas can occur in multiminicore disease, myofibrillar myopathy, Ulrich form of congenital muscular dystrophy. [16],[17],[18] One of the biopsies in this series showed uniform type 1 fibers with well-defined cores on oxidative enzyme reactions. Congenital neuromuscular disease with uniform type 1 fibers is also characterized by exclusive presence of type 1 muscle fibers (>99%) without any other pathological changes and is due to RYRI gene mutations. [19] As cores may be formed in age dependent manner, sampling of tissue and time of biopsy may explain the absence of cores. [1] Biopsy in the other patients showed type 1 predominance and atrophy with central or peripherally located cores. Biopsy in one of the patients mimicked LGMD and showed marked fiber size variation, splitting and adipose tissue infiltration. Presence of cores and IHC helped in making the diagnosis in this patient. Cores can coexist with rods as in one of our patients and they may be associated with RYRI mutations. [20] The coexistence of rods and cores is genetically heterogeneous. There were no cases of multiminicore disease in our series.

The clinical spectrum of nemaline myopathy is wide and six categories have been described based on clinical severity and age of onset. [9] All our patients can be classified into the classical type. There was no cardiac involvement in any patient. Histologically all biopsies characteristically revealed nemaline rods on MGT. Their number varied from abundance to few and from subsarcolemmal location to cytoplasmic location. These typical observations were similar to the earlier descriptions. [2],[4],[8],[9],[21] Nemaline rods have also been described in a number of unrelated conditions. [4]

CFTD is characterized by hypotonia and delayed milestones as seen in our patients. All biopsies showed type 1 predominance and atrophy. Central nuclei have been described in CFTD. [3],[8] However, we have not observed any central nuclei or structural abnormalities in our patients. The clinical syndrome of CFTD has to be differentiated from other CMs, spino-muscular atrophy, arthrogryposis, LGMD, Pompe disease; however, the hypotonia and weakness in CFTD improve with age.

The term myofibrillar myopathy was proposed for a pathological pattern of myofibrillar dissolution associated with accumulation of myofibrillar degradation products and ectopic expression of multiple proteins that include desmin, alpha β crystalline, dystrophin and congophilic amyloid material. [22] Our patient had myofibrillar myopathy with ARVD. Patients with mutations in desmin gene present with cardiomyopathy as seen in our patient. Melberg et al. described 21 members of Swedish family suffering from myopathy and cardiomyopathy and found three men with ARVD. [23] There was only one earlier report of desmin related myopathy from India. [6] Our patient is unique in his presentation with ARVD and documentation of desmin accumulation in both skeletal and cardiac muscle by IHC.

CMs are rare. Diagnosis requires muscle biopsy with histochemistry and enzyme histochemistry. Proper diagnosis facilitates differentiation from other muscle diseases and also in genetic counseling.

 » References Top

1.1. Fujimura-Kiyono C, Racz GZ, Nishino I. Myotubular/centronuclear myopathy and central core disease. Neurol India 2008;56:325-32.  Back to cited text no. 1
2.2. Dubowitz V, Sewry CA, editors. Muscle Biopsy: A Practical Approach. 3 rd ed. Edinburh: Sanders/Elsevier; 2007.  Back to cited text no. 2
3.3. Sharma MC, Ralte AM, Atri SK, Gulati S, Kalra V, Sarkar C. Congenital fiber type disproportion: A rare type of congenital myopathy: A report of four cases. Neurol India 2004;52:254-6.  Back to cited text no. 3
4.4. Sharma MC, Gulati S, Atri S, Seth R, Kalra V, Das TK, et al. Nemaline rod myopathy: A rare form of myopathy. Neurol India 2007;55:70-4.  Back to cited text no. 4
5.5. Ghosh A, Narayanappa G, Taly AB, Chickbasavaiya YT, Mahadevan A, Vani S, et al. Tubular aggregate myopathy: A phenotypic spectrum and morphological study. Neurol India 2010;58:747-51.  Back to cited text no. 5
6.6. Sridhar E, Sharma MC, Sarkar C, Singh S, Das T. Desmin-related myopathy: Report of a rare case. Neurol India 2005;53:229-31.  Back to cited text no. 6
7.7. Sundaram C, Mohan Das S, Meena AK, Murthy JM. Centronuclear myopathy. J Assoc Physicians India 1997;45:948-50.  Back to cited text no. 7
8.8. Jain D, Sharma MC, Sarkar C, Gulati S, Kalra V, Singh S, et al. Congenital myopathies: A clinicopathological study of 25 cases. Indian J Pathol Microbiol 2008;51:474-80.  Back to cited text no. 8
9.9. Thaha F, Gayathri N, Nalini A. Congenital myopathies: Clinical and immunohistochemical study. Neurol India 2011;59:879-83.  Back to cited text no. 9
10.10. Nonaka I. Clinical and pathologic aspects of congenital myopathies. Neurol J Southeast Asia 2001;6:99-106.  Back to cited text no. 10
11.11. Blondeau F, Laporte J, Bodin S, Superti-Furga G, Payrastre B, Mandel JL. Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway. Hum Mol Genet 2000;9:2223-9.  Back to cited text no. 11
12.12. McEntagart M, Parsons G, Buj-Bello A, Biancalana V, Fenton I, Little M, et al. Genotype-phenotype correlations in X-linked myotubular myopathy. Neuromuscul Disord 2002;12:939-46.  Back to cited text no. 12
13.13. Pierson CR, Agrawal PB, Blasko J, Beggs AH. Myofiber size correlates with MTM1 mutation type and outcome in X-linked myotubular myopathy. Neuromuscul Disord 2007;17:562-8.  Back to cited text no. 13
14.14. Jeannet PY, Bassez G, Eymard B, Laforêt P, Urtizberea JA, Rouche A, et al. Clinical and histologic findings in autosomal centronuclear myopathy. Neurology 2004;62:1484-90.  Back to cited text no. 14
15.15. Isaacs H, Heffron JJ, Badenhorst M. Central core disease. A correlated genetic, histochemical, ultramicroscopic, and biochemical study. J Neurol Neurosurg Psychiatry 1975;38:1177-86.  Back to cited text no. 15
16.16. Sewry CA, Müller C, Davis M, Dwyer JS, Dove J, Evans G, et al. The spectrum of pathology in central core disease. Neuromuscul Disord 2002;12:930-8.  Back to cited text no. 16
17.17. Ferreiro A, Quijano-Roy S, Pichereau C, Moghadaszadeh B, Goemans N, Bönnemann C, et al. Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: Reassessing the nosology of early-onset myopathies. Am J Hum Genet 2002;71:739-49.  Back to cited text no. 17
18.18. Kaindl AM, Rüschendorf F, Krause S, Goebel HH, Koehler K, Becker C, et al. Missense mutations of ACTA1 cause dominant congenital myopathy with cores. J Med Genet 2004;41:842-8.  Back to cited text no. 18
19.19. Wu S, Ibarra MC, Malicdan MC, Murayama K, Ichihara Y, Kikuchi H, et al. Central core disease is due to RYR1 mutations in more than 90% of patients. Brain 2006;129:1470-80.  Back to cited text no. 19
20.20. Monnier N, Romero NB, Lerale J, Nivoche Y, Qi D, MacLennan DH, et al. An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Hum Mol Genet 2000;9:2599-608.  Back to cited text no. 20
21.21. Wallgren-Pettersson C. congenital nemaline myopathy: A longitudinal study. In: Commentationes Physico Mathematicae. Helsinki: University of Helsinki; 1990.  Back to cited text no. 21
22.22. Selcen D, Ohno K, Engel AG. Myofibrillar myopathy: Clinical, morphological and genetic studies in 63 patients. Brain 2004;127:439-51.  Back to cited text no. 22
23.23. Melberg A, Oldfors A, Blomström-Lundqvist C, Stålberg E, Carlsson B, Larrson E, et al. Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q. Ann Neurol 1999;46:684-92.  Back to cited text no. 23


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1], [Table 2], [Table 3]

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